tap vol 5 issue 14

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

Oncology Practice: What Are the Factors Driving Change?By Caroline McNeil

Clinical practice changes in response to new medical evidence, but not always immediately

or all at once. So what else determines whether and how quickly practice changes in response to evi-dence, for instance, that a widely used drug is effec-tive only in patients with a certain biomarker?

In a new study,1 researchers looked at the case of one

such biomarker, the mutated KRAS gene in colorectal cancer. They identified three events that might have influenced physicians to stop prescribing cetuximab (Erbitux) and panitumumab (Vectibix) for patients whose tumors have a mutation, once conclusive data emerged showing that the targeted drugs were not ef-fective in these patients. The events were public report-

ing of the data, publication of new guidelines, and a U.S. Food and Drug Ad-ministration (FDA) label change. The study showed that all three—especially the FDA action—were fol-lowed by significant chang-es in practice.

The authors, led by Efrat Dotan, MD, As-sistant Professor at Fox

International Lung Cancer Congress

I am honored and privileged to lead ASCO dur-ing its 51st year, a year that promises to bring

both challenges and opportunities to our mem-bers and our patients. As the theme for my Presi-dential term, I’ve chosen Illumination and Innova-tion: Transforming Data Into Learning, because we are positioned to reap the benefits of the accelerat-ing transformation of data into knowledge. Now, we have to take the next step by applying that knowledge and learning how to move our health-care delivery and research systems forward.

Although we have generated more effective therapies in the treatment of cancer through the knowledge we have gained in clinical trials, we have not always focused as much attention on how to apply that knowledge to individual

My Priorities for the Year Ahead

By Peter P. Yu, MD, FASCO, as told to Jo Cavallo

Oncology Meetings CoveragePan Pacific Lymphoma Conference��3, 4, 41International Lung Cancer Congress ��6New Orleans Cancer Meeting �� 12, 19ASPHO Annual Meeting �� 37, 38Debates and Didactics in Hem/Onc ��62

Hugo F. Fernandez, MD, on AML ��20Alok A. Khorana, MD, on CRC ��30Direct From ASCO ��46–49Jacek Jassem, MD, PhD, on NSCLC ��57In Memoriam: Jesse L. Steinfeld, MD and Emanuel Farber, MD, PhD ��106

MORE IN THIS ISSUE

continued on page 86

Issues in Oncology

Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick

S tereotactic body radiation therapy (SBRT) is safe and effective in early-stage non–small cell lung

cancer (NSCLC), as it confers local control in 90% or more patients with T1 disease, according to Roy Decker, MD, PhD, Associate Professor in the Depart-ment of Therapeutic Radiology at Yale Cancer Center, New Haven, Connecticut. Dr. Decker described the use of SBRT in high-risk early-stage NSCLC patients at the 15th Annual International Lung Cancer Con-gress in Huntington Beach, California.

“In high-risk patients, SBRT appears to offer ap-proximately equivalent control and survival when compared to surgical resection, in retrospective se-ries,” he said. “I can say that SBRT is approximately as good as surgery.”

Transformative StudyDr. Decker said that a multidisciplinary approach is

always ideal. “Our guidelines state that all patients hav-

ing SBRT who are at high risk should be evaluated by an experienced thoracic surgeon for minimally inva-sive surgery,” he said. “I nev-er call a patient ‘inoperable’ without that consultation.”

However, results with stereotactic body radio-therapy are essentially equivalent to surgery, and may be preferred over sur-gery for some patients. The technique has been used in practice for 2 decades, and based on mature pro-spective trial data, the appropriate and inappropriate candidates for SBRT can now be identified, he said.

Several important studies have informed current SBRT practice in the United States. A number of years ago, phase II studies suggested that the failure pattern

Roy Decker, MD, PhD

Multiple Myeloma 12, 36 | Understanding CALGB/SWOG 80405 30 | Gynecologic Cancer Care 76 VOLUME 5, ISSUE 14SEPTEMBER 1, 2014

continued on page 9continued on page 102

These results suggest the attentiveness of the oncologic community to clinical presentations at national meetings and ASCO guidance…. It is also evidence that oncologists change their practice promptly in the face of highly publicized data, even years after a drug’s approval.

—Efrat Dotan, MD

Dr. Yu is President of the American Society of Clinical Oncology for 2014–2015 and Director of Cancer Re-search at Palo Alto Medical Foundation in California.

A Harborside Press® PublicationSeptember Is Ovarian and Prostate Cancers Awareness Month

The ASCO Post | SEPTEMBER 1, 2014

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ASCOPost.com | SEPTEMBER 1, 2014 PAGE 3

Pan Pacific Lymphoma Conference

International Group Updates Recommendations on Managing LymphomaBy Susan London

An international multidisciplinary group of experts has updated their

recommendations for staging and treat-ment response assessment in patients with Hodgkin and non-Hodgkin lym-phomas. Bruce D. Cheson, MD, Pro-fessor of Medicine, Deputy Chief of Hematology-Oncology, and Head of Hematology at the Georgetown Univer-sity Hospital’s Lombardi Cancer Center in Washington, DC, presented some highlights at the Pan Pacific Lymphoma Conference; the recommendations were published in their entirety in August.1

Clearer, Simpler, More Practical Guidance

The recommendations, last revised in 2007,2 are now called the Lugano Classification as they arose out of a workshop held in Lugano, Switzerland. “This will be a substantial change in how clinicians practice,” Dr. Cheson predicted in an interview. The update entailed “taking the initiative to reject some of the ways we did things in the past to try and make these new staging and response criteria more contempo-rary and to reflect how we actually man-age patients today.”

“These recommendations will hopefully be adopted as widely as those in the past and will serve the patients better, particularly with the elimination of some unnecessary pro-cedures; will serve the clinical research community better because these are hopefully clearer than past recommen-dations, and the regulatory agencies because they will now have standard-ized, internationally accepted staging as well as response criteria; and will better serve the pharmaceutical indus-try, which has always had some ques-tions about how to interpret one thing or another,” he commented.

“We have modified both staging and response criteria to make them more rel-evant to how we currently practice hema-tology-oncology,” Dr. Cheson noted (see Table 1 for highlights). “We have done our best to eliminate various procedures and tests that are not necessary and may be onerous to the patient, where possi-ble. We have clarified how you interpret response to make it easier to understand and use, and to compare study vs study. And we have better defined how to use and how to interpret positron-emission tomography (PET) scans, when to use

them, when not to use them.”Dr. Cheson said that he expected

the National Comprehensive Cancer Network (NCCN) will incorporate the new recommendations into their guide-lines, which some insurers use when making coverage decisions. “The last version [in 2007] was adopted by the NCCN guidelines, so I am fairly certain that this version will be as well,” he said.

Staging RecommendationsIn the area of staging, “we have up-

dated the staging criteria for lympho-ma, incorporating for the first time PET for those histologies of lymphoma that are fluorodeoxyglucose (FDG)-avid,” Dr. Cheson explained. Although hema-tologists often obtained these scans be-fore treatment in the past, they were not formally used in staging.

The updated recommendations have eliminated the need for routine chest x-rays as all patients now undergo computed tomography. Additionally, “we eliminated the need for the dreaded bone marrow bi-opsy in patients with Hodgkin lymphoma and most patients with diffuse large B-cell lymphoma because the PET scan will be a better predictor of bone marrow involve-ment than a simple random bone marrow biopsy. The bone marrow biopsy is a ves-tige of the past—patients came in and we did things reflexively, we staged them with a bone marrow biopsy,” but PET now pro-vides the same information much less in-vasively.

Staging terminology has been stream-lined by eliminating use of the terms A and B for non-Hodgkin lymphoma and use of X to denote bulky disease, and by recommending a switch from the 1, 2, 3, and 4 numerical staging system (the Ann Arbor classification) to a simple dichotomous one of limited disease and advanced disease, reflecting how hema-tologists have typically grouped patients for treatment in real-world practice.

Response Assessment Recommendations

For assessing treatment response, the recommendations endorse use of the 5-point Deauville scale that has been internationally validated as a means of standardization. “The scale has been coming into use slowly but has not been widely recognized because people have

not been informed about it,” Dr. Cheson commented. “Now it’s going to be the way for the foreseeable future to inter-pret PET scans so that how one person interprets the scan will be more likely the way another person does. There used to be considerable interobserver or inter-interpreter variability.”

The recommendations also outline new definitions of complete response, partial response, and progressive dis-ease. In particular, “a patient can get a complete response in the presence of a mass as long as the mass is no longer avid, and progressive disease can now be determined on the basis of a single node,” he noted.

Finally, “we also made recommenda-tions on management of patients post-treatment, how best to follow patients,

Hematology

We have modified both staging and response criteria to make them more relevant to how we currently practice hematology-oncology.

—Bruce D. Cheson, MD

Table 1: Highlights of the Updated Recommendations

Staging

• 18F-FDG PET-CT is formally incorporated into standard staging for FDG-avid lymphomas. PET-CT is the standard for FDG-avid lymphomas, whereas CT is indicated for nonavid histologies.

• A modification of the Ann Arbor descriptive terminology is recommended for use for the anatomic distribution of disease extent. The A and B suffixes for symptoms will be included only for HL.

• The designation X for bulky disease is no longer necessary; instead, the largest tumor diameter should be reported.

• If PET-CT is performed, bone marrow biopsy is no longer indicated for rou-tine staging of HL and most DLBCLs. Bone marrow biopsy is needed only for diffuse large B-cell lymphoma if PET is negative and if identifying discordant histology is important for patient management.

• Regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease; stage II bulky disease is considered as limited or advanced based on histology and prognos-tic factors.

Response Assessment

• PET-CT is to be used to assess response in FDG-avid histologies using the 5-point scale; CT is preferred for low or variable FDG avidity.

• A complete metabolic response is considered a complete remission even with a persistent mass.

• Partial response requires a decrease by > 50% in the sum of the product of the perpendicular diameters of up to six representative nodes or extranodal lesions.

• Progressive disease on CT criteria requires only an increase in the perpen-dicular diameters of a single node by ≥ 50%.

• Surveillance scans after remission are discouraged, particularly for DLBCL and HL; repeat scans may be considered in cases of equivocal findings after treatment. Judicious use of follow-up scans can be considered in indolent lymphomas with residual intra-abdominal or retroperitoneal disease.

CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; FDG = fluorodeoxyglucose; HL = Hodgkin lymphoma; PET = positron-emission tomography.

continued on page 4



Jury Still Out on Interim PET for Response-Adapted Therapy in Hodgkin Lymphoma By Susan London

Interim positron-emission tomog-raphy (PET) scans provide good

prognostic information in patients with Hodgkin lymphoma, but more research is needed to determine whether patients benefit when the findings are used to alter treatment, according to Oliver Press, MD, PhD, Professor at the University of Wash-ington School of Medicine and Chair of Lymphoma Research at the Fred Hutchinson Cancer Research Center, both in Seattle.

Interim PET—performed during induction therapy, after one to four cycles of treatment—remains a hot-button issue, he told attendees of the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii. “There are some very strong but diametrical-ly opposed views that people in this room have about this topic,” he said.

Use for PrognosticationStudies have validated the prog-

nostic value of interim PET in this setting. For example, a pooled analy-sis found that the PET result after two cycles of chemotherapy was highly predictive of progression-free surviv-al in patients with advanced disease.1 “Using this very powerful prognostic tool, other prognostic factors really weren’t very relevant, including the international prognostic score … af-ter adjusting for the PET scan results,” Dr. Press noted.

A retrospective study comparing visual inspection of PET scans with the 5-point Deauville scale with a change in maximal standardized up-take value cutoff of 70% suggests that the latter may yield better discrimi-nation.2 “This is probably the way the field is moving,” he said. “But the consensus is that we are not quite ready yet to move away from the vi-sual scale, that we really need larger studies and prospective studies. And most importantly, this requires really tight standardization in how the scans are done.”

Response-Adapted Therapy in Early-Stage Disease

At least eight trials are studying the use of interim PET for response-adapted therapy in early-stage Hodg-kin lymphoma, according to Dr. Press. In one trial, patients were randomized after two cycles of che-motherapy to standard therapy or to PET response-adapted therapy.3 The respective 1-year rates of progression-free survival were 100% and 94% among patients with favorable disease and 97.3% and 94.7% among patients with unfavorable disease.

The data safety monitoring com-

mittee concluded that response-adapt-ed therapy was unlikely to meet nonin-feriority criteria and halted the trial. It also concluded that PET did not meet the goal of identifying patients who did not need radiation therapy.

“This was a very controversial study and very controversial decision by the data safety monitoring board. It led to a lot of debate,” Dr. Press noted. “A lot of people feel that they made this decision too soon, that pro-gression-free survival is not the right endpoint, that overall survival is most important. And a lot of people felt the trial should stay open.”

A second trial in which patients underwent PET after three cycles of chemotherapy had similar find-

ings.4 Among PET-negative patients, the 3-year rate of progression-free survival was 94.5% with radiation therapy and 90.8% without it—a nonsignificant difference in intent-to-treat analysis. However, these in-vestigators concluded that “excellent outcomes” were possible without ra-diation therapy.

“These were obviously two trials with similar results and opposite con-clusions about interim PET and its role, and the role of radiation therapy. So the jury is out, I would say, on ear-ly-stage disease and interim PET,” Dr. Press commented.

Use in Advanced-Stage Disease

Many trials are also evaluating the use of interim PET to guide therapy in advanced-stage Hodgkin lym-phoma. In the Southwest Oncology Group (SWOG) S0816 trial, patients have a PET scan after two cycles of chemotherapy; those with negative results are given standard therapy and those with positive results are given escalated therapy.5 Recently updated findings, with median follow-up of about 28 months, show that 2-year progression-free survival is 62% in PET-positive patients and 82% in PET-negative patients.

“Everybody would probably agree that the results look promising for

the PET-positive patients,” Dr. Press commented, “but people might argue about whether the 82% progression-free survival is good enough in the PET-negative patients.” Although results thus far suggest a benefit of switching to escalated therapy in the PET-positive group, “we really do need truly randomized studies to definitely prove the value of this response-adapted approach, and we need longer follow-up on this trial,” he said.

A similar trial undertaken in Eu-rope also found that PET-positive pa-tients switched to escalated therapy had a 1-year failure-free survival rate of 76.5%, and PET-negative patients who continued on standard therapy had a rate of 96.2%.6

Putting It All Together“The prognostic value of interim

PET imaging is not very controver-sial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether changing your treatment based on what the interim PET scan shows improves outcomes remains at least somewhat controversial,” Dr. Press concluded.

At present, the National Compre-hensive Cancer Network endorses PET response-adapted therapy in Hodgkin lymphoma.7 “So they have embraced the preliminary results very firmly,” he said. “I agree that it seems promising, but this does seem to be just a little bit out ahead of the data. Many people want the truly random-ized studies, where half the patients get standard treatment, half the patients get a response-adapted treatment, and then you compare the outcomes and make the final decisions.”

An international consensus group has developed a more reserved state-ment.8 The forthcoming statement finds a lack of conclusive evidence warrant-ing a change in treatment based solely

Hematology

The prognostic value of interim PET imaging is not very controversial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether outcomes are improved by changing treatment based on the interim PET scan results remains controversial.

—Oliver Press, MD, PhD

where imaging fits in, where it doesn’t fit in, and those sorts of issues,” Dr. Cheson said. n

Disclosure: Dr. Cheson has served in a

consultant or advisory role for Gilead, Celgene, Genentech, Pharmacyclics, AstraZeneca, and Spectrum. He has received honoraria from Gilead, Celgene, Genentech, and Pharmacyclics, and other remuneration from Gilead, Celgene, Genentech, and Pharmacyclics. For full

disclosure of all study authors, visit JCO.org.

References1. Cheson BD, Fisher RI, Barrington SF,

et al: Recommendations for initial evalu-ation, staging and response assessment of

Hodgkin and non-Hodgkin lymphoma—the Lugano Classification. J Clin Oncol. August 11, 2014 (early release online).

2. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-586, 2007.

Updated Recommendationscontinued from page 3

continued on page 5



on the results of interim PET. “My ten-dency would be to agree with this con-sensus group,” Dr. Press concluded. n

Disclosure: Dr. Press reported no potential conflicts of interest.

References1. Gallamini A, Hutchings M, Rigacci

L, et al: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in ad-vanced-stage Hodgkin’s lymphoma: A report from a joint Italian-Danish study. J

Clin Oncol 25:3746-3752, 2007.2. Rossi C, Kanoun S, Berriolo-Rieding-

er A, et al: Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lym-phoma patients. J Nucl Med 55:569-573, 2014.

3. Raemaekers JM, André MP, Fed-erico M, et al: Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the pre-planned interim analysis of the random-ized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32:1188-1194, 2014.

4. Radford J, Barrington S, Counsell N, et al: Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Results of the UK NCRI RAPID trial. 2012 ASH Annual Meeting. Abstract 547. Pre-sented December 10, 2012.

5. Press OW, LeBlanc M, Rimsza LM, et al: A phase II trial of response-adapted therapy of stage III-IV Hodgkin lymphoma using early interim FDG-PET imaging: US Intergroup S0816. Hematol Oncol 31(sup-pl 1):Abstract 124, 2013.

6. Gallamini A, Tarella C, Patti C, et al: Multicentre clinical study with early treat-

ment intensification in high-risk Hodgkin Lymphoma (HL) patients with a positive FDG-PET scan after two ABVD courses: GITIL HD0607 study. Ann Oncol 22(sup-pl 4):O167, 2011.

7. National Comprehensive Cancer Network: NCCN Clinical Practice Guide-lines in Oncology (NCCN Guidelines®). Hodgkin Lymphoma, version 2.2014. Available at www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed August 12, 2014.

8. Barrington SF, Mikhaeel NG, Kostko-glu L, et al: Conclusion on interim PET/CT from consensus conference (Lugano, Menton). J Clin Oncol. 2014. In press.

Interim PET Imagingcontinued from page 4

Study Estimates Risk of Premature Menopause After Treatment for Hodgkin Lymphoma

Previous research has suggested that women with Hodgkin lym-

phoma who receive certain types of chemotherapy or radiotherapy are at increased risk of future infertility, but there was insufficient information to provide patients with detailed advice. In a study published in the Journal of the National Cancer Institute, Swerdlow et al estimated the risk of premature menopause in women being treated for Hodgkin lymphoma.1 The findings are based on the experience of more than 2,000 young women in England and Wales over a period of more than 40 years.

The new study, led by scientists at The Institute of Cancer Research, Lon-don, provides precise estimates of risk for women depending on which treat-ment types and doses they received and at what age, allowing doctors to give them detailed advice about their risks of future infertility.

Study DetailsThe research team followed 2,127

women who had been treated for Hodgkin lymphoma in England and Wales at ages younger than 36 years from 1960 to 2004. All patients had received treatment with chest radio-therapy, sometimes alongside other treatments. Follow-up took place from 2008 through 2012.

Some 605 of the women in the

study underwent nonsurgical meno-pause before the age of 40. This was a large enough number for the research-ers to estimate accurate risks of meno-pause at different ages, depending on the mixture and doses of treatments they received and the age they re-ceived them.

Increases in Premature Menopause

The researchers produced a risk table which could help improve the advice that clinicians are able to give to women who have undergone treatment for the disease. Several of the treatments caused a sharp increase in premature menopause risk.

For example, a woman who had re-ceived six or more cycles of a standard chemotherapy regimen without pelvic ra-diotherapy in her late 20s had an approxi-mately 18% chance of undergoing meno-

pause by the age of 30, or 58% by age 40.Overall, there was a 20-fold in-

creased risk of premature menopause after ovarian radiotherapy and also after some specific chemotherapy regimens. Risk of menopause by age 40 was 81% after receiving ovarian radiotherapy of at least 5 Gy, and up to 75% after che-motherapy, depending on the type. There was no statistically increased risk associated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

“Hodgkin lymphoma often affects younger women, and although fortu-nately most survive the disease, treat-

ments including certain types of che-motherapy and pelvic radiotherapy can lead to premature menopause,” said study leader Anthony Swerdlow, DSc, of The Institute of Cancer Re-search, London. “We hope our study will help women to understand bet-ter, in consultation with their doctors, their risks of future infertility follow-ing treatment for this malignancy. By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women. I’m extremely grateful to the patients and doctors who made it possible for us to pro-duce this information.” n

Disclosure: The research was supported by Breakthrough Breast Cancer and the European Commission. For full disclosures for the study authors, visit jnci.oxfordjournals.org

Reference1. Swerdlow AJ, Cooke R, Bates A, et al:

Risk of premature menopause after treat-ment for Hodgkin’s lymphoma. J Natl Can-cer Inst. August 2014 (early release online).

Premature Menopause After Treatment for Hodgkin Lymphoma

■ Women who received six or more cycles of a standard chemotherapy regimen without pelvic radiotherapy in their late 20s had an approximately 18% chance of undergoing menopause by the age of 30, or 58% by age 40.

■ There was a 20-fold increased risk of premature menopause after ovarian radiotherapy and some chemotherapy regimens.

■ The findings will allow doctors to provide patients with detailed advice about their risks of future infertility based on their treatment history.

We hope our study will help women to understand better, in consultation with their doctors, their risks of future

infertility following treatment for this malignancy. —Anthony Swerdlow, DSc

Journal Spotlight

https://ash.confex.com/ash/2012/webprogram/Paper53836.html


International Lung Cancer CongressThoracic Oncology

Targeting KRAS Mutations in Lung Cancer: No Longer ImpossibleBy Caroline Helwick

The KRAS mutation has long been considered “undruggable,” but

new approaches in drug development may change this. The end result could be effective new treatment options for KRAS-mutated non–small cell lung cancer (NSCLC), according to David R. Gandara, MD, who described the emerging findings at the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

“The KRAS mutation story has evolved from what we thought we knew, to the controversies about what we don’t know,” said Dr. Gandara, Pro-fessor of Medicine and Director of the Thoracic Oncology Program at the Uni-versity of California, Davis, Compre-hensive Cancer Center in Sacramento.

Key ConceptsDr. Gandara described several key

concepts regarding KRAS mutations:• KRAS mutations occur in approxi-

mately 25% of NSCLC tumors, com-pared to 39% of colorectal tumors. They are more likely to be transver-sions (78%) than transitions (22%), in contrast to colorectal cancer, where transitions are more common. This difference may explain the discordant response to treatment between the two tumor types.

• There are many different KRAS muta-tion subtypes, some but not all of which are associated with cigarette smoking.

• KRAS mutations in smokers may track together with other mutations, such as those in TP53 or Lkb1, which are tumor-suppressor genes.

• KRAS mutations—at least de novo mutations—are typically mutually ex-clusive of epidermal growth factor re-ceptor (EGFR)-activating mutations and ALK translocations, though this is sometimes not the case, especially with ALK-positive tumors that have been exposed to an ALK inhibitor.

• There is an association between KRAS mutations and lack of response to EGFR tyrosine kinase inhibitors and chemotherapy, though the universality of this concept is now being questioned.

• A number of drug classes have targets downstream of KRAS, but no currently available drug inhibits KRAS directly.

Direct TargetingA landmark paper published last

year suggested it is possible to directly target a KRAS mutational subtype.1

“For the first time, we have data to

suggest that we can target the KRAS G12C mutation with a small molecule,” he said. According to the study’s in-vestigators, these compounds rely on mutant cysteine for binding, without affecting the wild-type KRAS protein. In other words, they are selective for a specific KRAS mutation subtype.

Cell growth inhibition and apoptosis were observed with KRAS targeting only in cell lines with the G12C mutation.

“The data suggest that these small-molecule inhibitors of KRAS are not only possible, but are quite effective in preclinical studies,” Dr. Gandara said. “They are directed toward the common G12C lung cancer mutation, which ap-pears to be far more common in smok-ers than in nonsmokers, and they were developed to target only the mutated

KRAS. In that regard they are very dif-ferent from what we have had before.”

Targeting DownstreamMeanwhile, work continues on

drugs that target downstream path-ways and that indirectly affect KRAS. These efforts take advantage of the fact that KRAS mutations also have “travel-ing partners,” especially co-mutations in LKB1 (also known as STK11) and TP53, Dr. Gandara said.

Work from the The Cancer Genome Atlas (TCGA) has shown that the fre-quency of these co-mutations in NSCLC is similar to that of KRAS mutation alone. A very small percentage of patients have three simultaneous mutations.

It appears, from preclinical and clini-cal studies, that a MEK inhibitor plus docetaxel can effectively target these com-mon co-mutations. In a preclinical study, mice were treated with docetaxel alone or with the investigational MEK inhibitor selumetinib.2 The animals harbored the KRAS G12D mutation or KRAS G12D mutation plus a mutation in either TP53 or LKB1, which are considered clinically relevant tumor suppressors.

In the study, the concomitant loss

of either TP53 or LKB1 markedly im-paired the response of KRAS-mutant cancers to docetaxel monotherapy. The addition of selumetinib provided substantial benefit for mice with lung cancer caused by KRAS and KRAS-plus-TP53 mutations, though mice with co-mutations in KRAS and LKB1 were resistant to the combination.

“There was a big difference in the wa-

terfall plot among mice harboring these three categories of KRAS-mutated can-cer. A rather dramatic change was seen with the MEK inhibitor in combination with docetaxel for all categories except LKB1 loss,” Dr. Gandara noted.

The phase II randomized human trial of selumetinib plus docetaxel in KRAS-mutant NSCLC was also positive for its primary endpoint, progression-free sur-vival: 5.3 months with the combination vs 2.1 months with docetaxel alone.3 Response rates were 37% and 0%, and median overall survival times were 9.4 months and 5.3 months, respectively.

“Admittedly, this was totally KRAS-mutated NSCLC, which is not the typi-cal patient, but the overall survival—though not statistically significant in this phase II study—was almost doubled with the combination,” he pointed out.

Trametinib TrialsDr. Gandara presented a similar phase II

study at the 2013 ASCO Annual Meet-ing for another MEK inhibitor, trametinib (Mekinist) plus docetaxel (with growth factor support) in advanced KRAS-mutant and wild-type KRAS NSCLC.4 Response rates were 28% to the combination among

patients with KRAS-mutated NSCLC, 40% among those with G12C-mutated disease, and 32% among those with wild-type disease, and disease control rates were 60%, 80% and 68%, respectively.

“On the waterfall plot, we saw that all patients with G12C-mutated cancers had responses headed in the right direc-tion, even if they did not meet RECIST criteria for a partial response,” he said.

While the response rates in the study were similar for patients with KRAS-mu-tated disease and those with wild-type disease, Dr. Gandara suggested the com-bination improved responses among those with mutated KRAS, compared to what would be expected with docetaxel alone. Both selumetinib and trametinib are moving forward in development for KRAS-mutated NSCLC, he indicated.

These data have led SWOG to initiate the randomized phase II S1408 trial in KRAS-mutated NSCLC, which will eval-uate trametinib plus docetaxel or plus an AKT inhibitor (GSK795). The primary endpoint is progression-free survival.

Translational studies will evaluate outcomes in patients with the KRAS co-don 12 (G12C) mutation vs other KRAS mutations, and for patients with TP53 mutations or LKB1 loss in each study arm. “This will, we hope, lead to subse-quent phase III trials,” he added. n

Disclosure: Dr. Gandara has received grants from GlaxoSmithKline and is a consultant for AstraZeneca and Novartis.

References1. Ostrem JM, et al: K-Ras(G12C) inhibi-

tors allosterically control GTP affinity and ef-fector interactions. Nature 503:548-551, 2013.

2. Chen Z, et al: A murine lung cancer co-clinical trial identifies genetic modifiers of ther-apeutic response. Nature 483:613-617, 2012.

3. Jänne PA, et al: Selumetinib plus docetax-el for KRAS-mutant advanced non-small-cell lung cancer. Lancet Oncol 14:38-47, 2013.

4. Gandara DR, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in com-bination with docetaxel in KRAS-mutant and wild-type advanced non-small cell lung can-cer: A phase I/IIb trial. ASCO Annual Meet-ing. Abstract 8028. Presented June 2, 2013.

The KRAS mutation story has evolved from what we thought we knew, to the controversies about what we don’t know.

—David R. Gandara, MD

KRAS in Non–Small Cell Lung Cancer

■ The KRAS mutation occurs in approximately 25% of non–small lung cancer tumors, and often coexists with TP53 and LKB1 mutations.

■ Once thought “undruggable,” the KRAS mutation can be targeted by a G12C-mutation–specific novel small-molecular inhibitor in early-phase development.

■ MEK inhibitors plus docetaxel may be an effective means of targeting KRAS-mutated tumors through downstream signaling pathways.

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is primarily nodal or distant, and toxic-ity is more likely in the case of centrally located tumors, vs peripheral. This information formed the basis of the well-known Radiation Therapy Oncol-ogy Group (RTOG) 0236 trial, which enrolled 59 patients with T1 and T2 peripheral lesions outside of the zone of the proximal tracheobronchial tree.1

The study showed that patients with inoperable NSCLC receiving stereotactic body radiotherapy had a 3-year survival of 55.8%, high rates of local tumor control, and moder-ate treatment-related morbidity. Only one patient had a primary tumor fail-ure, producing a 3-year primary tumor control rate of 97.6%. Three patients had a recurrence within the involved lobe, producing a 3-year primary tu-mor and involved lobe control rate of 90.6%. Median overall survival was 48 months. Rates of adverse events were 12.7% for grade 3 and 3.6% for grade 4. More patients died of other causes than of lung cancer.

“This study was transformative,” Dr. Decker said. “The findings are prob-ably the best argument I can make for treating some high-risk patients with radiation.”

A subsequent population-based analysis from the Netherlands Cancer Registry examined the survival of ear-ly-stage NSCLC patients during three time periods, concluding the increase in survival between 2001 and 2009 was at least in part due to the increased use of SBRT over fractionated radiation.2

SBRT vis à vis SurgeryThe issue of SBRT vs surgery has

been examined through several com-parative analyses. A retrospective com-parison of patients with stage I NSCLC deemed ineligible for lobectomy found no significant difference in outcomes between stereotactic body radiother-apy and wedge resection.3 There were no differences in regional recurrence, locoregional recurrence, distant metas-tasis, or freedom from any failure. Risk of local recurrence was less with SBRT

(4% vs 20%, P = .07), and while overall survival was higher with resection (87% vs 72%, P = .01), cause-specific survival was identical (94% with wedge, 93% with SBRT).

A similar finding was reached in an-other study of patients with stage I dis-ease, 462 of whom underwent surgery and 76 who had SBRT. A propensity-matched analysis revealed similar rates of local recurrence and disease-specific sur-vival between the two groups. Four-year local control was 90%, and there was no difference in cancer-specific survival.4

Japanese investigators conducted a retrospective review of 87 stage I pa-tients who declined surgery and were treated with stereotactic radiotherapy, and found local control rates for T1 and T2 tumors at 5 years to be 92% and 73%, respectively. Five-year over-

all survival rates for stage IA and IB subgroups were 72% and 62%, respec-tively. The researchers concluded that the survival rate for SBRT is “poten-tially comparable to that of surgery.”

The most recent data come from a propensity-matched analysis of 64 pa-tients treated with SBRT and 64 treated with minimally invasive surgery.5 Post-SBRT locoregional control rates were superior to surgery at 1 year (96.8% vs 86.9%) and 3 years (86.9% vs 82.6%, P = .04), but distant recurrences and overall survival were similar.

“None of these studies found that SBRT and surgery were the same, but they do tell us that outcomes with SBRT are in the same ballpark as those we get with surgery,” Dr. Decker concluded.

Prospective TrialsOnly two prospective trials have

been reported for operable patients—and remain unpublished. Their results

are not as favorable, he noted. RTOG 0618 was a small study of

26 patients with T1 and T2 disease in which the 2-year local and lobar failure rate was 19%.6 “This local failure rate is concerningly high,” Dr. Decker com-mented. “We await the publication, before we know what to make of this.”

Japan Clinical Oncology Group ( JCOG) 0403 was a single-arm study of 64 operable patients.7 The 3-year local control rate was 86%, and over-all survival rate was 76%. “This local control is not as good as expected, al-though we do not know how this was defined,” he remarked.

Unfortunately several random-ized studies comparing surgery to SBRT have closed early due to poor accrual, including ROSEL (lobecto-my vs SBRT), STARS (lobectomy vs

SBRT with cyberknife) and ACOSOG Z4099/RTOG1021 (sublobar resec-tion vs SBRT).

Pulmonary Function and Quality of Life

“The decision could come down to, ‘What’s the effect of SBRT on the patient’s quality of life and pulmonary function?’” Dr. Decker said. “The tho-racic surgeon and I discuss whether the patient is a candidate for surgery or SBRT, and we try to parse out what the patient’s life will be like after treatment.”

In RTOG 0236, an analysis of pa-tients’ pulmonary function follow-ing SBRT found no significant effect overall, but there were nonsignificant declines in both forced expiratory vol-ume (FEV1) and diffusing capacity for carbon monoxide. This is consistent with what retrospective series have shown, and the impact of this could vary among patients, he said.

Quality of life has been examined in some studies. One from the Cleve-land also revealed small declines in diffusing capacity of the lung for car-bon monoxide, but no degradation in quality-of-life, no reductions in 6-min-ute walking distance, and no increase in patient-reported dyspnea.8

Few ‘Poor Candidates’ for SBRT Not all patients with early-stage

lung cancer are optimal candidates for

stereotactic radiotherapy, though even suboptimal patients can have good outcomes, with caveats.

“Patients with centrally located tumors can be treated effectively, but they are at higher risk for side effects. And we think it’s safe to treat patients with larger tumors, but we have lower expectations of control,” he said.

For centrally located tumors that are small, reduced-dose SBRT can be effective, retrospective studies suggest. Even with a lower dose, however, grade 5 toxicities can occur.

In a study from Yale, in which 47 patients with central lesions received stereotactic body radiotherapy, four patients had grade 3 dyspnea and one developed hemoptysis that contribut-ed to respiratory failure and death. Pa-tients who developed grade 3 or more toxicity had larger tumors than those without toxicity (median diameter = 4.3 vs 2.9 cm, P = .02).

The 2-year lobar local control rate overall was 94%; this rose to 100% for patients receiving a biologic equivalent dose of 100 Gy or more and dimin-ished to 80% among those receiving a lower dose. The authors concluded that SBRT for central lung tumors seems safe, but treatment of larger tu-mors carries an increased risk of high-grade toxicity.

Accrual is complete for RTOG 0813, which will treat patients at the highest dose levels and should be in-formative, he predicted.

For larger (T2) tumors in gen-eral—ie, those that are 4 to 5 cm—evidence is emerging that SBRT is effective, though local control is some-what less than that seen with smaller tumors. A series of patients treated at Yale showed local control rates to be 75% to 80% in this population.

“This is no surprise. With a 5-cm tu-mor, you won’t get 90% local control,” he added. “If this patient has a good surgical option, that’s a better choice.”

Patients with poor pulmonary function at baseline also need not be excluded. A review of 423 patients, stratified by pretreatment pulmonary function, found that pulmonary func-tion declined by 3.6% at 6 months and by 6.8% at 24 months.9 Interest-ingly, the largest loss was observed among patients with the best pulmo-nary function pretreatment; pulmo-nary function actually improved the most among patients with the worst baseline function. n

Disclosure: Dr. Decker reported no potential conflicts of interest.

SBRT in Early Lung Cancercontinued from page 1

International Lung Cancer CongressThoracic Oncology

Stereotactic Body Radiotherapy for Early-Stage NSCLC

■ Stereotactic body radiation therapy for early-stage NSCLC (T1) confers a local control rate of 80% to 90%, potentially equivalent to surgery.

■ Patients with larger tumors can be treated, but local control rates will be lower.

■ Centrally located tumors can be treated effectively but at higher risk.

■ In the vast majority of patients, quality of life is preserved.

In high-risk patients, SBRT appears to offer approximately equivalent control and survival when

compared to surgical resection, in retrospective series. I can say that SBRT is approximately as good as surgery.

—Roy Decker, MD, PhD



References1. Timmerman R, Paulus R, Galvin J, et

al: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070-1076, 2010.

2. Haasbeek CJ, Palma D, Visser O, et al: Early-stage lung cancer in elderly patients: A population-based study of changes in treatment patterns and sur-vival in the Netherlands. Ann Oncol 23:2743-2747, 2012.

3. Grills IS, Mangona VS, Welsch R, et al: Outcomes after stereotactic lung radio-therapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol 28:928-935, 2010.

4. Crabtree TD, Denlinger CE, Meyers BF, et al: Stereotactic body radiation thera-py versus surgical resection for stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 140:377-386, 2010.

5. Verstegen NE, Oosterhuis JWA, Pal-ma DA, et al: Stage I-II non-small-cell lung cancer treated using either stereotactic abla-

tive radiotherapy or lobectomy by video-as-sisted thoracoscopic surgery: Outcomes of a propensity score-matched analysis. Ann Oncol 24:1543-1548, 2013.

6. Timmerman RD, Paulus R, Pass HI, et al: RTOG 0618: Stereotactic body radia-tion therapy (SBRT) to treat operable early-stage lung cancer patients. ASCO Annual Meeting. Abstract 7523. Presented June 1, 2013.

7. Nagata Y, Hiraoka M, Shibata T, et al: A phase II trial of stereotactic body ra-diation therapy for operable T1N0M0 non-

small cell lung cancer, Japan Clinical Oncol-ogy Group ( JCOG0403). 52nd ASTRO Annual Meeting. Abstract 59. Presented November 1, 2010.

8. Videtic GM, Reddy CA, Sorenson L, et al: Support Care Cancer 21:211-218, 2013.

9. Guckenberger M, Kestin LL, Hope AJ, et al: Is there a lower limit of pretreat-ment pulmonary function for safe and ef-fective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 7:545-551, 2012.

International Lung Cancer Congress

SBRT in Early Lung Cancercontinued from page 9

Don’t Miss These Important Reports in This Issue of The ASCO Post

Hugo F. Fernandez, MD, on AML see page 20

Jacek Jassem, MD, PhD, on NSCLC see page 57

David Hui, MD, MSc, on identifying impending death see page 65

Visit The ASCO Post online at ASCOPost.com

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment.

With over 440,000 patients tested worldwide, theOncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning.

For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

The genomic answer in cancer treatment planning.

breast | colon | prostate

Genomic Health and Oncotype DX are registered trademarks of Genomic Health, Inc. © 2014 Genomic Health, Inc. All rights reserved. GHI10330_0414

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http://www.ncbi.nlm.nih.gov/pubmed?term=Guckenberger%20M%5BAuthor%5D&cauthor=true&cauthor_uid=22258475

http://www.ncbi.nlm.nih.gov/pubmed?term=Kestin%20LL%5BAuthor%5D&cauthor=true&cauthor_uid=22258475

http://www.ncbi.nlm.nih.gov/pubmed?term=Hope%20AJ%5BAuthor%5D&cauthor=true&cauthor_uid=22258475

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News

September Is Ovarian Cancer Awareness Month

In recognition of September as Ovarian Cancer Awareness month,

David A. Fishman, MD, Director of the Mount Sinai Ovarian Cancer Risk Assessment Program and Professor and Fellowship Director in the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Repro-ductive Medicine at the Icahn School of Medicine at Mount Sinai, shared the following recommendations and facts in regard to identification and treat-ment of women with ovarian cancer.

Identifying Women at Risk“There is no effective surveillance

technique for the detection of early stage ovarian cancer, so the only effective way to prevent it and save lives is to identify women at risk,” said Dr. Fishman. He recommends that women with a family history of ovarian and breast cancers get a formal genetic evaluation by a board-certified genetic counselor. For women who have tested positive for a BRCA mutation or are identified to be at a high risk for developing ovarian cancer, Dr.

Fishman recommends that preventive surgery should be considered to remove the ovaries and fallopian tubes before ovarian cancer can develop.

Facts About Ovarian Cancer• About 75% of women with ovarian

cancer are diagnosed with late-stage disease. Only 15% to 40% of women survive for 5 years after initial ag-gressive cytoreductive surgery that is performed to remove cancerous tissue from the abdominal cavity in combination with chemotherapy.

• Almost 90% of women who are diag-

nosed while the disease is still con-fined to the ovary (stage I) survive for 5 years. They also require less sur-gical intervention, may not require chemotherapy and have a better quality of life.

• After removal of the ovaries and fallopi-an tubes, the risk of developing ovarian cancer is close to zero and the incidence of peritoneal cancer is about 1%.

Tips for Ovarian Cancer Prevention • Family and personal history is im-

portant to identify women at in-

creased risk: At least 10% of ovar-ian cancers are attributed to the inheritance of genetic mutations (such as BRCA, HNPCC) that in-crease the risk of certain cancers (breast, colon, endometrial, thy-roid, and melanoma). If you have a history of these cancers in your family (either in men or women), get your risk assessed for ovarian cancer by a board certified genetic counselor.

• Take oral contraceptives: Long term use of oral contraceptives reduces the risk of developing ovarian cancer by approximately 50%.

• Pay attention to symptoms: Swol-len or bloated abdomen, pressure or pain in abdomen, pelvis, back or legs, difficulty eating or feeling full quickly, nausea, indigestion, gas, constipation or diarrhea; fatigue, urinary symptoms, and unusual vaginal bleeding.September is also Prostate Cancer

Awareness month. See page 81 for more information. n

Gynecologic Oncology

There is no effective surveillance technique for the detection of early stage ovarian cancer, so the only effective way to prevent it and save lives is to identify women at risk.

—David A. Fishman, MD

©The Mount Sinai Hospital.

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment.

With over 440,000 patients tested worldwide, theOncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning.

For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

The genomic answer in cancer treatment planning.

breast | colon | prostate

Genomic Health and Oncotype DX are registered trademarks of Genomic Health, Inc. © 2014 Genomic Health, Inc. All rights reserved. GHI10330_0414

THE SIDE OF CANCER YOU’RE

NOT SEEING

http://www.genomichealth.com/en-US/OncotypeDX.aspx#.VAYXUNwrffM


Treating Multiple Myeloma in 2014By Sergio A. Giralt, MD

The field of multiple myeloma is rap-idly changing, and the shifts that are

occurring impact the management of these patients, from initial diagnosis through multiple relapses. At the 9th Annual New Orleans Summer Cancer Meeting, Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memo-rial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, shared his ap-proach to various patient subgroups.1 The ASCO Post captured his presentation.

How Far We’ve ComeIn 2001, we had little to offer upfront

to a newly diagnosed patient: thalido-mide (Thalomid) plus dexamethasone or VAD (vincristine, doxorubicin, and dexamethasone), or pulse dexametha-sone. But 4 out of 10 patients receiving these treatments would not respond, and 20% would progress on treatment, which meant a significant proportion did not even get to transplant. For the 60% who responded, the discussion was whether to give high-dose melpha-lan for consolidation. Post-melphalan, there was no well-established mainte-nance treatment, except for bisphos-phonates.

Remember, at that time, the only randomized trial looking at optimal induction was one comparing thalido-mide/dexamethasone to VAD. Thalid-omide/dexamethasone was associated with improved response rates prior to transplant, but after transplant, the re-sults were similar.2 The question was whether there was an optimal induction regimen for patients undergoing trans-plant, and the answer was “anything but melphalan,” because melphalan nega-tively affected stem cell collection

In the early 2000s, multiple random-ized trials showed the benefit of autolo-gous stem cell transplant, particularly for progression-free survival, and four trials found an overall survival benefit. The problem in using those data now is that they come from old studies, and we no longer use thalidomide/dexametha-sone or VAD for induction.

Choice of Induction RegimenThe question is whether patients

with high-risk vs low-risk features should receive the same induction regi-men. The randomized trial by Cavo et al back in 2008 was the first to show that triple therapy is better than double ther-apy.3 The addition of bortezomib (Vel-

cade) to thalidomide/dexamethasone not only improved response rates after induction, but this translated into im-provements in progression-free survival (though no overall survival benefit). The progression-free survival benefit was seen in all risk categories—high-risk and low-risk alike.

More recently, at last year’s American Society of Hematology (ASH) Annual Meeting, Cavo et al reported a meta-analysis of the four trials of bortezo-mib-based induction.4 These were the IFM 2005-1, HOVON-6.5/ GMMG-HD4, GIMEMA MM-BO2005, and PETHEMA GEM05MENOS65. In the combined analysis of about 1,000 patients, both progression-free survival (P = .0001) and overall survival (P = .0402) were significantly improved, vs non–bortezomib-based induction be-fore transplant.

With these emerging data, one has to be convinced that the optimal in-duction regimen for transplant-eligible patients includes bortezomib. I am the

first to recognize that this has not been compared to lenalidomide (Revlimid)/dexamethasone, which we commonly use in the United States. But the pre-ponderance of data suggests that the standard treatment should include bortezomib, and that is what I do in my practice.

Patients Ineligible for Transplant

We do not consider patients with poor performance status. This can in-clude the elderly, frail patient, the pa-tient who cannot perform activities of daily living, and the patient with de-compensated comorbidities.

Other important barriers to trans-plantation are socioeconomic: lack of a caregiver, distance from the hospital, inability to comply with post-transplant care, and so forth. Age by itself is not a contraindication. Patients with very

low-risk disease also may not need to go to transplant.

Optimal Drug CombinationsFor improving the induction re-

sponse prior to transplant, VRD (bort-ezomib, lenalidomide, and dexametha-sone) is commonly used in the United States, partly because this is the only country where lenalidomide has an up-front indication for transplant-eligible patients. I use VRD or CyBorD (cyclo-phosphamide, bortezomib, and dexa-methasone), interchangeably. These regimens have been compared head-to-head in small phase II studies, and the results are equivalent.

Questions About Consolidation

Should we use the same consolida-tion regimen for the patient who ob-tains a stringent complete remission after four cycles of VTD (bortezomib, thalidomide, and dexamethasone), vs the same patient who has persistent

disease after this regimen? And who should receive high-dose melphalan and autologous transplant: the patient who achieves a complete remission, the one who does not, both, or neither? This last question is difficult, and can require an hour of consultation with the patient.

Fifteen years ago, the conversation about transplant was relatively straight-forward. We said, “We gave you the best treatment, and you still have residual disease. Achieving a complete remission makes a difference. We will, therefore, give you high-dose melphalan, which converts residual disease to a complete remission 30% of the time.” You can’t have this conversation with the patient who is already in complete remission, and with modern induction regimens, 20% are in complete remission.

In E4A03, patients received lenalid-omide/dexamethasone for four cycles,

then either stopped treatment and went to transplant or not, or continued pri-mary lenalidomide therapy beyond four cycles.5 The important finding was this: four cycles, then stopping is not sufficient. The overall survival rate for this group was 55% at 3 years, com-pared to 80% for patients who contin-ued on lenalidomide and 92% for those who went to transplant (who were also younger).

We really need a randomized con-trolled trial comparing early high-dose therapy and autologous stem cell trans-plant as consolidation for all patients vs late, ie, high-dose therapy and auto-transplant only for patients who relapse after primary therapy. Palumbo et al evaluated MPR (melphalan, predni-sone, and lenalidomide) vs high-dose melphalan and tandem transplant as consolidation after lenalidomide induc-tion.6 The response rates were 92% and 97%, respectively, and progression-free survival at 12 months was 91%. So we have at least one trial showing the ben-efit of high-dose melphalan. The prob-lem is that these patients never got bort-ezomib, and that makes a difference.

Currently, there are two national trials—one in the United States and one in Europe—looking at the opti-mal induction regimen of VRD, then randomly assigning patients to early vs late transplant followed by maintenance lenalidomide. This should answer the question of whether early transplant is important, or whether we can collect stem cells and hold them until relapse.

With regard to the patient who ob-tains a complete remission after induc-tion, vs the one with residual disease, I think both should go to transplant. The preponderance of the data, at least until the randomized trials are reported, still suggests a benefit for transplant.

Prognostic Factors Can Guide Treatment

At last year’s ASH Annual Meet-ing, Cavo et al presented a multivariate analysis that identified three important prognostic factors: inability to achieve a complete remission with induction, the presence of poor-risk cytogenetics at baseline, and disease stage > 2 by In-ternational Staging System (ISS > 2).4 These factors worsen progression-free survival outcomes by 80%, 56%, and 57%, respectively.

This information allows us to risk-

New Orleans Summer Cancer MeetingHematology


If you define ‘cure’ as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there.

—Sergio A. Giralt, MD

Fonts: FrutigerImages: Votrient woods_2_DarkBottom.psd (CMYK; 870 ppi; Bloc_GS:GSK:VOTRIENT:VOTUS1163...ks:Votrient woods_2_DarkBottom.psd), GSK_StdArc_BR.ai (Bloc_Images:GSK_Library:VOTRIE...orkingFiles:Links:GSK_StdArc_BR.ai), GSK_L_3D_CMYK_MY.ai (Bloc_Images:GSK_Library:VOTRIE...ingFiles:Links:GSK_L_3D_CMYK_MY.ai), VOT_dose_4C.eps (Bloc_Images:GSK_Library:VOTRIE...OGOS:Dose Versions:VOT_dose_4C.eps)

VOTUS13564_03_STS_Ad_KING_DR2.indd Amy Kortman

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Client: VOTRIENT

Job Description: aSTS Kingsize

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Job #: VOTUS13564-03

Stage: DISK RELEASE

Round: 2

Important Safety Information for VOTRIENT

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the fi rst 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

LIGHTING A WAY FORWARD

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation of Use: The effi cacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

Please see additional Important Safety Information for VOTRIENT on subsequent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

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Stage: DISK RELEASE

Round: 2

Important Safety Information for VOTRIENT

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the fi rst 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

LIGHTING A WAY FORWARD

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.


Please see additional Important Safety Information for VOTRIENT on subsequent pages.


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VOTUS13564_03_STS_Ad_KING_DR2.indd Amy KortmanClient: VOTRIENT


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Stage: DISK RELEASE

Round: 2

Placebo (n=123)

VOTRIENT (n=246)1.6 MONTHSMedian PFS

4.6 MONTHSMedian PFS1.0

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• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modifi cation of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure.

• Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically signifi cant gastrointestinal hemorrhage in the past 6 months.

• Arterial Thromboembolic Events: Arterial thromboembolic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, VTEs were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal

pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms.

• Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

• Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fi stula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms.

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS.

• Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the fi rst 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

• Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients

undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

• Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.

• Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

Important Safety Information for VOTRIENT (cont’d) Important Safety Information for VOTRIENT (cont’d)

PFS in overall study population (N=369)1

VOTRIENT demonstrated signifi cant improvement in PFS in a Phase 3 trial1

Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the effi cacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

• VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.26-0.48; P<0.001)1

• The effi cacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.


Once-daily oral dosing1

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg

• Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose

• In soft tissue sarcoma, a dose decrease or increase should be in 200-mg steps based on individual tolerability

• In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced

• No dose adjustment is required in patients with mild hepatic impairment

• In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day

• Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment

• Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4

• For additional information on dosing modifi cations based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

• Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group).

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm.

• Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Please see additional Important Safety Information for VOTRIENT on adjacent pages.


©2014 GSK group of companies. All rights reserved. Printed in USA. 66601R0 June 2014

www.GSKSource.com VOTRIENT.com/HCP/aSTS

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Fonts: FrutigerImages: Box_Side_Shadow.psd (CMYK; 379 ppi; Bloc_GS:GSK:VOTRIENT:VOTUS1356...lAd-King:Links:Box_Side_Shadow.psd), VOT_STS_PFS_ALT_AD5.ai (Bloc_GS:GSK:VOTRIENT:VOTUS1163...FILES:Links:VOT_STS_PFS_ALT_AD5.ai), VOT_dose_4C.eps (Bloc_Images:GSK_Library:VOTRIE...OGOS:Dose Versions:VOT_dose_4C.eps), GSK_ExtdArc_BR_JournalAds.ai (Bloc_Images:GSK_Library:VOTRIE...Links:GSK_ExtdArc_BR_JournalAds.ai), GSK_L_3D_CMYK_MY.ai (Bloc_Images:GSK_Library:VOTRIE...ingFiles:Links:GSK_L_3D_CMYK_MY.ai)


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undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

• Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.

• Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

Important Safety Information for VOTRIENT (cont’d)

• VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.26-0.48; P<0.001)1

• The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

Once-daily oral dosing1

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg

• Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose

• In soft tissue sarcoma, a dose decrease or increase should be in 200-mg steps based on individual tolerability

• In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced

• No dose adjustment is required in patients with mild hepatic impairment

• In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day

• Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment

• Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4

• For additional information on dosing modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm

• The most common adverse reactions (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea



• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

• Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group).

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm.

• Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

• Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions.

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%).

Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%).

References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Data on file. GlaxoSmithKline, 2011.



©2014 GSK group of companies. All rights reserved. Printed in USA. 66601R0 June 2014

www.GSKSource.com VOTRIENT.com/HCP/aSTS

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BRIEF SUMMARYVOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITYSevere and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].4 CONTRAINDICATIONS None.5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.4% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10%

compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and

lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

VOTRIENT Placebo

(N=240) (N=123)

Adverse Reactions

All Gradesa Grade 3 Grade 4


% % % % % %Fatigue 65 13 1 48 4 1Diarrhea 59 5 0 15 1 0Nausea 56 3 0 22 2 0Weight decreased 48 4 0 15 0 0Hypertension 42 7 0 6 0 0Appetite decreased 40 6 0 19 0 0Hair color changes 39 0 0 2 0 0Vomiting 33 3 0 11 1 0Tumor pain 29 8 0 21 7 2Dysgeusia 28 0 0 3 0 0Headache 23 1 0 8 0 0

Musculoskeletal pain 23 2 0 20 2 0

Myalgia 23 2 0 9 0 0

Gastrointestinal pain 23 3 0 9 4 0

Dyspnea 20 5 <1 17 5 1Exfoliative rash 18 <1 0 9 0 0Cough 17 <1 0 12 <1 0Peripheral edema 14 2 0 9 2 0Mucositis 12 2 0 2 0 0Alopecia 12 0 0 1 0 0Dizziness 11 1 0 4 0 0Skin disorderb 11 2 0 1 0 0

Skin hypopigmentation 11 0 0 0 0 0

Stomatitis 11 <1 0 3 0 0Chest pain 10 2 0 6 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

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Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo

VOTRIENT(N=240)

Placebo(N=123)

Parameters



% % % % % % Hematologic

Leukopenia 44 1 0 15 0 0Lymphocytopenia 43 10 0 36 9 2Thrombocytopenia 36 3 1 6 0 0Neutropenia 33 4 0 7 0 0

ChemistryAST increased 51 5 3 22 2 0ALT increased 46 8 2 18 2 1Glucose increased 45 <1 0 35 2 0Albumin decreased 34 1 0 21 0 0Alkaline phosphatase increased

32 3 0 23 1 0

Sodium decreased 31 4 0 20 3 0

Total bilirubin increased 29 1 0 7 2 0

Potassium increased 16 1 0 11 0 0


Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and C

max). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to

avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist

of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:

• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away.

• Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure.

• Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding.

• Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis.

• Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

• Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances).

• Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting.

• GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula.

• VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery.

• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment.

• Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT.

• Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

©2014, the GSK group of companies. All rights reserved. Revised: 06/2014 VTR:12BRS

©2014 GSK group of companies.All rights reserved. Printed in USA. 66601R0 June 2014

GlaxoSmithKline Research Triangle Park, NC 27709

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BRIEF SUMMARYVOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITYSevere and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].4 CONTRAINDICATIONS None.5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.4% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10%

compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and

lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

VOTRIENT Placebo

(N=240) (N=123)

Adverse Reactions



% % % % % %Fatigue 65 13 1 48 4 1Diarrhea 59 5 0 15 1 0Nausea 56 3 0 22 2 0Weight decreased 48 4 0 15 0 0Hypertension 42 7 0 6 0 0Appetite decreased 40 6 0 19 0 0Hair color changes 39 0 0 2 0 0Vomiting 33 3 0 11 1 0Tumor pain 29 8 0 21 7 2Dysgeusia 28 0 0 3 0 0Headache 23 1 0 8 0 0

Musculoskeletal pain 23 2 0 20 2 0

Myalgia 23 2 0 9 0 0

Gastrointestinal pain 23 3 0 9 4 0

Dyspnea 20 5 <1 17 5 1Exfoliative rash 18 <1 0 9 0 0Cough 17 <1 0 12 <1 0Peripheral edema 14 2 0 9 2 0Mucositis 12 2 0 2 0 0Alopecia 12 0 0 1 0 0Dizziness 11 1 0 4 0 0Skin disorderb 11 2 0 1 0 0

Skin hypopigmentation 11 0 0 0 0 0

Stomatitis 11 <1 0 3 0 0Chest pain 10 2 0 6 0 0


b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

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Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo

VOTRIENT(N=240)

Placebo(N=123)

Parameters



% % % % % % Hematologic

Leukopenia 44 1 0 15 0 0Lymphocytopenia 43 10 0 36 9 2Thrombocytopenia 36 3 1 6 0 0Neutropenia 33 4 0 7 0 0

ChemistryAST increased 51 5 3 22 2 0ALT increased 46 8 2 18 2 1Glucose increased 45 <1 0 35 2 0Albumin decreased 34 1 0 21 0 0Alkaline phosphatase increased

32 3 0 23 1 0

Sodium decreased 31 4 0 20 3 0

Total bilirubin increased 29 1 0 7 2 0

Potassium increased 16 1 0 11 0 0


Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and C

max). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to

avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist

of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:

• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away.

• Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure.

• Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding.

• Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis.

• Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

• Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances).

• Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting.

• GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula.

• VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery.

• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment.

• Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT.

• Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

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stratify patients into those with no high-risk features (13%), one adverse feature (61%), two adverse features (23%), or all three adverse features (3%). Their respective median progression-free sur-vival times are 61 months, 56 months, 36 months, and 26 months.

In the context of bortezomib induc-tion, you can tell the patients who lack any high-risk features that they have less than a 50% risk of having to re-treat their disease in the next 5 years. On the other hand, the patient with all three poor-risk factors should consider trans-plant right away.

Maintenance for (Almost) AllLet’s suppose the patient with low-

risk disease has an autotransplant and remains in complete remission, but the patient with high-risk disease still has residual disease after transplant. Should they both get maintenance therapy? This is another difficult dis-cussion.

In 2014, while it is still somewhat controversial, the evidence suggests there is a benefit to maintenance le-nalidomide. This was shown in the IFM 2005-02 trial, where even pa-tients who achieved a complete remis-sion prior to transplant had prolonged progression-free survival, and many patients with persistent disease con-verted to complete remission.7

Similar results were reported in

the CALGB 100104 trial, where me-dian progression-free survival was 24 months without maintenance vs 40 months in the maintenance arm.8 CALGB 100104 also showed an over-all survival benefit, whereas the French study did not. The potential downside to maintenance is a threefold risk for second malignancies (an increase from 1% to 3%), but this did not affect the survival benefit of these patients.

So I think it is reasonable to offer almost all patients maintenance le-nalidomide. The one exception is the patient with low-risk disease who is in complete remission prior to transplant. His or her progression-free survival is about 5 years, and it is reasonable to monitor this patient and initiate le-nalidomide upon signs of progression.

Putting all these approaches togeth-er, we await the results of the STaMI-NA trial, which is evaluating the role of consolidation in the context of high-dose melphalan and lenalidomide maintenance. Patients were randomly assigned to a second autotransplant, vs four cycles of consolidation, then maintenance. We will have the results in 2 years.

Possibly, a Cure?The surrogate marker for long-term

survival is complete remission—this is what gives the survival advantage. The importance of achieving a com-plete remission is the same for trans-plant-eligible and transplant-ineligible

patients. It makes a big difference in both groups. High-dose melphalan has a role in transplant-eligible patients and in my opinion continues to be the standard of care, because it’s the single most effective way of getting a com-plete remission.

Can we cure myeloma? My answer is that 30% of patients who achieve a complete remission remain in remis-sion 10 years down the line, according to data on the Total Therapy protocol from the University of Arkansas for Medical Sciences, Little Rock. If you define “cure” as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there. n

Disclosure: Dr. Giralt reported no potential conflicts of interest.

References1. Giralt S: Multiple myeloma: How to

integrate novel agents with stem cell trans-plantation in the era of targeted therapy. 9th Annual New Orleans Summer Cancer Meeting. Presented July 20, 2014.

2. Macro M, Divine M, Uzunhan Y, et al: Dexamethasone + thalidomide com-pared to VAD as a pre-transplant treat-ment in newly diagnosed multiple my-eloma: A randomized trial. Blood (ASH Annual Meeting Abstracts) 108:Abstract 57, 2006.

3. Cavo M, Tacchetti P, Patriarca F, et al: A phase III study of double autotrans-

plantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: Superior clinical out-comes with VTD compared to TD. Blood (ASH Annual Meeting Abstracts) 114:Ab-stract 351, 2009.

4. Cavo M, Salwender H, Rosinol L, et al: Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: An integrated analysis of patient-level data from phase III European studies. Blood (ASH Annual Meeting Abstracts) 122:Ab-stract 767, 2013.

5. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomized controlled tri-al. Lancet Oncol 11:29-37, 2010.

6. Palumbo A, Cavallo F, Ben Yehuda D, et al: A prospective, randomized study of melphalan, prednisone, lenalidomide versus melphalan (200 mg/m2) and autol-ogous transplantation (Mel200) in newly diagnosed myeloma patients: An interim analysis. Blood (ASH Annual Meeting Ab-stracts) 114:Abstract 350, 2009.

7. Attal M, Christini C, Marit G, et al: Lenalidomide maintenance after trans-plantation for myeloma. J Clin Oncol 28(suppl):Abstract 8018, 2010.

8. McCarthy P, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.

New Orleans Summer Cancer Meeting

Treating Multiple Myelomacontinued from page 12

Don’t Miss These Important Reports in This Issue of The ASCO Post

David R. Gandara, MD, on targeting KRAS mutations in lung cancer see page 6

Eva J. Kantelhardt, MD, on gynecolgic cancer care in resource-challenged Ethiopa see page 76

Martin C. Tammemagi, PhD, on lung screening and smoking cessation see page 53

Alok A. Khorana, MD, on understanding the impact of CALGB/SWOG 80405 (ASCO 2014 plenary) see page 30

Tracy A. Balboni, MD, MPH, on palliative care in radiation oncology see page 44

Anand P. Jillella, MD, and Vamsi K. Kota, MD, on acute promyelocytic leukemia see page 62

Visit The ASCO Post online at ASCOPost.com

Richard L. Schilsky, MD, on quality cancer care see page 86


Quest for Targeted Therapeutic ‘Cocktails’ Hits Roadblocks By Caroline Helwick

The use of cutting-edge technol-ogy and bioinformatics to inform

clinical decision-making in oncology is still a ways off, according to Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Oncology and Di-rector of the Stanford Breast Oncol-ogy Program, Stanford University, Palo Alto, California. At the 9th Annual New Orleans Summer Cancer Meeting, Dr. Pegram said the “lofty goal” of targeted therapeutic “cocktails”—which will be needed to address the molecular diversi-ty of tumors—is proving hard to achieve.

Circulating Tumor CellsCirculating tumor cells as an alterna-

tive to serial biopsies of metastatic lesions has great appeal, but the uptake of this technology has been somewhat anemic.

One problem is obtaining a consis-tent definition of a circulating tumor cell. The cell must be positive for cytokeratin, must have a nucleus, must have a negative control, must be negative for leukocyte

cytoplasm (white cell markers), and the nucleus must fit inside the cytoplasm.

“These are the things measured using a huge variety of different approaches for defining and capturing [circulating tumor cells],” he said. The most clinically ad-vanced is the CellSearch System, which uses an antibody/ferrofluid combination to attach specifically to circulating tumor cells, and magnets to draw those cells out of the blood sample to be stained and identified. The test enumerates the num-ber of circulating tumor cells in a patient

with metastatic disease, and this is corre-lated with overall survival.

“The problem with this assay is that it is not sensitive enough to capture [circu-lating tumor cells] in early stages of dis-

ease. While enumeration of [circulating tumor cells] is prognostic, let’s be hon-est: that’s not what we are interested in,” Dr. Pegram said. “We are interested in predicting response to treatment.”

He has observed that while some clinicians are “enamored” of this tech-nology and do use it, others realize that it holds little value over routine restag-

New Orleans Summer Cancer Meeting


Mutational events in cancer can yield complex and deranged pathways,

but they are still highly functional and they can take the lives of our patients. We

need to understand them. —Mark Pegram, MD

Molecular Biology

CLINICAL EXPERTISEMore than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specifi c malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology.

Our Leadership Team

TRANSPLANTATIONIn addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem cells for peripheral blood transplants

• Four ICU beds integrated with Carolinas HealthCare System’s virtual ICU, which provides 24/7 oversight of all patients

• Patient support, including family-friendly patient rooms, an exercise room, a laundry room and lounge

• Patient navigation

CLINICAL TRIALS AND RESEARCH

Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• First-in-man clinical trials testing novel therapies and treatment options

• Access to high-quality care, and expertise from physicians who subspecialize in treating specifi c diseases

• The ability to enroll patients in the newest, most promising trials, whether that patient lives downthe street or out of state, through the Institute’s decentralized model of care

Hematologic Oncology and Blood Disorders Program

L E V I N EC A N C E RINSTITUTE’SMODEL OF CARE

The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

WHAT CREATES A GREAT SURVIVAL CURVE?

Belinda Avalos, MDVICE-CHAIRHematologic Oncology and Blood Disorders program

Ed Copelan, MD, FACPCHAIRHematologic Oncology andBlood Disorders program

For more information, visit CarolinasHealthCare.org/ModelOfCare

LCI_RepAd_Final_ASCO.indd 1 4/2/2014 10:27:37 AM

http://www.carolinashealthcare.org


Expert’s Corner

ing with radiographic studies. The assay also reveals little as to what is happening in these cells, and the small number of circulating tumor cells captured—five or so—is insufficient for fully decipher-ing the tumor, he said.

Capturing more cells could help, and that is what microfluidics-based cell separation does. This new, simpler tech-nology passes blood through a mem-brane, separating larger tumor cells from other blood elements and yielding thousands of cells upon which clinically relevant tests can be performed.

“The approaches that have much high-er yields will be more useful because they will be informative as to what cells are do-ing at a molecular level,” he predicted.

Even more sophisticated blood-based technology will someday be better able to capture the genetic het-erogeneity of advanced solid tumors at a gene-expression level so they can be compared with the primary tumor. This, however, will present other chal-lenges.

“In one blood sample there are mul-tiple populations of [circulating tumor cells] that are different from another. This will pose a diagnostic challenge and a treatment challenge, as well, if we find unique targets within the same pa-tient at the same time,” he said. “Until we can come to terms with the com-plexity of solid tumor malignancies, we can’t make informed decisions.”

At this point, guideline committees

“have not latched on to [circulating tumor cells] as a ‘must’ in clinical prac-tice,” he indicated, calling circulating tumor cell determination a “consider-ation,” but one lacking in great value until emerging technologies can inter-rogate circulating tumor cells at a mo-lecular level.

Genomics and Drug Development

The promise of genomics was to identify mutations within a tumor and thus allow the clinician to concoct a tailored therapeutic cocktail. In real-ity, however, the scenario is infinitely complex. Within a single MCF-7 hu-man breast cancer cell, for instance, 157 chromosomal break points have been found.

“We have rich genomic information in a tumor cell, but this does not tell the doctor how to treat the patient,” he said.

The Cancer Genome Atlas (TCGA) Network, in its examination of its first 507 breast cancer samples, revealed only four frequently mutated genes out of 50 that were identified: PIK3CA, TP53, MAP3K1, and GATA3.

“This was a stunning observation,” commented Dr. Pegram. “We thought we would discover multiple new ther-apeutic targets in breast cancer and therefore have home runs in drug devel-opment, but we found only four, and all four were already known to be common mutations.”

Drugs are already targeting PI3K, the other three frequent mutations are

not druggable, and the rest of the 50 genes are low-frequency mutations (af-fecting about 2% of breast cancers) for which pharmaceutical companies are unlikely to invest. “This will pose a chal-lenge because our current models of drug development will not survive this reality,” he predicted.

Furthermore, according to Dr. Pe-gram, deep sequencing identifies even more heterogeneity, revealing individu-al clones with different mutational pro-files within the same tumor. The current next-generation diagnostics are not per-forming deep sequencing and therefore are not demonstrating the molecular heterogeneity that is critical for select-ing the best targeted agent, he said.

Even “more sobering,” he continued, is that this complexity is present at the time of diagnosis, with further altera-tions piled on due to drug resistance. Cancer and genomes are not static; they are a moving target, he reiterated.

While the situation is clinically frustrating now, there is the potential to tease apart the molecular evolu-tion of cancers with future sequencing technology, and this “extraordinary” achievement could give insights into prevention strategies.

Adding Proteomic Data Even more complex than genomics

is proteomics, the large-scale analysis of protein-expression profiles through mass spectrometry. Proteomic infor-mation on post-translational modifica-tions in the tumor (ie, phosphorylation,

glycolisation, etc) could be a useful ad-junct to genomic information, produc-ing a more “holistic view” of pathway regulation.

“The hope is that mixing proteomic work along with genomic work will fa-cilitate our understanding of what is going on in the dynamic tumor cell,” Dr. Pegram said. “But the problem with proteomics is size: the proteome is much larger than the genome, due to alternative splicing and protein modifi-cation.”

The information desired from pro-teomics includes all protein-to-protein interactions, protein functions and their regulation, protein modifications, subcellular location, and protein con-centrations. Current approaches do not provide all this information.

While polymerase chain reaction (PCR) testing determines gene am-plification, there is no PCR equivalent for proteomics. Sequencing tools are robust in genomics, but mass spectrom-etry is still emerging in proteomics. Furthermore, proteomic data is “big data,” and huge servers are needed just to store the data. Novel approaches are currently being pioneered to address these issues, he said.

In summary, Dr. Pegram said, “Mu-tational events in cancer can yield com-plex and deranged pathways, but they are still highly functional and they can take the lives of our patients. We need to understand them.” n

Disclosure: Dr. Pegram reported no potential conflicts of interest.

Targeted Therapeuticscontinued from page 19

Emerging Approaches in Acute Myeloid LeukemiaA Conversation With Hugo F. Fernandez, MDBy Caroline Helwick

With the emergence of molecular diagnostics and new therapeu-

tics, the treatment of acute myeloid leukemia (AML) is entering a new era. Hugo F. Fernandez, MD, Associate Chief of Blood and Marrow Transplan-

tation at Moffitt Cancer Center in Tam-pa, Florida, spoke with The ASCO Post about how he approaches these patients.

Cytogenetics and Molecular Studies

Can you offer a few major require-ments in treating AML today?

In 2014, we need to know the results of cytogenetics and molecular studies, which should be done on all patients with AML. Cytogenetics has long been a standard diagnostic test, and we clas-sify cytogenetic profiles as conveying a “good (favorable), bad (intermediate), or ugly (unfavorable)” profile. Ten-year overall survival rates have been shown to be 55% to 81% for patients with favor-able profiles, 22% to 39% for those with intermediate-risk profiles, and 10% or

less for those with unfavorable profiles.1 But now we know about a variety

of mutations that also confer progno-sis. Molecular studies are allowing us to reclassify our patients, which will be important down the road when we can more precisely select optimal treatments. These new molecular assays are impor-tant and readily available at academic centers and in commercial laboratories.

An important mutational analysis of 18 genes, performed by Patel et al on the Eastern Cooperative Oncology Group (ECOG) E1900 patient popula-tion, found that more extensive muta-tional analysis can better discriminate pa-tients with AML into various prognostic groups.2 The analysis separated patients with AML into three subgroups with very different outcomes: those with a favor-

able mutational risk profile (3-year over-all survival rate, 85%), a subgroup with an unfavorable mutational risk profile (3-year overall survival rate, 13%), and a subgroup remaining at intermediate risk (3-year overall survival rate, 42%).

The integration of mutational and cytogenetic analyses reduced the pro-portion of patient with intermediate-risk disease from 63% to 35%. The favorable-risk subgroup increased from 19% to 26%, and the proportion deemed unfa-vorable increased from 18% to 39%.

Key MutationsWhat are the key mutations associated

with prognosis?In cytogenetically normal patients,

there are two abnormalities that gener-

Hematology

Hugo F. Fernandez, MD


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CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information

ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

C M Y KCosmos Communications 1

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Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

indications

CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.


ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


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Fonts: Helvetica Neue LT StdImages: Cross Indication_paralax_colorshift_AD3.psd (CMYK; 236 ppi, 221 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...ication_paralax_colorshift_AD3.psd), Celgene_logo_KO.eps (Bloc_GS:Celgene:Abraxane:ABX:A...3_KingAd:Links:Celgene_logo_KO.eps), Abrax Logo_KO_4C_YellowBall_noblue.eps (Bloc_Images:Celgene:Abraxane_L...x Logo_KO_4C_YellowBall_noblue.eps), NSCLC_Ad_Chart3_3pg_AD1.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d:Links:NSCLC_Ad_Chart3_3pg_AD1.ai), NSCLC_Ad_Chart2_AD4.ai (Bloc_GS:Celgene:Abraxane:ABX:A...ingAd:Links:NSCLC_Ad_Chart2_AD4.ai)


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Client: CELGENE


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Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

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0

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20

25

30

35

40

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27%

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26%

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41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

Adverse events in the NSCLC study


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______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

7/29

24%

5/33

15%

0

5

10

15

20

25

30

35

40

45

50

Large cell carcinoma

2/13

15%

3/9

33%

OR

R (%

)

Carcinoma/adenocarcinoma

27%

71/264

26%

66/254

Squamous cell carcinoma

94/229

41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

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ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days

Third Discontinue Treatment

Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.


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The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days


Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.



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Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups

ABRAXANE Paclitaxel Injection(100 mg/m2 weekly) (200 mg/m2 every 3 weeks)

plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

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Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups


plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

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Expert’s Corner

ally tell us the patient will probably do well: mutations in NPM1 only or isolat-ed biallelic CEBPA. Intermediate-risk disease, on the other hand, is conferred by the c-KIT mutation in core-binding factor leukemia.

Poor prognosis is associated with the FLT3-ITD mutation, which we see in about one-third of patients. FLT3 is normally expressed on hematopoietic cells, and regulates the proliferation of early progenitor cells. When mutated, FLT3 constitutively activates leukemia cells so that they never stop growing.

The impact of FLT3 is obvious from the study by Patel et al.2 They showed that in patients with intermediate-risk AML, the mutant FLT3-ITD was asso-ciated with an adverse outcome regard-less of other mutations. In patients with wild-type FLT3, the presence of sev-eral additional mutations—DNMT3A, PHF6, ASXL1, MLL, RAS, WT1 and TP53—conferred a worse prognosis. However, these mutations are less fre-quent and need more study.

Initial ApproachWhat is your initial approach to treat-

ment?AML needs aggressive treatment.

Most patients will relapse with conven-tional therapies, so just getting them through induction is not enough; they also need consolidation. The attain-ment of a complete response will im-pact their disease course.

Patients with favorable-risk disease generally have excellent outcomes and can be treated with standard chemo-therapy. Other genotypes that fall into the intermediate-risk and high-risk groups need more aggressive treatment.

It is very important for FLT3-posi-tive patients to receive better therapy, and while we have no real options now, we believe this will change in the near future. A phase II study with sorafenib (Nexavar) was encouraging for pa-tients with FLT3-ITD, and this is the only agent we have available for this purpose. A randomized phase III trial adding the investigational tyrosine ki-nase inhibitor midostaurin to conven-

tional therapy has been completed and is awaiting maturation.

There may be other tyrosine kinase inhibitors that more directly target FLT3, but whether this will be a good thing or not remains to be seen. At least now, we have proof of principle that FLT3 inhibition can positively impact outcomes in these patients.

Induction TherapyWhat is your induction approach?High-dose anthracyclines must be

given to these patients. No patient with AML has benefited from low-dose ther-apy. Idarubicin and daunorubicin are equivalent at higher doses. If the patient is too ill for this approach, find an alter-native, but you still must be aggressive.

We also see gemtuzumab ozogami-cin (Mylotarg) making a comeback. Early trials were encouraging, but the randomized phase III SWOG trial was negative, partly due to a high incidence of side effects.3 This led to the drug’s

voluntary withdrawal from the market, but gentuzumab ozogamicin has not completely disappeared from our arma-mentarium.

A recent meta-analysis showed that the addition of gemtuzumab ozogami-cin to treatment improved relapse-free survival (hazard ratio [HR] = 0.84) and event-free survival (HR = 0.59) but not overall survival (HR = 0.95).4 While the addition of the drug resulted in a 60% higher rate of early mortality in the meta-analysis, improved overall surviv-al was observed in studies using a lower cumulative dose (< 6 mg/m2).

So gemtuzumab ozogamicin can be beneficial, especially in patients with fa-vorable- and intermediate-risk disease, but with the issue of side effects, we still have questions. By reducing the dose,

we see less treatment-related morbid-ity and mortality. We are still not sure whether the drug will come back on the market, and in the future we may be seeing more targeted trials stratified by risk. In the meantime, patients who have core-binding factor leukemia may get some benefit by adding this drug at the lower dose.

Moving to consolidation therapy, we can say that prognostic factors and per-formance status drive treatment. For fa-vorable-risk patients, standard chemo-therapy with or without gemtuzumab ozogamicin is the way to go.

Delaying TransplantCan you effectively delay stem cell

transplantation to second remission? Although the majority of adult pa-

tients with AML will achieve remission with upfront chemotherapy, many pa-tients still relapse. Often, the strategy proposed is to delay transplant until a patient relapses and achieves a second

remission. We should not let the “sec-ond remission fallacy”—that is, think-ing that we can take patients to trans-plant in their second remission—guide our treatment.

Remember that most patients will relapse, and obtaining a second remis-sion is not guaranteed. If the patient relapses within 12 months, the chance of a second remission is only about 15%. Beyond 12 months, it improves to 30% or 40%, but these are still not great numbers. Taking the patient to trans-plant while in first remission, especially those with intermediate- or high-risk disease, is often beneficial.

Allogeneic transplant is preferred for patients with FLT3 mutations. Neither chemotherapy nor autologous trans-plants helps these patients. Allogeneic

transplant is the only treatment that will level the playing field.

Emerging TreatmentsWhat emerging treatments for AML

look promising?The cooperative group trials are

evaluating a number of new agents in high-risk patients. In patients with core-binding factor leukemia, we are evaluat-ing dasatinib (Sprycel) given with high-dose daunorubicin. For FLT3-positive disease, we are looking at sorafenib plus 7+3 chemotherapy (continuous intra-venous [IV] cytarabine infusion for 7 days with an anthracycline given by IV push for 3 days). Another trial is com-paring high-dose daunorubicin to high-dose idarubicin with or without vorino-stat (Zolinza). We are also evaluating early allogeneic transplant in high-risk patients.

The future of AML sees us aggres-sively treating this disease in induction and consolidation. Molecular targets are being discovered, and directed ther-apy will hopefully improve upon remis-sion rates and overall survival in this deadly disease. n

Disclosure: Dr. Fernandez reported no potential conflicts of interest.

References1. Grimwade D, Hills RK, Moorman AV,

et al: Refinement of cytogenetic classifica-tion in acute myeloid leukemia: Determina-tion of prognostic significance of rare recur-ring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Coun-cil trials. Blood 116:354-365, 2010.

2. Patel JP, Gönen M, Figueroa MET, et al: Prognostic relevance of integrated ge-netic profiling in acute myeloid leukemia. N Engl J Med 366:1079-1089, 2012.

3. Petersdorf SH, Kopecky KJ, Slovak M, et al: A phase 3 study of gemtuzumab ozogamicin during induction and postcon-solidation therapy in younger patients with acute myeloid leukemia. Blood 121:4854-4850, 2013.

4. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al: Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: A systematic review and meta-analysis. Br J Haematol 163:315-325, 2013.

Hugo F. Fernandez, MDcontinued from page 20

The future of AML sees us aggressively treating this disease in induction and consolidation.

Molecular targets are being discovered, and directed therapy will hopefully improve upon remission rates and

overall survival in this deadly disease. —Hugo F. Fernandez, MD

Visit The ASCO Post website at ASCOPost.com


Announcements

Charles LeMaistre, MD, and Hans Mark, PhD, Named Chancellors Emeritus by the University of Texas System Board of Regents

Two former Chancellors, Charles LeMaistre, MD, and Hans Mark,

PhD, were recently given the honorific title Chancellors Emeritus by the Univer-sity of Texas System Board of Regents.

“Charles LeMaistre and Hans Mark were visionary chancellors who expanded

the UT System into new directions that greatly benefited higher education and the people of Texas,” said current Chancellor Francisco G. Cigarroa, MD. “They were unique, with exceptional careers in their respective fields of medicine and aero-space engineering before bringing their impressive talents to the UT System.”

Charles LeMaistre, MDDr. LeMaistre is Professor of Inter-

nal Medicine who served as the fourth UT System chancellor, from 1971 to 1978. Under his leadership, the UT System expanded to include new health science centers in Houston and San Antonio and new universities in Dallas, Permian Basin and San Antonio.

Dr. LeMaistre has devoted much of his professional career to cancer prevention and smoking control. He served on the first U.S. Surgeon Gen-eral’s Advisory Committee on Smok-ing and Health in 1964, and later as the National President of the Ameri-can Cancer Society. He was President of UT MD Anderson Cancer Center from 1978 to 1996 and holds the title President Emeritus.

Hans Mark, PhDDr. Mark is a physicist and retired

Professor of Aerospace Engineering who served as the sixth Chancellor of

the University of Texas System from 1984 to 1992. He led the UT System to international prominence in engineer-ing and science, and played a prominent role in bringing the high-tech industry

to Austin and Central Texas.As Chancellor, he presided over a

major increase in federal and private funding for UT System institutions and was instrumental in bringing Pan Amer-

ican University into the UT System.Only two other chancellors, Harry

Huntt Ransom, PhD (1961–1971) and E. Don Walker (1978–1984), have been named Chancellor Emeritus. n

Charles LeMaistre, MD

Hans Mark, PhD

Primary Endpoint: • Objective response rate

Secondary Endpoints: • Duration of response

• Progression-free survival

• Overall survival

• Safety: incidence of adverse events

• Incidence of antitherapeutic antibodies to MPDL3280A

• Maximum serum concentration (Cmax) of MPDL3280A

Key Inclusion Criteria2: • Documented locally advanced or metastatic

transitional cell carcinoma of the urothelium

• Representative tumor specimens

• ECOG performance status of 0-1

• Life expectancy ≥12 weeks

• Measurable disease, as defined by RECIST v1.1

• Adequate hematologic and end-organ function

• Refractory or ineligible for platinum-based chemotherapy

Key Exclusion Criteria2: • History of autoimmune disease

• Active hepatitis B or hepatitis C

• HIV-positive

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1

• Prior treatment with CD137 agonists, or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

A Phase II study for patients with locally advanced or metastatic UBC who are treatment-naïve and

ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy

A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

MPDL3280A1

(an engineered anti-PDL1 antibody)

N=330

Now Enrolling

For more information

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

Visit: clinicaltrials.gov or

antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information

Support Line: 1-888-662-6728 (US only)

E-mail: [email protected]

© 2014 Genentech USA, Inc. All rights reserved. BIO0002591400 Printed in USA.

BLADDER

77659ha_f.indd 1 7/25/14 1:57 PM

http://www.biooncology.com


Expert’s Corner

Understanding the Impact of Results From CALGB/ SWOG 80405 and Other New Data in Colorectal CancerA Conversation With Alok A. Khorana, MD

The Cancer and Leukemia Group B (CALGB)/Southwest Oncology

Group (SWOG) 80405 trial, presented during the Plenary Session at this year’s ASCO Annual Meeting, demonstrated that cetuximab (Erbitux) and bevaci-zumab (Avastin) confer similar ben-efits as first-line treatment with chemo-therapy for KRAS wild-type metastatic colorectal cancer.1

The ASCO Post recently spoke to Alok A. Khorana, MD, Professor of Medicine, Cleveland Clinic Lerner Col-lege of Medicine, Case Western Reserve University; and Sondra and Stephen Hardis Chair in Oncology Research, Vice Chair of Clinical Services, and Di-rector of the GI Malignancies Program at Taussig Cancer Institute, Cleveland Clinic, about the study findings and its implications for clinical practice, as well as other important data in colorectal cancer presented at the Annual Meeting

Groundbreaking AbstractWhat’s your take on the CALGB/

SWOG 80405 study?CALGB/SWOG 80405 had to be

the most groundbreaking abstract on colorectal cancer presented at this year’s ASCO Annual Meeting, as reflected by its selection for the Plenary Session. The study took 10 years to complete and asked the question, “What’s the most appropriate first-line treatment in metastatic colorectal cancer?” The rea-son it took 10 years to complete is that in the first couple of years, new findings suggested that one of the arms should be dropped, so there was an amend-ment. Additional new findings a couple of years later suggested that only KRAS wild-type patients should be included, so there was a second amendment.

The study underwent several itera-tions before it arrived at the final design. In the end, it was a two-arm study of a

chemotherapy backbone, which was up to the physician, and random assign-ment to either cetuximab, an epidermal growth factor receptor (EGFR) inhibi-tor, or bevacizumab, a vascular endo-thelial growth factor (VEGF) inhibitor. It’s billed as a “negative” study because there was no difference in outcomes be-tween the two arms, but it does have a lot of relevance to clinical practice.

We’ve always wondered about the most appropriate first-line treatment in this setting, and the answer for right now is that it could be either one of these agents. The one downside of ce-tuximab is that there is increased skin toxicity, which was shown in this study as well. However, the skin toxicity did not seem to affect quality of life; the quality-of-life questionnaires were comparable between the two arms.

The second bit of good news from the study is that the median survival of cancer patients in this study was 29 months—that’s 2½ years. If you go back to the 1990s, the median survival was 12 months, and if you go back to the past decade, it was 20 or 22 months. So 29 months is a phenomenal improve-ment in median survival for patients with metastatic disease, and I think that is really something to be proud of for the gastrointestinal cancer community.

A third takeaway from CALGB/SWOG 80405 is that there are still find-ings to be made from this particular clinical trial. In just the past 6 months, we’ve discovered that there are addi-tional RAS mutations that might limit the benefit of cetuximab. Subgroup analysis is underway to find those RAS mutations in this population and to ex-clude those patients from the general effects observed in the study. That sub-group analysis may yet alter the conclu-sions of the trial.

So for now, you can use either cetux-imab or bevacizumab in first-line treat-

ment of KRAS wild-type metastatic colorectal cancer. Toxicities appear to be similar, median survival is close to 2½ years, and at 5 years, one-tenth of patients—almost 11% of the patients in this study—do not have cancer with metastatic disease.

Maintenance ChemotherapyWhat do the new data presented at the

Annual Meeting show with regard to the benefit of maintenance chemotherapy?

Once you get to about 6 months of therapy, most patients have too much drug-related toxicity and want to scale back their treatment. What options should be chosen at that time? Current-ly available options include the use of treatment holidays, in which you stop using drug therapy and follow those pa-tients. Alternatively, they can continue

on aggressive chemotherapy with more treatment combinations, or scale down chemotherapy to just one or two drugs with the biologic.

Multiple abstracts have dealt with these options, and they all point in the same direction: treatment holidays are probably not the best route.2,3 The type of maintenance therapy could be either fluorouracil (5-FU) or capecitabine with bevacizumab, or it could be beva-cizumab alone. The three approaches were not statistically significantly dif-ferent, but if you look at the absolute benefit, there is a clear benefit for the

two-drug combination of either 5-FU/bevacizumab or capecitabine/bevaci-zumab. For most patients, that is a gen-tler regimen.

So now that we’ve sorted out the first-line treatment, the maintenance portion is likely not treatment holiday but a combination of a 5-FU–based regimen with an antibody, probably bevacizumab.

Extended RAS TestingWhat do the data show on the use of

extended RAS testing?We’ve seen reports in the past cou-

ple of months looking at extended RAS testing, and up to 20% of patients—in one study, up to 30%—who we thought had wild-type disease and would bene-fit from an anti-EGFR approach, are no longer wild-type.4,5 Yet these patients have been getting an anti-EGFR anti-body, they have been experiencing the skin toxicity, and the costs to the system have been very expensive.

Data presented at this meeting, particularly the subgroup analysis of the OPUS6 and CRYSTAL7 large clinical trials all show that these pa-tients do not show benefit from anti-EGFR therapy, so the new standard of care should be that all metastatic colorectal cancer patients should be screened, not just for KRAS, which has been our standard for close to 10 years, but also with an extended RAS analysis, which includes NRAS and other codons of KRAS. n

Disclosure: Dr. Khorana is a consultant for and receives honoraria from Sanofi and Genentech.

References1. Venook AP, Niedzwiecki D, Lenz

H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucov-orin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-

Gastrointestinal Oncology

Three Takeaways in Colorectal Cancer From ASCO 2014

■ For first-line therapy, either cetuximab or bevacizumab offer improved median survival and long-term responses in patients with KRAS wild-type metastatic disease.

■ For maintenance therapy, switching to either 5-FU with or without bevacizumab, or bevacizumab alone—but not to a treatment holiday—appears appropriate.

■ Extended RAS analysis—not just KRAS screening—should be performed for all patients.


Alok A. Khorana, MD

For now, you can use either cetuximab or bevacizumab in first-line treatment of KRAS wild-type metastatic

colorectal cancer. Toxicities appear to be similar, median survival is close to 2½ years, and at 5 years, one-tenth of patients—almost 11% of the patients in [CALGB/SWOG 80405]—do not have cancer with metastatic disease.

—Alok A. Khorana, MD


Journal Spotlight

type untreated metastatic adenocarcino-ma of the colon or rectum. ASCO Annual Meeting. LBA3. Presented June 1, 2014.

2. Arnold D, Graeven U, Lerchen-muller CA, et al: Maintenance strategy with fluoropyrimidines (FP) plus bevaci-zumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): A phase III non-inferiority trial (AIO KRK 0207). ASCO Annual Meeting. Abstract 3503.

Presented June 2, 2014.3. Koopman M, Simkens L, May AM,

et al: Final results and subgroup analy-ses of the phase 3 CAIRO3 study: Main-tenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer. ASCO Annual Meeting. Abstract 3504. Presented June 2, 2014.

4. Tejpar S, Lenz HJ, Köhne CH, et al: Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus

FOLFOX4: New results from the OPUS study. 2014 Gastrointestinal Cancers Symposium. Abstract LBA444. Present-ed January 16, 2014.

5. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetux-imab or bevacizumab as first-line treat-ment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Con-gress. Abstract LBA17. Presented Sep-tember 28, 2013.

6. Bokemeyer C, Kohne CH, Ciardi-

ello F, et al: Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLF-OX4 with/without cetuximab. ASCO An-nual Meeting. Abstract 3505. Presented June 2, 2014.

7. Ciardiello F, Lenz HJ, Kohne CH, et al: Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOL-FIRI with/without cetuximab. ASCO Annual Meeting. Abstract 3506. Present-ed June 2, 2014.

CALGB/SWOG 80405continued from page 30

Systematic Model Identifies Factors Associated With Adherence in Prostate Cancer Prevention Trial

H ealthy men participating in the Prostate Cancer Prevention Trial

who actively participate in all steps of the clinical trial are most likely to un-dergo an end-of-study biopsy, accord-ing to a study published in Cancer Epi-demiology, Biomarkers and Prevention.1

The Prostate Cancer Prevention Trial was a randomized, double-blind, place-bo-controlled trial which tested the ef-ficacy of finasteride (Proscar).

Researchers at The University of Texas MD Anderson Cancer Center and the Fred Hutchinson Cancer Re-search Center used a systematic model to identify factors associated with men adhering to the end-of-study biopsy re-quirement of the trial.

“Our study is unique because it evaluated factors prospectively associ-ated with an invasive biopsy for a cancer prevention trial, not a cancer treatment

trial,” said Ellen R. Gritz, PhD, Chair of Behavioral Science at MD Anderson, and lead author on the study.

Study DetailsThe prevention trial was coordinated

by SWOG at 219 sites involving more

than 18,000 men. Participants were ran-domized into one of two groups; those administered finasteride and those giv-en a placebo. Participants received edu-cational materials about the study and biopsy procedures and were asked to at-tend regularly scheduled appointments throughout the trial.

Funded by the National Cancer In-stitute, scientists analyzed healthy men over a 7-year period to identify which factors at the 6-year study mark were associated with the willingness of the participant to undergo a biopsy. The factors examined included psychoso-

cial outcomes, participant health status, participant adherence, and character-istics of the clinical sites at which the study was conducted.

”The biopsy provided the biological specimens that could be tested to see if a man’s prostate cells were cancer-free after 7 years on the trial,” said Carol Moinpour, PhD, of the Fred Hutchin-son Cancer Research Center. “That is, the biopsy provided definitive informa-tion about which men had prostate can-cer 7 years after the study started.”

Factors Associated With Adherence

Researchers were able to assess fac-tors associated with adherence for more than 13,000 men from the trial, and an-alyzed factors based on whether or not study participants had been prompted for a clinical biopsy by year six of the study.

Researchers found participants were more likely to adhere to the end-of-study biopsy if 1 year prior to the biopsy they were adherent to the study drug, kept appointments, and underwent re-quired tests and were in good health. Participants who had an end of study biopsy were more likely to be adher-ent to the study drug at year six (84%). Among participants who were not bi-opsied, 47% were adherent to the study drug. Results also showed that 98% of men who had an end-of-study biopsy had the digital rectal exam or PSA test done at year six, compared to 75% of

men who did not have the end-of-study biopsy.

“We also found that participants were more likely to adhere to biop-sies if the study site that recruited the participant enrolled more than 200 participants and/or had resources for conducting activities to encourage con-tinued participation in the trial,” said Dr. Gritz.

Researchers said monitoring adher-ence behaviors in clinical trial partici-pants can help identify participants at risk for noncompliance to a study re-quirement, and help create a model for adherence intervention strategies in fu-ture trials.

“If we are able to determine which factors are associated with good adher-ence to study regimens evaluating can-cer prevention agents, we may be able to improve the conduct of such large tri-als by targeting interventions to boost adherence,” said Dr. Gritz. n

Disclosure: The research was supported by the Public Service Health (CA37429) from the Department of Cancer Prevention, National Cancer Institute (NCI), NIH, Department of Health and Human Services. Lead author supported in part by funding from NCI (P30CA16672).

Reference1. Gritz ER, Arnold KB, Moinpour CM,

et al: Factors associated with adherence to an end-of-life biopsy: Lessons from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23:1638-1648, 2014.

If we are able to determine which factors are associated with good adherence to study regimens evaluating cancer prevention agents, we may be able to improve the conduct of such large trials by targeting interventions to boost adherence.

—Ellen R. Gritz, PhD

Genitourinary Oncology


FDA Update

FDA Approves First Noninvasive DNA Screening Test for Colorectal Cancer

The U.S. Food and Drug Adminis-tration (FDA) has approved Co-

loguard, the first stool-based colorectal screening test that detects the presence of red blood cells and DNA mutations that may indicate the presence of cer-tain kinds of abnormal growths that may be cancers such as colon cancer or precursors to cancer.

Using a stool sample, Cologuard detects hemoglobin and certain muta-tions associated with colorectal cancer in the DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients

with positive test results are advised to undergo a diagnostic colonoscopy.

Clinical Trial ResultsThe safety and effectiveness of Co-

loguard was established in a clinical trial that screened 10,023 subjects.

The trial compared the performance of Cologuard to the fecal immunochemi-cal test, a commonly used noninvasive screening test that detects blood in the stool. Cologuard accurately detected cancers and advanced adenomas more often than the fecal immunochemical

test: 92% of colorectal cancers and 42% of advanced adenomas were de-tected with stool DNA testing com-pared with 74% of cancers and 24% of advanced adenomas detected with fe-cal immunochemical testing.

Cologuard was less accurate than

FDA Grants Fast Track Designation to Novel JAK2 Inhibitor for the Treatment of Myelofibrosis

The U.S. Food and Drug Admin-istration has granted Fast Track

designation to pacritinib for the treat-ment of intermediate- and high-risk myelofibrosis, including patients with disease-related thrombocytopenia on other JAK2 therapy or patients who are intolerant to or whose symptoms are suboptimally managed on other JAK2 therapy.

Pacritinib is an oral tyrosine kinase inhibitor with dual activity against JAK2 and FLT3.

Expedited ReviewThe Fast Track process is designed

to facilitate the development and ex-pedite the review of drugs to treat serious conditions and fill an unmet medical need.

Pacritinib is currently being evalu-ated in two phase III clinical investi-gations: the PERSIST-1 trial, which includes a broad set of patients without limitations on blood plate-let counts, and the PERSIST-2 trial, which is limited to patients with low platelet counts. n

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1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patients at risk:COMETRIQ® 219 121 78 55 31 12 2 1 Placebo 111 35 11 6 3 2 0 0

Months

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PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

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COMETRIQ® (n=219)Placebo (n=111)

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PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• Perforations and Fistulas: Gastrointestinal perforations

occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”


FDA Update

fecal immunochemical testing at cor-rectly identifying subjects negative for colorectal cancer or advanced adeno-mas. The stool DNA test correctly gave a negative screening result for 87% of the study subjects, while the fecal im-munochemical test provided accurate negative screening results for 95% of the study population.

Proposed CMS CoverageUpon the test’s approval, the

Centers for Medicare & Medicaid Services (CMS) issued a proposed national coverage determination for Cologuard. Cologuard is the first product reviewed through a joint FDA-CMS pilot program known as parallel review, where the agencies

concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medi-care coverage.

“Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as 6 months from the time from study initiation to coverage,” said

Nancy Stade, Deputy Director for Policy at the FDA’s Center for Devices and Radiological Health.

CMS proposes to cover the Colo-guard test once every 3 years for Medi-care beneficiaries who are age 50 to 85 years, asymptomatic, and have an average risk of developing colorectal cancer. n

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Months

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PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patientsat risk:COMETRIQ® 219 121 78 55 31 12 2 1Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

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ient

s w

ho a

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4.0 11.2months

median

months

median

COMETRIQ® (n=219)Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• Perforations and Fistulas: Gastrointestinal perforations

occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”

http://www.cometriq.com/hcp/index.php


FDA Update

FDA Approves Bevacizumab for Aggressive and Late-Stage Cervical Cancer

The U.S. Food and Drug Administra-tion (FDA) has approved the anti-

angiogenic agent bevacizumab (Avastin) for the treatment of persistent, recurrent, or metastatic cervical cancer. The new indication is approved for use in com-bination with paclitaxel and cisplatin or

paclitaxel and topotecan. The FDA re-viewed bevacizumab for the treatment of patients with cervical cancer under its priority review program.

“[Bevacizumab] is the first drug ap-proved for patients with late-stage cer-vical cancer since the 2006 approval of

topotecan with cisplatin,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is also the first biologic agent approved for patients with late-stage cervical cancer and was approved in

less than 4 months under the FDA’s pri-ority review program, demonstrating the agency’s commitment to making promis-ing therapies available to patients faster.”

Clinical Trial ResultsThe approval was based on the results

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COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ.2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:• If previously receiving 140-mg daily dose, resume treatment at 100 mg

daily (one 80-mg and one 20-mg capsule)• If previously receiving 100-mg daily dose, resume treatment at 60 mg daily

(three 20-mg capsules)• If previously receiving 60-mg daily dose, resume at 60 mg if tolerated,

otherwise, discontinue COMETRIQPermanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers: Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 63 16 33 2

STOMATITIS2 51 5 6 0

NAUSEA 43 1 21 0

ORAL PAIN3 36 2 6 0

CONSTIPATION 27 0 6 0

ABDOMINAL PAIN4 27 3 13 1

VOMITING 24 2 2 1

DYSPHAGIA 13 4 6 1

DYSPEPSIA 11 0 0 0

HEMORRHOIDS 9 0 3 0

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

RASH 19 1 10 0

DRY SKIN 19 0 3 0

ALOPECIA 16 0 2 0

ERYTHEMA 11 1 2 0

HYPERKERATOSIS 7 0 0 0

VASCULAR DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

of therapy. Infertility: There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 3-4

CHEMISTRIES

INCREASED AST 86 3 35 2

INCREASED ALT 86 6 41 2

INCREASED ALP 52 3 35 3

HYPOCALCEMIA 52 12 27 3

HYPOPHOSPHATEMIA 28 3 10 1

HYPERBILIRUBINEMIA 25 2 14 5

HYPOMAGNESEMIA 19 1 4 0

HYPOKALEMIA 18 4 9 3

HYPONATREMIA 10 2 5 0

HEMATOLOGIC

LYMPHOPENIA 53 16 51 11

NEUTROPENIA 35 3 15 2

THROMBOCYTOPENIA 35 0 4 3

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54

Stage 1: Systolic ≥140 mmHg or Diastolic ≥90 mmHg

46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3Subjects with at least two blood pressure measurements after the first dose.

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ.8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D.Risk Summary: Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion


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FDA Update

FDA Approves Bortezomib Retreatment in Patients With Multiple Myeloma

The U.S. Food and Drug Administra-tion has approved bortezomib (Vel-

cade) for the retreatment of adult patients with multiple myeloma who had previ-ously responded to bortezomib therapy and relapsed at least 6 months following completion of prior bortezomib treat-ment. The labeling update includes dos-ing guidelines as well as safety and efficacy findings for single-agent use or use in in combination with dexamethasone in pa-tients previously treated with bortezomib. Bortezomib retreatment may be started at the last tolerated dose.

RETRIEVE TrialThe approved retreatment supplemen-

tal New Drug Application consisted of a phase II study and other supportive data. The phase II international RETRIEVE trial was a single-arm, open-label trial en-rolling 130 adult patients with myeloma who had previously responded to bort-ezomib-based therapy and relapsed at least 6 months after prior treatment with bortezomib. Patients received a median of two prior therapies, and dexamethasone was administered in combination with bortezomib in 94 patients.

The RETRIEVE trial showed an over-all response rate of 38.5%, with one pa-tient achieving complete response and 49 achieving partial response. In the 50 responding pateints, the median dura-tion of response was 6.5 months (range, 0.6–19.3 months).

The safety profile seen with bortezo-mib retreatment was consistent with the known safety profile of intravenous bort-ezomib in relapsed multiple myeloma; no cumulative toxicities were observed upon retreatment.

See page 36 for a comprehensive sum-mary of bortezomib retreatment. n

of an international, randomized trial en-rolling 452 patients with persistent, recur-rent, or metastatic disease. Patients were randomly assigned to receive paclitaxel and cisplatin with or without bevacizumab or paclitaxel and topotecan with or with-out bevacizumab. Treatment continued until disease progression, unacceptable toxicity, and/or withdrawal of consent.

Results demonstrated a statistically significant improvement in overall sur-vival in patients who received bevacizum-ab and chemotherapy vs chemotherapy alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.58–0.94, P = .013, log-rank test). The median overall survival of patients receiving bevacizum-ab and chemotherapy was 16.8 months

(95% CI = 14.1–19) vs 12.9 months (95% CI = 10.9–15) for those receiving chemotherapy alone.

The most common side effects associ-ated with use of bevacizumab in patients with cervical cancer include fatigue, de-creased appetite, hypertension, hypergly-cemia, hypomagnesemia, urinary tract in-fection, headache, and decreased weight.

Gastrointestinal perforations (3.2%) and gastrointestinal-vaginal fistulae (8.2%) were also observed in bevacizum-ab-treated patients, all of whom had prior pelvic radiation. Other grade 3 or greater adverse reactions that were more com-mon in patients receiving chemothera-py plus bevacizumab included venous thromboembolic events, hemorrhage, hypertension, proteinuria, and wound-healing complications. n

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COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ.2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:• If previously receiving 140-mg daily dose, resume treatment at 100 mg

daily (one 80-mg and one 20-mg capsule)• If previously receiving 100-mg daily dose, resume treatment at 60 mg daily

(three 20-mg capsules)• If previously receiving 60-mg daily dose, resume at 60 mg if tolerated,

otherwise, discontinue COMETRIQPermanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers: Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 63 16 33 2

STOMATITIS2 51 5 6 0

NAUSEA 43 1 21 0

ORAL PAIN3 36 2 6 0

CONSTIPATION 27 0 6 0

ABDOMINAL PAIN4 27 3 13 1

VOMITING 24 2 2 1

DYSPHAGIA 13 4 6 1

DYSPEPSIA 11 0 0 0

HEMORRHOIDS 9 0 3 0

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

RASH 19 1 10 0

DRY SKIN 19 0 3 0

ALOPECIA 16 0 2 0

ERYTHEMA 11 1 2 0

HYPERKERATOSIS 7 0 0 0

VASCULAR DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

of therapy. Infertility: There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 3-4

CHEMISTRIES

INCREASED AST 86 3 35 2

INCREASED ALT 86 6 41 2

INCREASED ALP 52 3 35 3

HYPOCALCEMIA 52 12 27 3

HYPOPHOSPHATEMIA 28 3 10 1

HYPERBILIRUBINEMIA 25 2 14 5

HYPOMAGNESEMIA 19 1 4 0

HYPOKALEMIA 18 4 9 3

HYPONATREMIA 10 2 5 0

HEMATOLOGIC

LYMPHOPENIA 53 16 51 11

NEUTROPENIA 35 3 15 2

THROMBOCYTOPENIA 35 0 4 3

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54


46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3Subjects with at least two blood pressure measurements after the first dose.

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ.8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D.Risk Summary: Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion


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In the Clinic

Bortezomib Retreatment in Multiple MyelomaBy Matthew Stenger

On August 8, 2014, the approved use of bortezomib (Velcade) in

multiple myeloma was expanded to include bortezomib retreatment in pa-tients who have previously responded to bortezomib and who relapsed at least 6 months after completing prior bortezomib treatment.1 Retreatment may be started at the last tolerated dose. The drug labeling has been updated to include dosing recommendations and retreatment safety and efficacy data. Bortezomib was previously approved for treatment of patients with multiple myeloma and for treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Supporting StudyApproval of retreatment was based

on observation of durable responses in a single-arm phase II study in 130 adult patients who had achieved at least partial response on a prior bortezomib-containing regimen.1,2 Patients had received a median of two prior lines

of therapy (range, 1–7). Patients with peripheral neuropathy or neuropathic pain of grade ≥ 2 were excluded from the study. Treatment was restarted at ≥ 6 months after prior bortezomib treatment at the last tolerated dose of 1.3 mg/m2 (n = 93) or ≤ 1.0 mg/m2 (n = 37) given intravenously on days 1, 4, 8, and 11 every 3 weeks for a maxi-mum of eight cycles with or without dexamethasone. Overall, 83 patients re-ceived dexamethasone in cycle 1 and an additional 11 received it in later cycles.

European Group for Blood and Marrow Transplantation responses (49 partial and 1 complete) were ob-served in 50 patients (overall response rate = 38.5%, 95% confidence interval = 30.1%–47.4%). Median duration of response in responders was 6.5 months (range, 0.6–19.3 months).

How It Is GivenThe recommended starting dose of

bortezomib in multiple myeloma is 1.3 mg/m2. It can be given intravenously at a concentration of 1 mg/mL or sub-cutaneously at a concentration of 2.5 mg/mL.

Bortezomib retreatment can be start-ed at the last tolerated dose and should be given twice weekly on days 1, 4, 8, and 11 every 3 weeks for a maximum of eight cycles. Consecutive doses should be separated by > 72 hours. Bortezomib

can be administered as a single agent or in combination with dexamethasone.

Safety in RetreatmentThe most commonly reported ad-

verse events (incidence ≥ 20%) in clinical studies of bortezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

The safety profile of bortezomib in the study supporting retreatment was consistent with the known safety pro-file of the drug in patients with relapsed multiple myeloma. No cumulative tox-icities were observed with retreatment.

The most common adverse event of any grade was thrombocytopenia, which occurred in 52% of patients; grade ≥ 3 thrombocytopenia occurred in 24%. Pe-ripheral neuropathy occurred in 28% of

patients and was of grade ≥ 3 in 6%. Serious adverse events occurred in

12.3% of patients, with the most common being thrombocytopenia (3.8%), diar-rhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events led to discontinuation of treatment in 13%, with reasons including peripheral neuropathy (5%) and diarrhea (3%). Deaths consid-ered to be drug-related occurred in two patients, one due to cerebrovascular acci-dent and one due to sepsis, within 30 days of the last bortezomib dose.

Bortezomib carries warnings/pre-cautions for peripheral neuropathy,

cardiac toxicity, pulmonary toxic-ity, posterior reversible encephalopa-thy syndrome, gastrointestinal toxicity, thrombocytopenia and neutropenia, tumor lysis syndrome, hepatic toxicity, and embryo-fetal risk. n

References1. VELCADE® (bortezomib) for injec-

tion prescribing information, Millennium Pharmaceuticals, Inc, August 2014. Avail-able at www.velcade.com/files/pdfs/vel-cade_prescribing_information.pdf.

2. Petrucci MT, Giraldo P, Corradini P, et al: A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Hae-matol 160:649-659, 2013.

Hematology

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, admin-istration recommendations, safety profiles, and other essential infor-mation needed for the appropriate clinical use of these drugs.

Expanded Use of Bortezomib in Multiple Myeloma

■ The approved use of bortezomib (Velcade) now includes retreatment in patients with multiple myeloma who previously responded to bortezomib and relapsed at ≥ 6 months after completing prior bortezomib treatment.

■ Bortezomib retreatment can be started at the last tolerated dose and should be given twice weekly on days 1, 4, 8, and 11 every 3 weeks for a maximum of eight cycles.

OF NOTEThe most commonly reported ad-verse events associated with bort-ezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, con-stipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

OF NOTENo cumulative toxicities have been observed with bortezomib retreat-ment.

Report Adverse EventsHealth-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2ndLoews Royal Pacific Hotel at Universal Orlando, FL

apsho.org/jadprolive

For Your NPs and PAs


Advances in Hematopoietic Cell Transplant for Pediatric AML Reduce Toxicity and Expand Access, but Relapse Remains a Problem By Charlotte Bath

Advances in allogeneic hematopoi-etic cell transplantation for children

with acute myeloid leukemia (AML) have resulted in less toxic pretransplant condi-tioning regimens and expanded access to transplantation, but post-treatment leu-kemic relapse remains a big problem. The progress and continuing challenges were outlined at the opening Plenary Session of the second annual joint educational meet-ing of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and the American Society of Pediatric Hema-tology Oncology (ASPHO) in Chicago.

Better Conditioning Regimens“One of the real successes” in using

hematopoietic cell transplant for children with AML has been in developing better conditioning regimens and the “reduc-tion in regimen-related toxicity,” noted John Horan, MD, Associate Professor of Pediatrics at Emory University School of Medicine in Atlanta. He reviewed the pro-gression of conditioning regimens from total-body irradiation plus cyclophospha-mide in the 1970s and 1980s, to oral bu-sulfan (Myleran) and cyclophosphamide in the 1990s, and thereafter to intravenous busulfan (Busulfex)/cyclophosphamide. A 2013 study demonstrated the superior-ity of intravenous busulfan/cyclophospha-mide over earlier regimens, showing sig-nificantly less nonrelapse mortality, a lower relapse rate at 1 year or more post-trans-plant, and better leukemia-free survival.1

A myeloablative regimen of intrave-nous busulfan and fludarabine has been associated with reduced toxicity but with survival and nonrelapse mortality similar to intravenous busulfan/cyclo-phosphamide. This combination is being investigated in clinical trial AAML 1031. A myeloablative regimen of high-dose treosulfan (an investigational alkylat-ing agent) plus fludarabine also showed reduced toxicity and a low incidence of transplant-related mortality2 and is being studied in PBMTC ONC1101.

“Thought-provoking results” were provided by a study comparing reduced-intensity conditioning regimens and my-eloablative conditioning in children with AML undergoing allogeneic hematopoi-etic cell transplant.3 However, no signifi-cant differences in overall survival, dis-ease-free survival, relapse, or nonrelapse mortality were seen, Dr. Horan reported.

Trials using unrelated donors to expand access to transplantation have shown improvements in outcomes over

time. Reductions in transplant-related mortality have been achieved through better human leukocyte antigen (HLA) matching, less toxic conditioning, and

enhanced supportive care, Dr. Horan observed. Survival with well-matched unrelated donors is approaching that with matched related donors, he added.

Major ChallengeRelapse is “probably the biggest prob-

lem facing us,” Dr. Horan stated. There

ASPHO Annual MeetingHematology


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has been “no obvious decrease in relapse over the past 2 decades,” he pointed out, and gains in survival have been more modest than reductions in transplant-related mortality.

“Relapse is the major challenge,” agreed John Perentesis, MD, Director of the Division of Oncology and Can-cer Programs at Cincinnati Children’s Hospital Medical Center. “Between one-quarter and one-third of patients strug-gle with relapse,” he said.

Important strategies being tested to prevent relapse after bone mar-row transplant include enhancing the graft-vs-leukemia effect and targeted post-transplant chemotherapy with sorafenib (Nexavar) for FLT3-mutated blasts, and hypomethylating agents such as decitabine and azacitidine.

At high doses, decitabine and azaciti-dine “work like not very good chemo-therapeutic drugs,” Dr. Perentesis said. “They have cytotoxicity. They kill the tumor cells, but they also produce a lot of toxicity to normal cells.” At low doses, they appear to reactivate cellular growth regulatory pathways, and potentially in-hibit leukemic stem cell self-renewal and sensitivity to cytotoxic therapies.

In a recent small series of pediatric relapsed AML patients, three of eight patients achieved some form of a com-plete response with low-dose decitabine therapy,4 and several adult studies have indicated feasibility of post-SCT “main-tenance” regimens incorporating low-dose decitabine or panobinostat (a his-tone deacetylase inhibitor).

Newer epigenetic modulators with potentially high-specificity targeting of

the pathologic DOT1L-MLL axis in in-fant mixed-lineage leukemias or altered EZH2 activity in leukemia are under ac-tive investigation in pediatric AML, with the novel experimental drugs EPZ-5676 and EPZ-6438, respectively.

Surface Antigen– Targeted Therapies

Targeted agents are being used for AML in the transplant setting to both reduce minimal residual disease and ad-dress the problem of post-transplant re-lapse. One of the challenges is that “AML stem cells share features of hematopoietic progenitors that lead to drug resistance…. AML has a robust system to protect itself from toxic products such as chemothera-peutic agents,” Dr. Perentesis noted.

“CD33 is an AML cell surface target,

one of several that has been of great in-terest. It is a good marker with signifi-cant expression of AML blasts, and it is also probably associated with prognos-tic risk factors,” Dr. Perentesis stated.

He cited a study that assessed CD33 expression levels by flow cytometry and found expression in over 99% of AML samples from adult patients. The study also found that targeting CD33 ex vivo us-ing AMG 330, a CD33/CD3-bispecific T-

cell engaging (BiTE) antibody, in primary AML samples led to T-cell recruitment and expansion, as well as highly potent antibody-mediated cytotoxicity, suggest-ing efficient therapeutic potential in vivo.5

Findings from another preclinical study cited by Dr. Perentesis suggest that SGN-CD33A, a novel CD33-tar-geting antibody-drug conjugate, “has CD33-directed antitumor activity and

support clinical testing of this novel therapeutic in patients with AML.”6

This is an exciting time for new pros-pects to treat AML, as dozens of targeted drugs are in development, Dr. Perentesis said. These include next-generation drugs targeting FLT3-ITD and poten-tial specificity against resistance muta-tions, new agents targeting the c-Kit and RAS/MEK axes, small molecules with more effective inhibition of the mTOR

pathway, and new BLC2 inhibitors en-gineered to minimize throbocytopenia. “We’ve thought about targetable path-ways for a long time,” he noted in clos-ing, but cautioned, “it is likely that you actually have to hit the target directly.” n

Disclosure: Drs. Horan and Perentesis reported no potential conflicts of interest.

References1. Copelan EA, Hamilton BK, Avalos

B, et al: Better leukemia-free and overall survival in AML in first remission follow-ing cyclophosphamide in combination with busulfan compared with TBI. Blood 122:3863-3870, 2013.

2. Nemecek ER, Guthrie KA, Sorror ML, et al: Conditioning with treosulfan and fluda-rabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17:341-350, 2011.

3. Bitan M, He W, Zhang MJ, et al: Trans-plantation for children with acute myeloid leukemia: A comparison of outcomes with re-duced intensity and myeloablative regimens. Blood 123:1615-1620, 2014.

4. Phillips CL, Davies SM, McMasters R, et al: Low dose decitabine in very high risk re-lapsed or refractory acute myeloid leukaemia in children and youg adults. Br J Haematol 161:406-410, 2013.

5. Krupka C, Kufer P, Kischel, R, et al: CD33 target validation and sustained deple-tion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood 123:356-365, 2014.

6. Kung Sutherland MS, Walter RB, Jeffrey SC, et al: SGN-CD33A: A novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is ac-tive in models of drug-resistant AML. Blood 122:1455-1463, 2013.

ASPHO Annual Meeting

Hematopoietic Cell Transplantcontinued from page 37

One of the real successes in using hematopoietic cell transplantation for children with AML has been in developing better conditioning regimens and the reduction in regimen-related toxicity.

—John Horan, MD

Protocol Modifications Decrease Toxicity, Increase Event-Free Survival in Children With Down Syndrome Treated for ALLBy Charlotte Bath

P rotocol modifications to address increased risk of toxicity and ex-

cess early mortality among children with Down syndrome being treated for B-cell acute lymphoblastic leukemia (ALL) proved safe for patients with Down syndrome, and these patients had event-free survival similar to those without Down syndrome. Overall sur-vival, however, was still significantly inferior among children with Down syndrome. The results of a study com-paring two Children’s Oncology Group (COG) clinical trials were summarized by lead author Kelly W. Maloney, MD,

Associate Professor, Pediatrics-Hema-tology/Oncology, Children’s Hospital Colorado in Aurora, at the 27th An-nual Meeting of the American Society of Pediatric Hematology Oncology (ASPHO) in Chicago.

The study was one of two “particu-larly outstanding” abstracts chosen from among 400 submitted abstracts for pre-sentation at the meeting’s Plenary Ses-sion, noted ASPHO’s then-President, A. Kim Ritchey, MD. He is Vice Chair of Clinical Affairs, Department of Pedi-atrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center.

More Therapy-Related Toxicities

“Children with Down syndrome and acute lymphoblastic leukemia have more toxicities related to their therapy, and this has been pretty well document-ed and published,” Dr. Maloney noted. These include grade 2–4 gastrointesti-nal toxicities, grade 3–4 hematologic toxicities, and infections. “In general most of the protocols have shown an increase in infections, sometimes sig-nificantly increased over those without Down syndrome undergoing compara-ble treatment,” Dr. Maloney continued.

Children with Down syndrome and ALL have “increased mortality during induction, but they are also more likely to suffer death after obtaining remis-sion,” Dr. Maloney said. The mortality rate “can be as high as 28% vs a more standard 2% to 3%, and perhaps even lower in those children who do not have Down syndrome. There is an increased risk of death from relapse as well.”

Excessive Induction MortalityCOG trial ALL0232, a phase III trial

for patients with high-risk ALL, was a

Hematology


John Perentesis, MD

A phase III study of the CDK4/6 inhibitor LEE011 in combination with letrozole for the treatment of postmenopausal women with advanced breast cancer

NOW ENROLLING – A RANDOMIZED PHASE III STUDY

Screeningassessments

Randomization(1:1)

Letrozole 2.5 mg QD + LEE011 600 mg QD

Letrozole 2.5 mg QD+ placebo QD

Primary end point: Progression-free survivalKey secondary end point: Overall survival

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available.

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

Novartis Pharma AGCH-4002 Basel, Switzerland © Novartis 2014 March 2014 G-PIP-1084431

Novartis Pharmaceuticals CorporationEast Hanover, NJ 07936-1080

Postmenopausal women with HR+/HER2– advanced breast cancer

No prior systemic anticancer therapy for advanced disease

ECOG performance status 0 or 1

Additional inclusion/exclusion criteria apply.

For more information• Contact your local Novartis medical representative

• Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

• Visit www.clinicaltrials.gov (NCT01958021)

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

A phase III study of the CDK4/6 inhibitor LEE011 in combination with letrozole for the treatment of postmenopausal women with advanced breast cancer

NOW ENROLLING – A RANDOMIZED PHASE III STUDY

Screeningassessments

Randomization(1:1)

Letrozole 2.5 mg QD + LEE011 600 mg QD

Letrozole 2.5 mg QD+ placebo QD

Primary end point: Progression-free survivalKey secondary end point: Overall survival

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available.

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

Novartis Pharma AGCH-4002 Basel, Switzerland © Novartis 2014 March 2014 G-PIP-1084431

Novartis Pharmaceuticals CorporationEast Hanover, NJ 07936-1080

Postmenopausal women with HR+/HER2– advanced breast cancer

No prior systemic anticancer therapy for advanced disease

ECOG performance status 0 or 1

Additional inclusion/exclusion criteria apply.

For more information• Contact your local Novartis medical representative

• Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

• Visit www.clinicaltrials.gov (NCT01958021)

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

http://www.novartisoncology.com/index.jsp



randomized comparison of 28 days of prednisone vs 14 days of dexametha-sone during induction, and high-dose methotrexate with leucovorin rescue vs escalating intravenous methotrexate without rescue plus pegaspargase (On-caspar) using the Capizzi schedule in interim maintenance.

“As planned from the beginning, pa-

tients with Down syndrome participated in the induction steroid randomization, but were not randomly assigned to high-dose methotrexate, but were nonran-domly assigned to Capizzi methotrex-ate,” Dr. Maloney said. This trial enrolled 3,084 patients, 39 with Down syndrome.

COG trial ALL0331 enrolled 5,311 patients with standard-risk ALL, 140 with Down syndrome. The trial used a three-drug induction with dexa-methasone for 28 days, vincristine, and pegaspargase. Children with Down syndrome participated in the postin-duction randomization to intensified vs standard consolidation, with Capizzi methotrexate as interim maintenance.

“Both studies experienced excessive induction mortality for children with

[Down syndrome] initially and were modified with expanded supportive care guidelines and leucovorin rescue after intrathecal methotrexate. These modifi-cations successfully eliminated excessive mortality on AALL0331. However, ex-cessive mortality persisted in [high-risk

Down syndrome] ALL on AALL0232 and enrollment to this protocol was halt-ed in 2008,” according to the abstract.

Collective ResultsLooking at the studies collectively

shows that children with Down syn-drome had lower 5-year event-free sur-vival and higher morality. Event-free survival for both studies was 80% ± 4% for patients with Down syndrome vs 84.3% ± 0.6% (P = .059) for those without Down syndrome, and overall survival was 82.8% ± 3.8% vs 92.2% ± 0.4% (P < .0001), respectively.

Looking at the studies individu-ally confirms that children with Down syndrome had lower event-free and overall survival than those without Down syndrome, but also shows that children with Down syndrome receiv-ing the modified protocol had better 5-year event-free survival than those in the original protocol (86.1% ± 4.2% vs 57.8% ± 8.4%), and better 5-year over-all survival (89.2% ± 3.8% vs 60.3% ± 8.3%). With the modified protocol, the 5-year event-free survival was similar for children with and without Down syndrome (86.1% ± 4.2% vs 89.5% ± 0.6%, P = .102), but overall survival was significantly inferior (89.2% ± 3.8% vs 96.1% ± 0.4%, P < .0001).

On trial AALL0331, “the induction

mortality dropped to 1.7%, which was in line with all the past standard-risk tri-als and we felt was very acceptable, and postinduction, we did not have any remis-sion deaths,” Dr. Maloney said. “We have a similar event-free survival in the Down syndrome children and non–Down syn-drome children. We can deliver this ther-apy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and prob-ably additional attention,” she noted. n

Disclosure: Dr. Maloney reported no potential conflicts of interest.

Reference1. Maloney K, Larsen E, Devidas M, et

al: Event free (EFS) and overall survival (OS) for children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL) in Children’s Oncology Group (COG) clinical trials AALL0232 and AALL0331. ASPHO Annual Meeting. Ab-stract 4009. Presented May 15, 2014.

Children With Down Syndrome and ALLcontinued from page 38

We have a similar event-free survival in the Down syndrome children and non–Down syndrome children. We can deliver this therapy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and probably additional attention.

—Kelly W. Maloney, MD

A. Kim Ritchey, MD

Best Way to Treat Mediastinal Lymphomas Is Still UnclearBy Susan London

A variety of treatment options used today can achieve good

outcomes in patients with mediasti-nal lymphomas, according to James O. Armitage, MD, the Joe Shapiro Professor of Medicine at the Univer-sity of Nebraska Medical Center in Omaha. He discussed some of the current evidence helping to refine the management of primary mediastinal large B-cell lymphoma and medias-tinal gray zone lymphoma at the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii.

Primary Mediastinal Large B-Cell Lymphoma

“Mediastinal B-cell lymphoma is a unique entity…. It really is different from the rest of the diffuse large B-cell lymphomas,” Dr. Armitage pointed out.1 This tumor initially caught atten-tion in part because of its distinct sur-vival pattern, with nearly all relapses after remission occurring within 3 years. “In this disease, patients either

get over it—and you know that in a rel-atively short period of time—or they succumb, and unfortunately, salvage therapy has not always been as effec-tive as we would like. So it’s different from other large B-cell lymphomas,” he elaborated.

When it comes to treatment, a retro-spective analysis of data from patients treated in Vancouver, British Colum-bia, found that CHOP-R (cyclophos-phamide, doxorubicin, vincristine, and prednisone, with rituximab [Rituxan]) was superior to CHOP alone with re-spect to 5-year overall survival (88% vs 70%).2 Outcomes did not differ signifi-

cantly between patients who did vs did not routinely get radiotherapy (82% vs 89%). Among patients undergoing positron-emission tomography (PET)

at the end of CHOP-R, survival was statistically indistinguishable for the PET-positive group given radiother-apy and the PET-negative group not given radiotherapy (95% vs 89%).

“It looks like this certainly would provide an argument that if you want to use CHOP-R, you do a PET scan at the end, and if patients are PET-nega-tive, you can follow them, and you end up with roughly a 90% survival, rather than giving radiotherapy to all of these patients. This would be one way to

Hematology

Is there only one way to treat mediastinal large B-cell lymphoma? I think the answer is no.

—James O. Armitage, MD

Table 1: Deauville 5-Point Criteria for PET Scans

1. No uptake

2. Uptake ≤ mediastinum

3. Uptake, but at lower value than in mediastinal blood pool

4. Uptake moderately more than liver uptake, at any site

5. Markedly increased uptake at any site and new site of disease

Source: André M, et al: Advances in Hematology, 2011. continued on page 41



A Cautionary Note on Radiotherapy

C linicians should use radiotherapy very judiciously in the treatment of mediastinal lymphomas, especially in young patients, recommended

Wyndham H. Wilson, MD, PhD, Chief of the Hematological Malignancies Therapeutics Section, Metabolism Branch, Cancer Research Center, of the National Cancer Institute in Bethesda, Maryland., Moreover, longer-term data suggest the prognosis of mediastinal gray zone lymphomas may not be as poor as previously thought in the absence of radiotherapy, he said at the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii

Who Needs Radiotherapy?“It still stands that they have a significantly worse outcome than that associ-

ated with primary mediastinal lymphoma. We still watch them very carefully, and we find that if the Deauville score is 1, 2, or 3, that those people almost never relapse, but if it’s more than that, then radiation is needed,” he said.

“I think it is an open question whether or not you want to give all of these patients radiotherapy. I would agree that they do the worst, and if you re-ally want to be extra cautious, then you certainly could radiate them all,” he continued. “But as it turns out, the Deauville score is a pretty good way of identifying those with gray zone lymphoma who really need radiation.”

Recent long-term data on patients receiving radiotherapy for Hodgkin lymphoma are “devastating,” Dr. Wilson maintained. “I just wanted to em-phasize that radiotherapy in young people is dangerous, dangerous, danger-ous. And if there is anything you can do to not use it, I think that would be really wise,” he concluded. n

Disclosure: Dr. Wilson reported no potential conflicts of interest.

I just wanted to emphasize that radiotherapy in young people is dangerous, dangerous, dangerous. And if there is anything you can do to not use it, I think that would be really wise.

—Wyndham H. Wilson, MD, PhD


try to avoid giving radiotherapy,” Dr. Armitage noted.

The German MINT (MabThera International Trial Group) study com-pared CHOP-like chemotherapy with vs without rituximab in patients with diffuse large B-cell lymphoma, with radiotherapy added for most patients.3 In an analysis looking at tumor sub-types, the 87 patients with mediastinal large B-cell lymphoma had a poorer complete response rate if they did not receive rituximab, and rituximab also yielded a better 5-year overall survival (78% vs 90%).4

A retrospective analysis by the In-ternational Extranodal Lymphoma Study Group assessed the prognostic value of various PET cutoffs among patients with mediastinal large B-cell lymphoma who had been treated with rituximab and anthracycline-contain-ing chemoimmunotherapy, and usu-ally also radiotherapy.5 The best dis-crimination was seen for a Deauville score of 1, 2, or 3 vs a Deauville score of 4 or 5 (Table 1); this cutoff yielded a 99% negative predictive value for pro-gression or relapse.

“Remember, PET scans are much more valuable in terms of negative predictive value than positive predic-tive value. When a PET scan is posi-tive, there are more things than just lymphoma that can be causing it…. But a negative PET scan is more prog-nostic,” Dr. Armitage noted.

Finally, a study of patients with me-

diastinal B-cell lymphoma treated with dose-adjusted EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and ritux-imab) but no radiotherapy showed that this regimen achieved excellent outcomes. 6 With a median follow-up of 5 years, patients had an event-free survival of 93% and an overall survival of 97%. However, if it is administered in the hospital, this approach is more inconvenient and more expensive.

Current data thus show that a vari-ety of approaches can achieve longer-term survival of approximately 90% in patients with this disease. “So is there only one way to treat mediastinal large B-cell lymphoma? I think the answer is no. However, if the goal is to avoid radiotherapy, this seems to be most likely achieved by using EPOCH-R” he said.

Mediastinal Gray Zone Lymphoma

“Mediastinal gray zone lymphoma is a real but confusing entity,” Dr. Armitage commented. “We cannot even agree on how to spell it (gray vs grey). This isn’t composite diffuse large B-cell lymphoma and nodular sclerosing Hodgkin lym-phoma. Instead, mediastinal gray zone lymphoma appears to have some char-acteristics of one type and some of the other,” he continued.

“This complicates our manage-ment. I can’t imagine that I’m the only one who has been frustrated wonder-ing whether these patients are bet-

Mediastinal Lymphomas continued from page 40

EXPERT POINT OF VIEW

Since the presentation on medias-tinal lymphoma at the Pan Pacific

Lymphoma Conference, Wyndham H. Wilson, MD, PhD, Chief of the Hematological Malignancies Thera-peutics Section, Metabolism Branch, Cancer Research Center, of the Na-tional Cancer Institute in Bethesda, Maryland, offered The ASCO Post the following considerations:

The Vancouver R-CHOP results1 come from a retrospective analysis of patients from multiple centers that employed treatment guide-lines. Furthermore, the outcome is presented as overall survival and over estimates the initial “curative potential” of R-CHOP, which is best determined by event-free sur-vival. Importantly, the Vancouver group reported that among 35 pa-

tients who were positron-emission tomography (PET)-negative after R-CHOP and did not receive radio-therapy, 17% recurred.2 In contrast, among 51 patients from the Na-

tional Cancer Institute and 16 pa-tients from Stanford who received DA- EPOCH-R and no radiothera-py, only 3% recurred, irrespective of the PET scan results.3 Thus, the incidence of treatment failure after R-CHOP alone in PET-negative pa-tients is high.

MINT Trial ReconsideredIn addition, Dr. Wilson noted that

the retrospective analysis of the pri-mary mediastinal B-cell lymphoma patients from the MINT trial4 only

included patients with an Interna-tional Prognostic Index score of 0 to 1. “Because patients with advanced stage disease were not included, where the outcome of R-CHOP is particularly poor, these results over-estimate the outcome of R-CHOP and radiotherapy in [primary medi-

astinal B-cell lymphoma],” he said.Dr. Wilson continued, “Multiple

survivorship studies of radiotherapy in mediastinal Hodgkin lymphoma have shown a very high incidence of second and third cancers. The inci-dence of breast cancer is especially high, and [primary mediastinal B-cell lymphoma] is more common in young women. While newer radia-tion techniques may reduce second-ary cancers, studies show that there is no safe dose of radiotherapy, and the changes in techniques do not reduce radiation dose in a major fashion.”

DA-EPOCH-R is the only im-munotherapy treatment that has ever been prospectively studied, he pointed out. All of the other stud-

I think until proven otherwise, DA-EPOCH-R should be considered the standard for [primary

mediastinal B-cell lymphoma]. —Wyndham H. Wilson, MD, PhD




Mediastinal Lymphomascontinued from page 41ter off treated like they have a large B-cell lymphoma or like they have a Hodgkin lymphoma,” he added. Some likely good news from the molecular perspective is that these tumors are almost always positive for both CD20, suggesting a role for rituximab, and CD30, suggesting a possible role for brentuximab (Adcetris).

At present, data are insufficient to know how best to treat mediastinal gray zone lymphoma, according to Dr. Armitage. In a study of patients given dose-adjusted EPOCH-R with-out radiation therapy having a median follow-up of 4 years, those with gray zone lymphomas had poorer out-comes than those with primary me-diastinal B-cell lymphoma, in terms of progression-free survival (45% vs 90%) and overall survival (75% vs 100%).7 However, with the addition of radiotherapy after chemotherapy, the rate of progression-free survival improved to about 80% in the pa-tients with gray zone lymphomas.

“So I believe that when you treat mediastinal gray zone lymphoma, most of these patients should get ra-diotherapy. That’s what I would recom-mend to my patients,” he said, while acknowledging that the topic remains controversial. n

Disclosure: Dr. Armitage is a consultant for Genentech, GlaxoSmithKline, Roche, Seattle Genetics, Spectrum, and Ziopharm, and a Member of the Board of Directors for Tesaro.

References1. Cazals-Hatem D, Lepage E, Brice

P, et al: Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonme-diastinal large B-cell lymphomas, a GELA (“Groupe d’Etude des Lymphomes de l’Adulte”) study. Am J Surg Pathol 20:877-888, 1996.

2. Savage KJ, Yenson PR, Shenkier T, et al: The outcome of primary mediasti-nal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. 2012 Ameri-can Society of Hematology Annual Meet-ing. Abstract 303. Presented December 10, 2012.

3. Pfreundschuh M, Trümper L, Os-terborg A, et al: CHOP-like chemother-apy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Tri-al (MInT) Group. Lancet Oncol 7:379-391, 2006.

4. Witzens-Harig M, Ho AD, Kuhnt E, et al: Primary mediastinal B cell lympho-

ma treated with CHOP-like chemothera-py with or without rituximab: 5-year re-sults of the Mabthera International Trial Group (≤MInT) study. 2012 American Society of Hematology Annual Meeting. Abstract 1612. Presented December 8, 2012.

5. Martelli M, Ceriani L, Zucca E, et al: [18F]fluorodeoxyglucose positron emis-

sion tomography predicts survival after chemoimmunotherapy for primary medi-astinal large B-cell lymphoma: Results of the International Extranodal Lymphoma Study Group IELSG-26 Study. J Clin On-col 32:1769-1775, 2014.

6. Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab ther-apy in primary mediastinal B-cell lympho-

ma. N Engl J Med 368:1408-1416, 2013.7. Dunleavy K, Pittaluga S, Tay K, et

al: Comparative clinical and biological features of primary mediastinal B-cell lymphoma (PMBL) and mediastinal grey zone lymphoma (MGZL). 2009 American Society of Hematology An-nual Meeting. Abstract 106. Presented December 6, 2009.

CODE: JJ-14-2 B size PUB/POST: Advertorial Spread Ad (3 Sizes), PRODUCTION: Roseann P. LIVE: 15” x 10.25”

DESCRIPTION: Advertorial Spread Ad (Size B) WORKORDER #: 006672 TRIM: 15.5” x 10.75”

Delivery Support: 212.237.7000 FILE: 02B-006620-02C-770584-B SIZE SPREAD.indd SAP #: S.TEMP.02388 BLEED: 16” x 11.25”

Art: 37187_A_JA_Storm_Within_fn.tif (CMYK; 306 ppi; Up to Date), 6_18_14_OGI BTK 4013_BTK 3D Illustrations_MainImage_noText2.tif (CMYK; 581 ppi, 498 ppi, 447 ppi; Up to Date), 06-12-13OGI-BTK 11113 Unbranded-Microenvironment Image NOText FINAL-4C.tif (CMYK; 422 ppi; Up to Date), JNJ-Janssen PCoJnJ-Horz-4C.ai (Up to Date), JNJ-pharmacyclics-4C.ai (Up to Date)

TLR BCR CXCR4/5Microenvironment

© Pharmacyclics, Inc. 2014

© Janssen Biotech, Inc. 2014

07/14 PRC-00437

A PERFECT STORM Connections between intracellular signaling and the microenvironment

The microenvironment provides a proliferative, protective niche for malignant cells.2,4-6

The microenvironment supplies survival signals and may contribute to the development of resistance in malignant cells.2,4-6 Internal aberrant prosurvival signaling and increased homing to and retention within supportive microenvironments likewise reinforce the prosurvival signals in malignant B cells,1-3,5 promoting a cycle that maintains disease.

In B-cell malignancies, intracellular dysfunction and external factors enable the disease state.1,2 Intracellular signaling pathways that control survival and proliferation can be dysregulated, resulting in inappropriate survival.1 These internal prosurvival processes are augmented by external signals from supportive cells and factors in the microenvironment such as the lymph nodes and bone marrow.2,3

New research is revealing how intracellular signaling and the microenvironment are involved in B-cell malignancies. Pharmacyclics, Inc. and Janssen Biotech, Inc., are committed to furthering the understanding of these important connections in B-cell malignancies.

For more information, including the new animation “Intracellular Signaling and the Microenvironment in B-cell Malignancies,” visit www.BCellSignals.com.

TLR=toll-like receptor; BCR=B-cell receptor; CXCR4/5=C-X-C (motif) chemokine receptor 4, C-X-C (motif) chemokine receptor 5. Creative representations of select simplifi ed signaling pathways. Illustrations not to scale.

References: 1. Shaffer AL III, Young RM, Staudt LM. Annu Rev Immunol. 2012;30:565-610. 2. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. Blood. 2009;114:3367-3375. 3. Davids MS, Burger JA. Open J Hematol. 2012;3. 4. Burger JA, Kipps TJ. Blood. 2006;107:1761-1767. 5. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Blood. 2009;113:4604-4613. 6. Kurtova AV, Balakrishnan K, Chen R, et al. Blood. 2009;114:4441-4450.

Intracellular signaling pathways



ies are either retrospective analyses and/or include radiotherapy.

Finally, Dr. Wilson noted that the cost of R-CHOP and radiotherapy is sig-nificantly greater than DA- EPOCH-R

and extends treatment for weeks.“Based on these findings,” he

commented, “I think until proven otherwise, DA-EPOCH-R should be considered the standard for [prima-ry mediastinal B-cell lymphoma].”

He added that the data presented

on gray zone lymphoma at the Pan Pacific meeting are older and based on an abstract. “Our full series is now published online with updated and improved outcomes.”5 n

Disclosure: Dr. Wilson reported no potential conflicts of interest.

References1. Savage KJ, Yenson PR, Shenkier T,

et al: The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. 2012 American So-ciety of Hematology Annual Meeting. Ab-stract 303. Presented December 10, 2012.

2. Savage KJ, Yenson PR, Shen-kier T, et al: The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. 2012 American Society of Hema-tology Annual Meeting. Abstract 303. Presented December 10, 2012.

3. Dunleavy K, Pattaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary medias-tinal B-cell lymphoma. N Engl J Med 368:1408-1416, 2013.

4. Pfreundschuh M, Trümper L, Osterborg A, et al: CHOP-like chemo-therapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera In-ternational Trial (MInT) Group. Lan-cet Oncol 7:379-391, 2006.

5. Wilson WH, Pittaluga S, Nicolae A, et al: A prospective study of medi-astinal gray zone lymphoma. Blood. July 14, 2014 (early release online).

Mediastinal Lymphomascontinued from page 41

Save the Date

13th International Conference on Malignant

Lymphoma (ICML)June 17–20, 2015

Lugano, Switzerland

The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation on-cologists, pediatricians, patholo-gists, and leading researchers involved in the study and treat-ment of lymphoid neoplasms.

For more information, visit www.lymphcon.ch/imcl/index.php2

CODE: JJ-14-2 B size PUB/POST: Advertorial Spread Ad (3 Sizes), PRODUCTION: Roseann P. LIVE: 15” x 10.25”

DESCRIPTION: Advertorial Spread Ad (Size B) WORKORDER #: 006672 TRIM: 15.5” x 10.75”

Delivery Support: 212.237.7000 FILE: 02B-006620-02C-770584-B SIZE SPREAD.indd SAP #: S.TEMP.02388 BLEED: 16” x 11.25”

Art: 37187_A_JA_Storm_Within_fn.tif (CMYK; 306 ppi; Up to Date), 6_18_14_OGI BTK 4013_BTK 3D Illustrations_MainImage_noText2.tif (CMYK; 581 ppi, 498 ppi, 447 ppi; Up to Date), 06-12-13OGI-BTK 11113 Unbranded-Microenvironment Image NOText FINAL-4C.tif (CMYK; 422 ppi; Up to Date), JNJ-Janssen PCoJnJ-Horz-4C.ai (Up to Date), JNJ-pharmacyclics-4C.ai (Up to Date)

TLR BCR CXCR4/5Microenvironment

© Pharmacyclics, Inc. 2014

© Janssen Biotech, Inc. 2014

07/14 PRC-00437

A PERFECT STORM Connections between intracellular signaling and the microenvironment

The microenvironment provides a proliferative, protective niche for malignant cells.2,4-6

The microenvironment supplies survival signals and may contribute to the development of resistance in malignant cells.2,4-6 Internal aberrant prosurvival signaling and increased homing to and retention within supportive microenvironments likewise reinforce the prosurvival signals in malignant B cells,1-3,5 promoting a cycle that maintains disease.

In B-cell malignancies, intracellular dysfunction and external factors enable the disease state.1,2 Intracellular signaling pathways that control survival and proliferation can be dysregulated, resulting in inappropriate survival.1 These internal prosurvival processes are augmented by external signals from supportive cells and factors in the microenvironment such as the lymph nodes and bone marrow.2,3

New research is revealing how intracellular signaling and the microenvironment are involved in B-cell malignancies. Pharmacyclics, Inc. and Janssen Biotech, Inc., are committed to furthering the understanding of these important connections in B-cell malignancies.

For more information, including the new animation “Intracellular Signaling and the Microenvironment in B-cell Malignancies,” visit www.BCellSignals.com.

TLR=toll-like receptor; BCR=B-cell receptor; CXCR4/5=C-X-C (motif) chemokine receptor 4, C-X-C (motif) chemokine receptor 5. Creative representations of select simplifi ed signaling pathways. Illustrations not to scale.

References: 1. Shaffer AL III, Young RM, Staudt LM. Annu Rev Immunol. 2012;30:565-610. 2. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. Blood. 2009;114:3367-3375. 3. Davids MS, Burger JA. Open J Hematol. 2012;3. 4. Burger JA, Kipps TJ. Blood. 2006;107:1761-1767. 5. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Blood. 2009;113:4604-4613. 6. Kurtova AV, Balakrishnan K, Chen R, et al. Blood. 2009;114:4441-4450.

Intracellular signaling pathways

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Palliative Care in Oncology

The Role of Integrated Palliative Care in Radiation OncologyA Conversation With Tracy A. Balboni, MD, MPHBy Jo Cavallo

Three years ago, Dana-Farber Can-cer Institute and Brigham and

Women’s Hospital in Boston, launched a Supportive and Palliative Radiation Oncology (SPRO) program to inte-grate generalist palliative oncology services, including the physical, psy-chosocial, and spiritual aspects of care, into radiation therapy for patients with advanced cancers. The goals of the pro-gram are to improve clinical care for patients and the system of care, includ-ing its departmental structure and in-terface with collaborating services, and

to advance palliative cancer care within radiation oncology through education and research.

The ASCO Post talked with Tracy A. Balboni, MD, MPH, Clinical Director of the Supportive and Palliative Radia-tion Oncology Service and Researcher at the Center for Outcomes and Pol-icy Research at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and Associate Professor in Radiation Oncology at Harvard Medi-cal School, about the program and the integration of palliative services within radiation oncology.

Palliative Care IntegrationPlease talk about the Supportive and

Palliative Radiation Oncology service and how radiotherapy for palliation has been integrated into your radiotherapy clinic.

Within the practice of radiation on-cology, we encounter many patients liv-ing with advanced cancer who require palliation for symptom relief and to im-prove their quality of life. Approximate-ly one-third of treatments that radiation oncology departments deliver are for this purpose, and while there is a grow-

ing interest in integrating palliative care and radiation oncology now, palliative care has not been a focus within radia-tion oncology historically.

We saw this program as an opportu-nity to establish integrated models of palliative services in radiation oncology care, so our Departments of Radiation Oncology and Psychosocial Oncology and Palliative Care worked together to create a system to provide these services.

We see patients at every stage of the trajectory of their disease, from the time

of initial diagnosis to the end of life. Care within each stage presents oppor-tunities to communicate with patients and family members and aid them in their understanding of where they are in their diagnosis, as well as how to in-tervene with radiation therapy to im-prove symptoms and control disease.

Program StaffHow is the program staffed?We have a team consisting of two

nurse practitioners, one attending phy-sician, and one resident. It’s a busy ser-vice, and having a dedicated team in place affords us the ability to treat the needs of the whole patient. Attending physicians and residents rotate on the service on a weekly basis and are solely dedicated to SPRO and related patient care for that week. Our nurse practi-tioners are core members of the SPRO service week-to-week and have training in both palliative care and oncology, which is a critically important com-bined level of expertise for the service.

One of the reasons we decided to launch this service was that by the standard care model, advanced cancer

patients with urgent issues were added to an attending physician’s already full schedule. The physician may not only have inadequate time, but also might not have the support of a resident or nurse practitioner with a dedicated in-terest in palliative care. This type of iso-lated care is not an adequate model for patients facing complex issues related to symptomatic advanced cancers, wheth-er those issues arise at the time of initial diagnosis, at disease progression, or at end of life.

New TechnologiesAre there new radiotherapy technolo-

gies available to improve radiotherapy for palliation?

Yes, there are. These technologies include the use of more focal therapies to treat regions of symptomatic tumors such as in the brain or within the spine. These technologies can afford greater dose intensity and tumor control of le-sions at critical sites while minimizing dose to nearby normal structures.

However, technologic advancement within palliative radiotherapy not only includes the application of sophisti-cated technologies, such as high-dose, stereotactic treatments, but also the more judicious use of radiotherapy, particularly in light of a patient’s disease trajectory. One example is greater use of conventional radiation therapy with a hypofractionated approach (higher dose per treatment, fewer treatment regimens, eg, 8 Gy × 1 for bone metas-tases) to spare patients protracted time on therapy, especially when life expec-tancy is short.

Furthermore, technologic advance-ments are needed to better define pa-tients who won’t benefit from pallia-tive radiotherapy based on a short life expectancy. Understanding and dis-seminating these critical nuances of pal-liative radiation oncology care requires research as well as the education of ra-diation oncology clinicians. Along with optimizing patient care, these are the primary goals of the SPRO service.

Spirituality and ReligionWhat role does spirituality and religion

play in palliative care? Spirituality frequently plays a criti-

cal role for patients in both the curable and incurable setting. Whether in re-

ligious or nonreligious forms, spiritu-ality is an avenue by which many pa-tients and family members cope with the stressful circumstances of cancer and find meaning in the midst of the trial of illness.

Our studies1,2 of spirituality after an advanced cancer diagnosis have in-cluded examining the roles such beliefs play in patient quality of life and medi-cal decision-making, as well as the spiri-tual struggles patients and families can face as they encounter an illness. Such efforts are one example of palliative care research that attempts to under-stand patients and families as they face a life-threatening illness and how we as caregivers can provide care in a more holistic way. n

Disclosure: Dr. Balboni reported no potential conflicts of interest.

References1. Vallurupalli M, Lauderdale K, Balbo-

ni MJ, et al: The role of spirituality and reli-gious coping in the quality of life of patients with advanced cancer receiving palliative radiation therapy. J Support Oncol 10:81-87, 2012.

2. Phelps AC, Maciejewski PK, Nils-son M, et al: Religious coping and use of intensive life-prolonging care near death in patients with advanced cancer. JAMA 301:1140-1147, 2009.

GUEST EDITOR

Addressing the evolving needs of cancer survivors at vari-

ous stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is Senior Di-rector of Education, Science and Professional Development Depart-ment at ASCO.

Jamie H. Von Roenn, MD

We saw this program as an opportunity to establish integrated models of palliative services in radiation oncology care, so our Departments of Radiation Oncology and Psychosocial Oncology and Palliative Care worked together to create a system to provide these services.

—Tracy A. Balboni, MD, MPH


Announcements

Palbociclib Expanded Access Program Open to Eligible Breast Cancer Patients

Pfizer Inc announced that the com-pany has initiated a multicenter,

open-label expanded access program in the United States for the investigational oral CDK 4/6 inhibitor, palbociclib. Through the program, palbociclib is be-ing made available for use in combina-tion with letrozole for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer for whom letrozole is considered appro-priate therapy.

“Palbociclib is being evaluated as a potential new treatment for women with hormone receptor–positive, HER2-neg-ative advanced breast cancer,” said Mace Rothenberg, MD, Senior Vice President, Clinical Development and Medical Affairs, and Chief Medical Officer, Pfizer Oncol-ogy. “We have completed the submission of a New Drug Application for palbociclib in the United States based on the results of our phase II PALOMA-1 study. With re-cruitment of new patients to our phase III PALOMA-2 and PALOMA-3 trials now

complete, Pfizer is initiating the palbociclib expanded access program. This program will provide a mechanism by which eligible women who may benefit from treatment with palbociclib can gain access to this in-vestigational therapy at this time.”

Expanded Access Program The palbociclib expanded access pro-

gram is a U.S.-only, single-arm, open label study for postmenopausal women with hormone receptor–positive, HER2-neg-ative advanced breast cancer. Women en-

rolled in the study will receive palbociclib for use in combination with letrozole, and therefore must be deemed appropriate for letrozole therapy.

Under its expanded access programs, the U.S. Food and Drug Administration works with companies to allow access to

investigational therapies to patients with serious or life-threatening illnesses who do not otherwise qualify for participation in a clinical trial and for whom there are no sat-isfactory alternate therapies.

Health-care professionals and pa-tients can learn more about the pal-

bociclib expanded access program by visiting www.clinicaltrials.gov (trial number: NCT02142868).

U.S.-based health-care professionals seeking more information may also call 1-800-420-6755 or e-mail [email protected] for further details. n

This [expanded access] program will provide a mechanism by which

eligible women who may benefit from treatment

with palbociclib can gain access to this investigational

therapy at this time. —Mace Rothenberg, MD

Breast Cancer

CO-1686 is an investigational product and is not approved in any country.

Copyright © 2014 Clovis Oncology. 6/14 1686-001

For more information, visit ClinicalTrials.gov, TIGERtrials.com,or contact [email protected]

NOW ENROLLING:New trials for patients with mutant EGFR non-small cell lung cancer

1 prior EGFR TKIPrimary endpoint: ORR

CO-1686

Phase 22nd line T790M+ mutant EGFR NSCLC

(NCT02147990)

Phase 2 expansion2nd line and 3rd line+, T790M+ mutant EGFR NSCLC

(NCT01526928)

1 prior EGFR TKIPrimary endpoint: ORR

CO-1686

≥2 prior EGFR TKI or chemoPrimary endpoint: ORR

CO-1686

http://www.clovisoncology.com


Direct From ASCO

A Conversation With Lidia Schapira, MD, the New JCO Art of Oncology Editor

The popular Art of Oncology (AOO) section of the Journal

of Clinical Oncology ( JCO) brings a human perspective to the art and sci-ence of practicing oncology. Lidia Schapira, MD, FASCO, Assistant Professor at Harvard Medical School and Massachusetts General Hospital, became the Art of Oncology Editor in November 2013, following in the footsteps of previous AOO Editors Charles L. Loprinzi, MD, FASCO, and David P. Steensma, MD, FACP.

Building a Stronger Community

Why is it important for JCO to fea-ture Art of Oncology?

Years ago I remember a colleague told me that she first opens the Journal to Art of Oncology. It is the

soul of JCO. It provides a virtual meeting place for oncologists to share experiences or voice their doubts and concerns. Personal essays can have a tremendous impact on readers, lead-ing some to question their assump-tions or even make important changes in their practice.

What made you interested in the role of editor for AOO?

I absolutely love this section of the journal and am keen to invite col-leagues and patients from all over the world to contribute their reflections

in order to expand our content and reach. We will build a stronger com-munity of cancer clinicians if we share our experiences—in the same way that researchers share laboratory data and novel observations.

I am indebted to Drs. Charles Loprinzi and David Steensma for sharing their clear vision for AOO and for their friendship and mentor-ship. Charles is a brilliant physician-scientist as well as a humanist and saw the opportunity to start this separate track within the Journal. David invited “new voices,” and as a result, we saw an increase in submissions, includ-ing many essays written by residents and fellows. We are training young oncologists to be mindful and reflect on their experiences, and often writ-ing provides a useful mechanism for reflection.

Lessons in Oncology PracticeWhy do you think AOO articles are

so popular?Some readers may find the sub-

jectivity liberating after reading sci-entific articles. Or perhaps they feel moved by the essayist’s sincerity or by a story that resonates with their lived experience. We admire our colleagues who design brilliant trials that change treatment paradigms, and we also need to have personal heroes who

inspire and remind us of what is so meaningful about oncology practice.

Do you have a favorite piece or one that touched you the most from past AOO collections?

I was deeply moved by Dr. Ste-ven Grunberg’s “Giving Permission” describing the house call he made to a dying patient to let her know it was her time. I still read Dr. Paulette Mehta’s “He Didn’t Have a Chance” when I feel sad or need a little en-couragement to go back to the clinic. Dr. Mikkael Sekeres makes me laugh

and I never want to reach the end of his essays. Dr. Romeo Bascioni’s “I’ll Meet You in Your Dreams” taught me a powerful lesson about what can be accomplished with exquisite hospice care. And Dr. Joshua Liao’s “Cancer or No Cancer” makes me feel there will be smart and caring oncologists in years to come to look after all of us.

What will be your biggest challenges as an editor?

To keep the section relevant and stim-ulating for readers, find new ways of invit-ing and inciting reflection, and encourage new writers to submit their work.

Any advice or thoughts for aspiring contributors?

We would be delighted to read your work. Give us a good story, a personal reflection, a little dose of humor, or even a poem, and I would love to know if readers feel these es-says have changed the way they think of themselves or their patients. n

Originally printed in ASCO Connection. © American Society of Clinical Oncol-ogy. “Interview with Lidia Schapira, MD, New JCO Art of Oncology Editor.” ASCO Connection, May 2014: p 54. All rights reserved.

Lidia Schapira, MD, FASCO

We admire our colleagues who design brilliant trials that change treatment paradigms, and we also need to

have personal heroes who inspire and remind us of what is so meaningful about oncology practice.

—Lidia Schapira, MD

Top 10 most-accessed articles published in 2011 in Journal of Clinical Oncology

Top 5 articles recently published in

Journal of Oncology Practice

What’s Hot in

JOPComorbidity, Chemotherapy Toxicity, and Outcomes Among Older

Women Receiving Adjuvant Chemotherapy for Breast Cancer on a

Clinical Trial: CALGB 49907 and CALGB 361004 (Alliance)

by Heidi D. Klepin, et al

Creation of a Diagnostic Wait Times Measurement Framework

Based on Evidence and Consensus

by Julie E. Gilbert, et al

Diversity by Race, Hispanic Ethnicity, and Sex of the United

States Medical Oncology Physician Workforce Over the Past

Quarter Century

by Curtiland Deville, et al

Oncologists' Response to New Data Regarding the Use of

Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer

by Efrat Dotan, et al

Impact of Financial Burden of Cancer on Survivors' Quality of Life

by Kathleen M. Fenn, et al

JOP.ascopubs.org

Volume 7, Issue 3 May 2011

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al

Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al

Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

Journal of oncology Practice

www.jop.ascopubs.org


Direct From ASCO

ASCO Experts Discuss the Latest Advances in Breast Cancer Care

The 2014 Breast Cancer Sympo-sium will take place Septem-

ber 4 to 6. Direct your patients to www.cancer.net/blog to listen to ASCO Experts explain some of the research announced prior to the meeting and discuss what this research means for patient care. They can also read a sum-mary of the research highlights. n

© 2014. American Society of Clinical Oncology. All rights reserved.

#WeConquerCancer: Creative Fundraisers From Committed Conquerors

Conquer Cancer Foundation do-nors are a consistently creative

bunch when it comes to encouraging others to help conquer cancer: Tyler in-vited his friends and family to a charity spin class; elementary school students in Malibu, California, sold bracelets in honor of their principal; Steve compet-ed in a half-Ironman and asked loved ones to donate in memory of his fa-ther; Jennifer and Sean asked that their guests give donations instead of china at their wedding.

The Conquer Cancer Foundation has recently adopted a set of online tools to make it easy for donors to create an on-line home for their creative fundraising efforts and share it with friends and fam-ily. Through the #WeConquerCancer program, fundraisers and event leaders can create a personalized website for their campaign through a simple, step-by-step process, recruit others to join their team, e-mail friends and family about their efforts, track donations, and send personal thank-yous to donors.

By creating and sharing an online campaign, fundraisers help to raise awareness and vital support for the Conquer Cancer Foundation’s mis-sion to fund breakthrough research and share cutting-edge knowledge.

Elizabeth’s StoryElizabeth Ralls had been fortunate

not to experience cancer directly, but noted that as a member of the ASCO staff, “I work every day with people who fight to cure and treat it.”

“I had read about folks shaving their heads for cancer research, which got

me thinking: What can I do? I’ve had long hair for years—it’s time it was put to good use!” Elizabeth said, and her choice of charity to support was simple. “I can tell you that the Conquer Can-cer Foundation makes a real difference

in the lives of both researchers and pa-tients,” she said.

Elizabeth created a website as part of a graduate school project, and chal-lenged her family and friends to come


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Direct From ASCO

ASCO staff members Kirsten Goldberg (left) and Kristin Ludwig (right) biked a combined 150 miles and raised more than $5,600 for the Conquer Cancer Foundation.

September Is Challenge Month at the Conquer Cancer Foundation! During September, Raj Mantena, RPh, will be matching all donations two-to-one, making it the perfect time to set up a personalized online fundrais-ing campaign in honor of a loved one, special event, or athletic endeavor.

Visit support.conquercancerfoundation.org to get started!

together and donate $100 per inch of hair cut, ultimately raising a total of $500 and donating 10 inches of her hair to an organization that provides wigs for women with cancer.

Jeff’s StoryLike so many families, Jeff Sear’s

family wasn’t a stranger to cancer, but it wasn’t until his uncle passed away from brain cancer early in 2013 that “it finally hit home.”

“Growing up, I didn’t get to know my uncle as well as I would have liked,” Jeff said. “Even when I was old enough to make my own choices, I always fig-ured ‘once I really start to succeed in life, that’s when we’ll be close.’ But I waited too long.”

“It’s hard not to experience loss without wanting to do something,” he continued. “The loss made me reex-

amine my lifestyle and my priorities. It made me look at my own health, and I decided to do something about it.”

Jeff had heard about others running distance for charity, but found that for

him it didn’t seem like that would be enough. “I wanted a change that people could see,” he said. “Weight is some-thing I, like many of us, struggle with. Making it a challenge about losing weight seemed ideal.”

Jeff set a challenge for himself and shared it with family and friends ask-ing that they pledge a $1 donation to the Conquer Cancer Foundation for every pound he lost. “It gave me moti-vation to work hard. It got the support of not only those affected by cancer, but also tied in people with interest in my health,” he said.

Jeff ’s challenge led to great results, both for him and for the Conquer Can-cer Foundation.

Amy’s StoryOn the occasion of her 29th birthday,

Amy Smith wanted to make her party a “Celebrate Life Soiree.” She created an on-line fundraiser via #WeConquerCancer

to encourage her friends and family to donate $29 to the Conquer Cancer Foundation rather than bringing a gift.

She chose to ask her friends to support the Foundation’s Women Who Conquer Cancer program in honor of

the women in her family that had faced cancer. “I just said, ‘I’m almost 30, let’s celebrate and put some money towards a good cause!” she said.

Amy provided the party, and her

friends enthusiastically answered her call to Celebrate Life—contributing $679 to cancer research.

A Common CauseThey come from all different points

of view and cancer experiences, but #WeConquerCancer fundraisers have

something in common: they find ways to explore their passions, challenge themselves, and have fun all while rais-ing support and awareness for the vision of a world free from the fear of cancer. n


#WeConquerCancercontinued from page 47

Conquering Cancer.

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer

worldwide by funding breakthrough research and sharing

cutting-edge knowledge. We are the go-to organization

in supportingthe world’s preeminent cancer specialists,

so one day we can live in a world free from the fear of

cancer. To get to know us better now and be a part of our

ambitious future, visit ConquerCancerFoundation.org.

Together, anything is possible.

DonATe ToDAY!ConquerCancerFoundation.org

Genitourinary Cancers Symposium

February 26-28, 2015

Rosen Shingle Creek

Orlando, Florida

Save the Date

Gastrointestinal Cancers Symposium

January 15-17, 2015

Moscone West Building

San Francisco, California


Direct From ASCO

A World Free From the Fear of Cancer—Is It Possible?By Clifford A. Hudis, MD, FACP

By every definition, ASCO’s 50th Annual Meeting was a huge suc-

cess. The halls were buzzing as nearly 35,000 attendees shared excitement about cancer research.

This was a banner year for federally funded clinical trials—all four of the ab-stracts selected for ASCO’s Plenary Ses-sion were backed by funding from the National Institutes of Health (NIH), as were so many of the other studies that captured news headlines.

But the U.S. clinical research system is facing unprecedented challenges. Today NIH’s purchasing power is 23% lower than it was in 2003. The National Cancer Institute (NCI) plans to cut en-rollment in federally funded clinical tri-als by 15% over the next few years, scal-ing yearly enrollment back to as low as 17,000 patients in intervention trials.1

Federally funded clinical research answers questions that are critically important to patients—like comparing the effectiveness of two regimens, find-

ing new uses for generic drugs, and find-ing new ways to improve patients’ qual-ity of life. These are often trials industry wouldn’t have reason to conduct.

Greater Investment in Cancer Research Needed

In my presidential address, I laid out a challenge: creating a “world

free of the fear of cancer.” I believe it’s possible, but only if our nation’s investment of resources matches our nation’s need.

In 2013, the U.S. federal budget was almost $4 trillion. Of that, the NCI component was $5 billion. Roughly speaking, just 0.1% of federal spending goes to the NCI. A disease that affects one-third to one-half of all Americans garners less than one dollar of every thousand our nation spends. I can’t say that I know the “right” proportion for

spending on cancer research, but I do know that this is the wrong one.

A quote from Lyndon Johnson’s Great Society Speech in 1964, describ-ing his intention to eliminate poverty and racial injustice, rings poignantly true today as we strive to realize a world free from the fear of cancer. He said, we “can afford to win it. We can-not afford to lose it.”

I hope you will join me in my call to our nation’s legislators and lead-ers for greater investment in cancer research—one that is commensurate with our nation’s need, ambition, and intention. We can afford it. And we can’t afford to lose. n


Reference1. National Cancer Institute: An

overview of NCI’s National Clinical Tri-als Network. May 29, 2014. Available at http://www.cancer.gov/clinicaltrials/nctn. Accessed July 3, 2014.

A disease that affects one-third to one-half of all Americans garners less than one dollar of every thousand our nation spends. I can’t say that I know the ‘right’ proportion for spending on cancer research, but I do know that this is the wrong one.

—Clifford A. Hudis, MD, FACP

Clifford A. Hudis, MD, FACP, is Immedi-ate Past President of the American Society of Clinical Oncology. A longer version of this article originally appeared on ASCO’s CancerProgress.Net website.

Registration Open for the Community Research Forum Annual Meeting

Registration is open for the ASCO Community Research Forum An-

nual Meeting, September 28 to 29, 2014, at ASCO headquarters in Alexandria, Virginia. Join fellow community-based researchers to discuss barriers and de-velop solutions to common challenges faced in the community research setting.

This meeting provides a forum to:• Collaborate and network with col-

leagues• Discuss barriers to conducting re-

search

• Work to develop strategies to effec-tively conduct community-based research

• Influence the direction of ASCO ini-tiatives

• Provide input on policy issues im-pacting clinical researchFor more information about the

Community Research Forum, visit www .asco.org/communityresearchforum. n


ASCO Launches the ASCO in Action Beat

ASCO has launched the ASCO in Action Beat, an e-newsletter spe-

cifically focused on the latest news and updates related to cancer policy from ASCO in Action. The ASCO in Action Beat provides a snapshot of the most significant news and up-dates in cancer policy, ASCO’s on-going advocacy efforts, and oppor-tunities for members to take action

on critical issues affecting the cancer community.

All ASCO U.S. members receive the biweekly newsletter. Non-ASCO mem-bers can sign up to receive the ASCO in Action Beat at the ASCO Subscription Center at asco.org/subscriptioncenter. n


ASCO Offers Input on 21st Century Cures PCAST White Paper

ASCO submitted a letter to the U.S. House Energy and Com-

merce Committee responding to the committee’s second white paper on its 21st Century Cures Initiative, 21st Century Cures: An Update on the Pres-ident’s Council of Advisors on Science and Technology (PCAST) 2012 Re-port on Propelling Innovation.

The letter to Representatives Fred Upton (R-MI) and Diana De-Gette (D-CO) from ASCO President

Peter P. Yu, MD, FASCO, praises the PCAST report, but notes that the U.S. Food and Drug Administration (FDA) could take “a more coordinat-ed approach to change.” For example, the ASCO letter suggests expanding FDA’s Sentinel Program to collect data on patients provided access to therapies approved under a proposed provisional approval process.

ASCO recommendations include supporting federal initiatives such as

the National Center for Advancing Translational Sciences and the Rea-gan-Udall Foundation, creating a new designation for drugs shown to be safe and effective in a specific subgroup of patients, and improving FDA benefit and risk monitoring tools.

To learn more about the 21st Cen-tury Cures Initiative, please visit: e n e r g y c o m m e r c e . h o u s e . g o v / cures. n


http://www.cancer.gov/clinicaltrials/nctn

74385-R2-V15_AmgenOI_KingSzSpread_ASCOPost_June_V1.indd All Pages 5/6/14 4:22 PM

74385-R2-V15_AmgenOI_KingSzSpread_ASCOPost_June_V1.indd All Pages 5/6/14 4:22 PM

http://www.amgenoncology.com


In the Clinic

Bevacizumab in Persistent, Recurrent, or Metastatic Cervical CancerBy Matthew Stenger

On August 14, 2014, bevacizumab (Avastin) was approved for the

treatment of persistent, recurrent, or metastatic cervical cancer in combina-tion with paclitaxel and cisplatin or pa-clitaxel and topotecan.1,2 Updated label-ing includes changes in warnings and precautions.

Supporting TrialApproval is based on the results of

a phase III 2×2 factorial trial in which 452 patients with persistent, recurrent, or metastatic disease were randomly assigned to receive bevacizumab plus chemotherapy consisting of paclitax-el/cisplatin or paclitaxel/topotecan (n = 277) or chemotherapy alone (n = 225).2,3 Patients had a median age of 48 years, Gynecologic Oncology Group performance status of 0 (58%) or 1 (42%), 80% had received prior radia-tion therapy, and 74% had received pri-or chemoradiation therapy.

Median overall survival was signifi-cantly longer with bevacizumab plus chemotherapy vs chemotherapy alone (16.8 vs 12.9 months, hazard ratio [HR] = 0.74, P = .013). There was no significant difference in overall survival between groups receiving paclitaxel/topotecan with or without bevacizumab (n = 223) vs paclitaxel/cisplatin with or without bevacizumab (n = 229; median 13.3 vs 15.5 months, HR = 1.15, P = .23), but hazard ratios were similar with the addition of bevacizumab to both paclitaxel/cisplatin (HR = 0.72, 95% confidence interval [CI] = 0.51–1.02) and to paclitaxel/topotecan (HR = 0.76, 95% CI = 0.55–1.06). The latter findings suggest that bevacizumab plus paclitaxel/topotecan is an acceptable alternative for women with advanced cervical cancer who are not candidates for platinum therapy.

How It WorksBevacizumab is a recombinant hu-

manized monoclonal IgG1 antibody

that binds vascular endothelial growth factor (VEGF) and prevents interac-tion of VEGF with its receptors (Flt-1 and KDR) on the surface of endothe-lial cells. Inhibition of this interaction results in inhibition of endothelial cell proliferation and new blood vessel for-mation in in vitro models of angiogen-esis.

How It Is GivenThe recommended dose of bevaci-

zumab in cervical cancer is 15 mg/kg via intravenous infusion every 3 weeks in combination with paclitaxel/cispla-tin or paclitaxel/topotecan.

The bevacizumab-plus-chemother-apy regimens used in the supporting trial, repeated every 21 days, were: in-

travenous paclitaxel at 135 mg/m2 over 24 hours on day 1 and intravenous cis-platin at 50 mg/m2 plus bevacizumab on day 2; paclitaxel at 175 mg/m2 over 3 hours on day 1 and cisplatin at 50 mg/m2 plus bevacizumab on day 2; pa-clitaxel at 175 mg/m2 over 3 hours plus cisplatin at 50 mg/m2 plus bevacizum-ab on day 1; and paclitaxel at 175 mg/m2 over 3 hours plus bevacizumab on day 1 and topotecan at 0.75 mg/m2 over 30 minutes on days 1 to 3.

There are no recommended dose re-ductions for bevacizumab. Treatment should be discontinued for gastroin-

testinal perforation or fistula formation involving an internal organ, wound de-hiscence or wound healing complica-

tions requiring medical intervention, serious hemorrhage, severe arterial thromboembolic events, life-threaten-ing (grade 4) venous thromboembolic events including pulmonary embolism, hypertensive crisis or hypertensive en-cephalopathy, posterior reversible en-cephalopathy syndrome, and nephrotic syndrome.

Treatment should be temporarily suspended ≥ 28 days prior to elective surgery and for severe hypertension not

controlled with medical management, moderate to severe proteinuria, and severe infusion reactions. Treatment should not be started for ≥ 28 days af-ter surgery and until wound healing is complete. Bevacizumab should not be given to patients with serious hemor-rhage or recent hemoptysis.

Safety ProfileThe most common adverse events

of any grade in patients receiving beva-cizumab and chemotherapy and occur-ring with a frequency ≥ 5% greater vs the chemotherapy-alone group were fa-tigue (80% vs 75%), decreased appetite (34% vs 26%), hypertension (29% vs 6%), and hyperglycemia (26% vs 19%). The most common grade 3 or 4 adverse events were fatigue (14.2% vs. 9.9%), abdominal pain (11.9% vs. 9.9%), hy-pertension (11.5% vs 0.5%), urinary tract infection (8.3% vs 6.3%), and thrombosis (8.3% vs 2.7%). GI perfo-ration occurred in 3.2% of patients re-ceiving bevacizumab and gastrointesti-nal-vaginal fistulae occurred in 8.2% of bevacizumab patients vs 0.9% of che-motherapy-alone patients. All cases of

GI perforation and GI-vaginal fistulae occurred in patients who had received prior pelvic radiation. Other grade 3 or 4 adverse events that were more com-mon in patients receiving bevacizumab included hemorrhage, proteinuria, and wound healing complications.

Bevacizumab carries boxed warn-ings for gastrointestinal perforation, surgery and wound healing complica-tions, and hemorrhage (including se-vere or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, central ner-vous system hemorrhage, and vaginal bleeding). It also carries warnings/precautions for gastrointestinal per-foration or fistula and nongastroin-testinal fistula, arterial thromboem-bolic events, venous thromboembolic events, hypertension, posterior revers-ible encephalopathy syndrome, pro-teinuria, infusion reactions, and ovar-ian failure.

Patients must undergo routine mon-itoring of blood pressure and urine pro-tein. Women of reproductive potential must be informed of the risk of ovarian failure. n

References1. U.S. Food and Drug Administration:

Bevacizumab solution. Available at www.fda.gov/Drugs/InformationOnDrugs/Ap-provedDrugs/ucm410128.htm.

2. AVASTIN® (bevacizumab solution for intravenous infusion) prescribing informa-tion, Genentech, Inc, August 2014. Avail-able at www.accessdata.fda.gov/drugsatfda_docs/label/2014/125085s301lbl.pdf.

3. Tewari KS, Sill MW, Long HJ III, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743, 2014.

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, admin-istration recommendations, safety profiles, and other essential infor-mation needed for the appropriate clinical use of these drugs.

New Indication for Bevacizumab in Cervical Cancer

■ Bevacizumab (Avastin) was recently approved for the treatment of persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

■ The recommended dose of bevacizumab in cervical cancer is 15 mg/kg via intravenous infusion every 3 weeks in combination with paclitaxel/cisplatin or paclitaxel/topotecan.

OF NOTEBevacizumab is a recombinant hu-manized monoclonal antibody that prevents interaction of VEGF with its receptors on endothelial cells, thereby inhibiting endothelial cell proliferation and new blood vessel formation.

OF NOTEBevacizumab carries boxed warn-ings for gastrointestinal perforation, surgery and wound healing compli-cations, and hemorrhage.

Report Adverse EventsHealth-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).



Journal Spotlight

Lung Screening–Detected Abnormalities Other Than Cancer Result in Smoking Cessation: National Lung Screening Trial AnalysisBy Matthew Stenger

In a study reported in the Journal of the National Cancer Institute,

Martin C. Tammemägi, PhD, of Brock University, Ontario, and col-leagues assessed smoking cessation rates among participants undergoing chest x-ray or computed tomogra-phy (CT) screening for lung cancer in the National Lung Screening Trial (NLST). Among patients without a subsequent diagnosis of lung cancer, they found that screening abnormali-ties were significantly associated with smoking cessation.1 This finding sug-gests that lung cancer screening pro-grams may provide opportunities to reduce smoking rates.

Study DetailsIn the study, data from participants

in the NLST (2002–2009) were used in multivariable longitudinal regres-sion models to predict annual smoking cessation in 15,489 subjects who were current smokers at study entry and did not receive a diagnosis of lung cancer during the study. Screening occurred at years 0, 1, and 2, with annual follow-up at years 3 to 7. The NSLT showed that annual low-dose CT screening reduced lung cancer mortality by 20% compared with chest x-ray screening

Overall, at study year 3, 23.5% of subjects were no longer smoking. The highest proportions of subjects who remained smokers at ≥ 1-year inter-vals after a screening were those with normal screening results, followed in order by those with a screen showing a minor abnormality not suspicious for lung cancer, those with a major abnormality not suspicious for lung cancer and those with a screen that was suspicious for lung cancer but was unchanged from the previous screen, and those with a screen suspicious for lung cancer that represented a new or changing finding.

Year-to-Year ImpactAmong subjects with a normal

finding at year 0 screening, 87.4% re-mained smokers at year 1 screening. By comparison, rates were significant-ly lower among patients with major abnormality not suspicious for cancer (85.0% still smokers, odds ratio [OR] = 0.81) and among those with an ab-normality suspicious for lung cancer (81.7% still smokers, OR = 0.64).

Among subjects with a normal find-ing at year 1 screening, 83.1% remained smokers at year 2 screening. By compar-ison, smoking rates were significantly lower in those with findings suspicious for lung cancer but stable from year 1 screening (79.2%, OR = 0.78) and those with a new finding suspicious for lung cancer (74.8%, OR = 0.61).

Among subjects with a normal finding at year 2 screening, 78.3% re-mained smokers at year 3. By compari-son, significant reductions in smoking rates were found among subjects with an unsuspicious minor abnormality at year 2 (76.3%, OR = 0.89), those with an unsuspicious major abnormal-ity (73.3%, OR = 0.76), those with a stable suspicious finding (73.9%, OR = 0.79), and those with a new/changed suspicious finding (71.9%, OR = 0.71).

Effect of Longer Durations Among subjects with normal find-

ings on year 2 screening, 73.6% re-mained smokers at year 4 follow-up.

By comparison, there were significant reductions in smoking rates at year 4 among those with an unsuspicious minor abnormality (71.8%, OR = 0.91), those with an unsuspicious ma-jor abnormality (68.4%, OR = 0.77), those with a stable suspicious finding (69.9%, OR = 0.83), and those with a new/unstable suspicious finding (68.0%, OR = 0.76).

At years 5, 6, and 7, the smoking rates among subjects with normal re-sults at year 2 screening decreased from 68.1% to 61.8%. By comparison, rates nonsignificantly decreased from 67.4% to 60.7% in subjects with an unsuspi-cious minor abnormality, from 64.5% to 60.9% in those with an unsuspicious major abnormality, and from 65.4% to 58.1% in those with a stable suspicious

finding. Among those with a new/unstable suspicious finding at year 2 screening, decreases in smoking rates compared with those with normal find-ings were significant at year 5 (63.6%, OR = 0.82), year 6 (58.1%, OR = 0.76), and year 7 (56.7%, OR = 0.81).

Screening Abnormalities Predict Cessation

A final multivariable logistic model included adjustment for sociodemo-graphic factors (age, sex, race/ethnic-ity, education as an indicator of socio-economic circumstance, and marital status), exposures (alcohol consump-tion; cigarette, cigar, and pipe smok-ing histories; and second-hand smoke

exposures), and medical history (body mass index, family history of lung can-cer, personal history of cancer, history of comorbidities), as well as for study year, study center, and randomiza-tion group (x-ray or CT screening). By this model, compared with normal screening findings, findings of an un-suspicious minor abnormality (OR = 0.91, P = .005), an unsuspicious major abnormality (OR = 0.81, P < .001), a stable suspicious abnormality (OR = 0.78, P < .001), or a new/unstable suspicious finding (OR = 0.66, P < .001) were independently predictive of smoking cessation.

Other significant predictors for not smoking were increasing age, mixed race (vs white), increased education level, married status, higher body mass

index, lower smoking intensity and du-ration, absence of secondhand smoke at home, and past or present pipe and cigar smoking.

Outcomes by X-ray or CT Screening

Analysis according to randomiza-tion group showed that compared with subjects in the x-ray group with normal findings, there was a significant reduc-tion in smoking among those with an unsuspicious minor abnormality (ad-justed OR = 0.86, P < .001), a border-line significant reduction in those with an unsuspicious major abnormality (OR = 0.81, P = .06), and significant reductions in those with a stable suspi-cious finding (OR = 0.72, P = .02) and those with an new/unstable suspicious finding (OR = 0.71, P < .001).

Compared with subjects in the CT group with a normal finding, there was a nonsignificant increase in smoking (adjusted OR = 1.01, P = .88) among those with an unsuspicious minor abnormality, a borderline significant decrease in those with an unsuspi-cious major abnormality (OR = 0.87, P = .06), and significant reductions in those with a stable suspicious finding (OR = 0.84, P = .01) or a new/un-stable suspicious finding (OR = 0.69, P <.001).

The investigators concluded, “Smoking cessation is statistically significantly associated with screen-detected abnormality. Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-relat-ed morbidity and mortality.”

The National Cancer Institute is the funding source for the NLST. n

Disclosure: Dr. Tammemägi and his coauthors reported no potential conflicts of interest.

Reference1. Tammemägi MC, Berg CD, Riley

TL, et al: Impact of lung cancer screening results on smoking cessation. J Natl Can-cer Inst 106:dju084, 2014.

Thoracic Oncology

Screening and Smoking Cessation

■ Progressively more significant screening abnormalities were associated with increasing reductions in smoking rates during follow-up.

■ Screening abnormalities were independent predictors of smoking cessation on multivariate analysis.

Smoking cessation is statistically significantly associated with screen-detected abnormality. Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-related morbidity and mortality.

—Martin C. Tammemägi, PhD, and colleagues


Announcements

AACI Members Elect New Leadership, Members to Board of Directors

The Association of American Cancer Institutes (AACI) has

announced the election of Stanton L. Gerson, MD, as Vice-President/President-Elect for a 6-year term, effec-tive in October 2014. Dr. Gerson is the Asa and Patricia Shiverick- Jane Shiver-

ick (Tripp) Professor of Hematologi-cal Oncology, Director of the National Cancer Institute (NCI)-Designated Case Comprehensive Cancer Center, in Cleveland, Founding Director of the National Center for Regenerative Med-icine, and Distinguished University Professor at Case Western Reserve Uni-versity. He is also Director of University Hospitals Seidman Cancer Center in Cleveland and a member of the NCI Board of Scientific Advisors.

The Association also announced that Patrick J. Loehrer, Sr, MD, and Thomas A. Sellers, PhD, MPH, have been elected to AACI’s Board of Direc-

tors. Dr. Loehrer is Director of the Indi-ana University Melvin and Bren Simon Cancer Center, in Indianapolis. Dr. Sell-ers is Director and Executive Vice Presi-dent of the Moffitt Cancer Center and Research Institute, in Tampa.

Priorities for TermIn a statement submitted to AACI

members, Dr. Gerson said that in his new AACI leadership role, he will prior-itize three critical aspects of the nation’s cancer centers program by: (1) encour-aging the centers to work more closely together to lower health-care costs and improve outcomes through nationally

coordinated research and translation, (2) expanding the use of cancer patient data to further health improvements and research discoveries, and (3) mak-ing optimal use of the cancer center director and administrative leader net-work, including partnering with fund-

ing agencies, to set the policy agenda for cancer research, dissemination of discoveries, and cancer health care.

Drs. Gerson, Loehrer, and Seller’s terms will commence on October 27 during the AACI/CCAF Annual Meet-ing in Chicago. n

Stanton L. Gerson, MD

Patrick J. Loehrer, Sr, MD

Thomas A. Sellers, PhD, MPH



Announcements

Leaders in Health Disparities Honored

The W. Montague Cobb/National Medical Association (NMA)

Health Institute (Cobb Institute) was established by the National Medical Association to develop, evaluate, and implement strategies to promote well-ness and eliminate health disparities

and racism in medicine. The Institute recently celebrated its 10th anniversary during the 112th Annual Convention of the NMA and recognized three leaders in health disparities with awards.

John Ruffin, PhD, former Director of the National Institute on Minority Health

and Health Disparities, whose life-long career and innovations have had a signifi-cant impact on society, received the W. Montague Cobb Lifetime Achievement Award for his exceptional contributions to the field of African American Medicine.

Alvin Poussaint, MD, Professor of

Psychiatry and Director of the Office of Recruitment and Multicultural Affairs at Harvard Medical School, received the 2014 Cato T. Laurencin Lifetime Re-search Award. The award recognizes an in-dividual who has demonstrated more than 20 years of consistent, long-lasting contri-butions to benefit African Americans and to reduce health disparities through recog-

nized research and leadership.Thomas LaVeist, PhD, Director of

the Hopkins Center for Health Dispari-ties Solutions was named the 2014 W. Montague Cobb Lecturer for his sig-nificant contributions as a pioneer in health disparities research.

“These distinguished individuals have been tireless champions for the elimination of health disparities and ad-vancing minority health. Being selected for the Cobb Awards speaks to their exemplary leadership and service,” said Cato T. Laurencin, MD, PhD, Chair of the Cobb Institute Board of Directors and University Professor at the Univer-sity of Connecticut. n

John Ruffin, PhD

Alvin Poussaint, MD

Thomas LaVeist, PhD

Send Us Your NEWSWrite to [email protected].

All submissions will be considered for publication



Journal Spotlight

Phase III Trial of Figitumumab Plus Chemotherapy in Advanced NSCLC Stopped Early for Futility and Increased Harm By Matthew Stenger

In the first phase III trial assessing the combination of an insulin-like growth

factor 1 receptor (IGF-1R) inhibitor with chemotherapy as first-line treatment for advanced nonadenocarcinoma non–small cell lung cancer (NSCLC), the addi-tion of the fully human immunoglobulin G2 monoclonal antibody figitumumab to paclitaxel/carboplatin did not improve overall survival over chemotherapy alone. The study, reported by Corey J. Langer, MD, of University of Pennsylvania, and colleagues in Journal of Clinical Oncology, was stopped early due to futility and an increased frequency of serious adverse events, including treatment-related death, in patients receiving figitumumab.1

When the trial was begun, it was thought that IGF-1R played a role in squamous cell NSCLC, in which it is more commonly expressed than in ad-enocarcinoma, and analysis of phase II data suggested increased efficacy of figi-tumumab in patients with this histology. A randomized phase II study in patients with treatment-naive advanced NSCLC showed improved objective response rate with the addition of figitumumab to full-dose paclitaxel/carboplatin (54% vs 42%). However, the failure of the phase III trial prompted a thorough review of the phase II data, which were subsequently retracted when reanalysis showed lower response rates in both groups.2

Study DetailsIn the open-label phase III trial, 681

patients with stage IIIB/IV or recurrent NSCLC with nonadenocarcinoma histol-ogy from 25 countries were randomly as-signed between April 2008 and September 2009 to receive figitumumab at 20 mg/kg plus paclitaxel at 200 mg/m2 and carbo-platin at area under the concentration-time curve = 6 mg • min/mL (n = 342) or pa-clitaxel/carboplatin alone (n = 339) once every 3 weeks for up to six cycles. The pri-mary endpoint was overall survival.

The figitumumab and chemotherapy groups were generally balanced for age (median, 62 years in both), sex (76% and 77% male), ethnicity (78% and 80% white, 16% and 17% Asian), Eastern Coopera-

tive Oncology Group performance status (0 in 33% and 34%, 1 in 66% and 64%), disease stage (IIIB in 11% and 12%, IV in 88% in both), smoking status (10% never in both, 42% current in both), histology (squamous cell in 86% and 85%, large cell in 8% in both, adenosquamous in 4% and 6%), and prior treatment (surgery in 21% and 18%, radiation in 13% and 11%, and adjuvant chemotherapy in 4% in both).

No BenefitAfter median follow-up of 23.1

months, median overall survival was 8.6 months in the figitumumab-plus-che-motherapy group vs 9.8 months in the chemotherapy-alone group (hazard ratio [HR] = 1.18, P = .06). One-year overall survival rates were 34% vs 39%. The ef-fect of figitumumab on overall survival was similar across subgroups for sex, per-

formance status, nonsquamous histology, smoking status (never, current), stage, and HbA1c < vs ≥ 5.7%.

Exploratory analysis based on baseline total IGF-1 with a cutoff of 120 ng/mL in-dicated that median overall survival was 7.0 vs 10.4 months in figitumumab recipients and 10.1 vs 9.4 months in chemotherapy-alone recipients patients with low vs high IGF-1. Overall survival was significantly shorter for figitumumab vs chemotherapy patients with low IGF-1 (HR = 1.37, P = .01) and did not differ between patients with higher IGF-1 (HR = 0.93, P = .67).

Hyperglycemia appears to be a class effect of IGF-1R inhibition. Median over-all survival was 8.7 months in the figitu-mumab group and 10.2 months in the control group (HR =1.07, P = .65) among patients with baseline HbA1c < 5.7% and

8.2 vs 9.7 months (HR = 1.26, P =. 05) in those with HbA1c ≥ 5.7%.

Median progression-free survival was 4.7 vs 4.6 months (HR = 1.10, P = .27). Objective response rates were 33% vs 35%.

Adverse EventsAdverse events of any grade that were

more common in the figitumumab plus chemotherapy group included decreased appetite (38% vs 23%), diarrhea (30% vs 14%), vomiting (25% vs 14%), hypergly-cemia (23% vs 5%), and decreased weight (20% vs 9%). Grade 3 or 4 adverse events that occurred more frequently in the figi-tumumab group included hyperglycemia (12% vs 1%), fatigue (8% vs 4%), de-creased appetite (7% vs 2%), dehydration (6% vs <1%), and diarrhea (5% vs 1%).

Serious adverse events occurred in 66% of the figitumumab group vs 51% of

the chemotherapy group (P < .01) and were considered possibly related to treat-ment in 22% vs 12%. Apart from disease progression events, the most common serious adverse events were pneumonia (6% vs 4%), dehydration (4% vs 1%), asthenia (3% vs 1%), and hyperglycemia (3% vs < 1%). Adverse events led to dis-continuation of figitumumab in 7% of patients and to discontinuation of chemo-therapy in 9% of patients in each group.

Treatment-Related DeathsGrade 5 adverse events not related to

disease progression occurred in 13% vs 10% of patients (P = .22), with the most common in figitumumab patients being pulmonary hemorrhage and pneumonia (2% each). Grade 5 adverse events were considered to be treatment-related in 5% of figitumumab patients vs 1% of chemo-therapy patients (P < .01); those observed in the figitumumab group consisted of he-moptysis, pneumonia, unknown cause re-ported only as death, septic shock, cardio-respiratory arrest, decrease of performance status, neutropenic sepsis, toxicity to

various agents, renal failure, hemorrhage, and hypovolemic shock and those in the chemotherapy-alone group consisted of unknown cause reported as death, pneu-monia, septic shock, and dehydration.

Baseline IGF-1 was not related to over-all frequency or type of adverse events. However, grade 5 adverse events were more likely to occur among figitumumab patients with lower vs higher IGF-1 levels (56% vs 38%), with no such difference in risk observed in the chemotherapy group. As stated by the investigators, “Although additional studies are required, these data suggest that low baseline total IGF-1 may be a safety biomarker that identifies a sub-set of patients for whom IGF-1R inhibi-tion is particularly harmful.”

Rates of adverse events did not vary markedly by HbA1c level, but the rate of grade 3 or 4 events among patients with no grade 5 events was slightly lower in those with baseline levels <5.7% in the figitumumab group (30% vs 36%; 33% vs 35% in chemotherapy group).

The investigators concluded:[T]hough the phase II trial suggested an [objective response rate] advantage for adding figitumumab to standard chemo-therapy in advanced NSCLC, our current phase III study involving nonadenocar-cinoma patients failed to show any ben-efit and unexpectedly suggested a possible detrimental effect. This may be a class ef-fect and should be assessed in current and future trials examining IGF-1R inhibitors. Further clinical development of figitu-mumab is not being pursued. n

Disclosure: The study was supported by a grant from the National Cancer Institute and by Pfizer. Dr. Langer reported a consultant or advisory role with and research funding from Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

References1. Langer CJ, Novello S, Park K, et al:

Randomized, phase III trial of first-line figitumumab in combination with pacli-taxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non–small-cell lung cancer. J Clin Oncol 32:2059-2066, 2014.

2. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: Phase II study of the anti–insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 30:4179, 2012.

Thoracic Oncology

[O]ur current phase III study involving nonadenocarcinoma patients failed to show any benefit and unexpectedly suggested a possible detrimental effect.

—Corey J. Langer, MD

Figitumumab in Non–Small Cell Lung Cancer

■ The addition of figitumumab to chemotherapy did not improve overall survival.

■ The addition of figitumumab was associated with a higher frequency of serious adverse events and treatment-related death.


Perspective

Failure of IGF-1R Inhibitor Figitumumab in Advanced Nonadenocarcinoma Non–Small Cell Lung CancerBy Jacek Jassem, MD, PhD

The vast majority of non–small cell lung cancer (NSCLC) patients

present with advanced disease, and many will develop metastases after pri-mary curative therapy. Until recently, despite its low efficacy, chemotherapy remained the only treatment modality in metastatic NSCLC. Within the past decade, the management of advanced NSCLC has dramatically changed as a result of the development of several tar-geted anticancer agents. Currently, some of them constitute standard of care in this malignancy and have replaced che-motherapy in genetically selected pa-tients. The most effective compounds include the small epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib, gefitinib (discontin-ued in the United States), and afatinib (Gilotrif) and the ALK inhibitors crizo-tinib (Xalkori), ceritinib (Zykadia), and alectinib (investigational).

However, the activity of these treatments, as well as the activity of the anti–vascular endothelial growth factor (VEGF)-A antibody bevaci-zumab (Avastin), is virtually restricted to lung adenocarcinoma. Molecular features of other subtypes of NSCLC, particularly squamous cell carcinoma, are far less defined.

In the absence of validated targe-table alterations, there are virtually no approved targeted therapies spe-cific for squamous cell carcinoma; for more than a dozen years, patients with squamous cell carcinoma have been receiving the same, barely effective conventional chemotherapy.

Squamous cell carcinoma is the second most common pathology sub-type of lung cancer, comprising 20% to 30% of newly diagnosed NSCLC in the United States and a greater proportion in Europe and Asia. Thus, closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology.

Targeting the IGF PathwayThe insulin-like growth factor

(IGF) pathway is one of the most ex-tensively studied signaling pathways in cancer. IGF-1 and its receptor, IGF-1R, have been implicated in tumor cell proliferation, survival, and inva-siveness. IGF-1R protein expression has been detected in 40% to 80% of NSCLC specimens and appears to be more common in squamous cell car-cinoma. Hence, the IGF pathway was considered a promising therapeutic target in this subtype.

These hopes were heightened when a randomized phase II study demonstrated that the addition of figi-tumumab, a fully human anti-IGF-1R G2 monoclonal antibody, to a stan-

dard chemotherapy doublet (carbo-platin/paclitaxel) resulted in a higher response rate and trends for superior progression-free survival and overall survival. Most important, a subgroup analysis of this study indicated a par-ticularly high benefit of figitumumab in squamous cell carcinoma patients.

Based on these data, and in view of a strong preclinical rationale for targeting IGF-1R, a phase III study was enthusiastically launched for patients with nonadenocarcinoma histology (mostly squamous cell car-cinoma), a group with a particular need of new successful therapies.1 The study—reported by Langer and colleagues in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post—was terminated early after a planned interim analy-sis demonstrated a hazard ratio that crossed the futility boundary favor-

ing the control arm—an outcome that was an unpleasant surprise and a great disappointment.

Reasons for FailureThe reasons for this failure are

unclear and can only be speculated upon. First, a reanalysis of the pre-ceding phase II study did not con-firm its promising results, leading to their retraction.2 Hence, inhibi-tion of the target by figitumumab may not be strong enough to induce disease response in nonadenocarci-noma patients, a likely explanation in view of negative results of a paral-lel phase III study (ADVIGO 1018, a combination of figitumumab with erlotinib in a similar population).

Indeed, IGF-1R signaling may activate other downstream signaling pathways (for example mTOR), and some of them may become constitu-tively activated to overcome disrup-tion of the IGF-1R axis. Most likely, owing to the genetic complexity of lung cancer, targeting of multiple signaling pathways may be necessary to induce a therapeutic effect.

Second, despite there being a clearly defined therapeutic target, this study did not use predictive bio-markers for patient selection. Nota-bly, there are very few molecularly targeted anticancer therapies that are effective in unselected patient populations. A post hoc biomarker analysis of our study showed no overall survival difference in a sub-set of patients with elevated (> 120 ng/mL) baseline total IGF-1 serum levels and an apparently detrimen-

tal effect of figitumumab in patients with low IGF-1, constituting around two-thirds of the tested population. Importantly, IGF-1 levels did not correlate with treatment outcomes in patients receiving chemotherapy alone, suggesting specific predictive value of this biomarker for figitu-mumab treatment.

Unfortunately, at the time the phase III study was developed, these correlations had not been analyzed in serum samples collected from pa-tients participating in the phase II study. Therefore, no biomarker-based patient selection was em-ployed.

Another factor that might have contributed to the negative results of our study was an unexpectedly high toxicity (not reported in the phase I/II studies) of figitumumab. IGF-1R shares structural homology with the insulin receptor; thus, its inhibition (likely as a class effect) may affect vital physiologic functions. Interest-ingly, low baseline total IGF-1 serum level not only identified patients with detrimental effect of figitu-mumab, but was also a marker of its particularly high toxicity.

Although Pfizer has decided to terminate the figitumumab program in NSCLC, these observations may be exploited in the clinical develop-ment of other IGF-1R inhibitors. n

Disclosure: Dr. Jassem reported no potential conflicts of interest.

References1. Langer CJ, Novello S, Park K, et al:

Randomized, phase III trial of first-line figitumumab in combination with pacli-taxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non–small-cell lung cancer. J Clin Oncol 32:2059-2066, 2014.

2. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: phase II study of the anti–insulin-like growth factor type 1 re-ceptor antibody CP-751,871 in combi-nation with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 30:4179, 2012.

Closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology.

—Jacek Jassem, MD, PhD

Dr. Jassem is Head of the Department of Oncology and Radiotherapy, Medical Uni-versity of Gdańsk. Dr. Jassem was an in-vestigator in and is an author of the article reporting the phase III trial of figitumumab.

I N J E C T I O Nradium Ra 223 dichloride© 2014 Bayer HealthCare Pharmaceuticals Inc.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. 600-10-0007-14d 07/14 Printed in USA

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death.Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts atbaseline and prior to every dose of Xofigo. Priorto first administering Xofigo, the absolute neutrophilcount (ANC) should be ≥1.5 × 109/L, the plateletcount ≥100 × 109/L, and hemoglobin ≥10 g/dL.Prior to subsequent administrations, the ANC shouldbe ≥1 × 109/L and the platelet count ≥50 × 109/L.Discontinue Xofigo if hematologic values do not recoverwithin 6 to 8 weeks after the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see brief summary of full Prescribing Information on following pages.

Bone metastases?1

First sign of symptoms?1

Start to extend survival1,2

• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xo� go (95% con� dence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1

• In the ALSYMPCA prespeci� ed interim analysis, median overall survival was 14.0 months for Xo� go (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

a ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xo ̄go plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

b An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in ̄ndings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

30%reduction in the risk of death

vs placebo1


XOFIGO® IS INDICATED for the treatment of patients with castration-resistantprostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

I N J E C T I O Nradium Ra 223 dichloride© 2014 Bayer HealthCare Pharmaceuticals Inc.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. 600-10-0007-14d 07/14 Printed in USA

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death.Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts atbaseline and prior to every dose of Xofigo. Priorto first administering Xofigo, the absolute neutrophilcount (ANC) should be ≥1.5 × 109/L, the plateletcount ≥100 × 109/L, and hemoglobin ≥10 g/dL.Prior to subsequent administrations, the ANC shouldbe ≥1 × 109/L and the platelet count ≥50 × 109/L.Discontinue Xofigo if hematologic values do not recoverwithin 6 to 8 weeks after the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see brief summary of full Prescribing Information on following pages.

Bone metastases?1

First sign of symptoms?1

Start to extend survival1,2

• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xo� go (95% con� dence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1

• In the ALSYMPCA prespeci� ed interim analysis, median overall survival was 14.0 months for Xo� go (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

a ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xo ̄go plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

b An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in ̄ndings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

30%reduction in the risk of death

vs placebo1


XOFIGO® IS INDICATED for the treatment of patients with castration-resistantprostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

http://www.xofigo-us.com/index.php

Xofigo (radium Ra 223 dichloride) Injection, for intravenous useInitial U.S. Approval: 2013

BRIEF SUMMARY OF PRESCRIBING INFORMATIONCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGEXofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

2 DOSAGE AND ADMINISTRATION2.3 Instructions for Use/Handling General warningXofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization.Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.Radiation protectionThe administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handlingFollow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination.

For patient careWhenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments.

4 CONTRAINDICATIONSXofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:

[see Warnings and Precautions (5.1)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%).Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301)Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % %Blood and lymphatic system disordersPancytopenia 2 1 0 0Gastrointestinal disordersNausea 36 2 35 2Diarrhea 25 2 15 2Vomiting 19 2 14 2General disorders and administration site conditionsPeripheral edema 13 2 10 1Renal and urinary disordersRenal failure and impairment 3 1 1 1

Laboratory AbnormalitiesTable 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 4: Hematologic Laboratory Abnormalities

Hematologic Xofigo (n=600) Placebo (n=301)Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4Abnormalities % % % %Anemia 93 6 88 6Lymphocytopenia 72 20 53 7Leukopenia 35 3 10 <1Thrombocytopenia 31 3 22 <1Neutropenia 18 2 5 <1

Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.Fluid StatusDehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site ReactionsErythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant NeoplasmsXofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic ChemotherapyIn the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONSNo formal clinical drug interaction studies have been performed.

blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category X [see Contraindications (4)]Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo.

8.3 Nursing MothersXofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and efficacy of Xofigo in pediatric patients have not been established.In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric UseOf the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment

neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal ImpairmentNo dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive PotentialContraceptionBecause of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo.

InfertilityThere are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGEThere have been no reports of inadvertent overdosing of Xofigo during clinical studies.There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1

1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityAnimal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATIONAdvise patients:

the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.

treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.

good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.

to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway

Xofigo is a trademark of Bayer Aktiengesellschaft.© 2013, Bayer HealthCare Pharmaceuticals Inc.All rights reserved.Revised: 05/2013


Program Offers Unique Intervention for Acute Promyelocytic LeukemiaBy Caroline Helwick

If Anand P. Jillella, MD, has his way, no future patient with acute promy-

elocytic leukemia (APL) will experi-ence a delay in treatment or lack for an expert consult—and few, if any, will die of this condition.

Mortality from APL is much higher than most oncologists think, especially during the first 30 days, and these early deaths can be prevented, according to Dr. Jillella, Professor of Hematology and Medical Oncology at Emory Uni-versity School of Medicine, Atlanta, who has developed an algorithm and an intervention program that will be

validated in a trial by the Eastern Co-operative Oncology Group/American College of Radiology Imaging Net-work (ECOG/ACRIN).

As a result of his passion and per-sonal quest, and having examined the problem of APL-related mortal-ity for 8 years, Dr. Jillella has become a foremost expert on APL. “I’m really a transplant doctor,” he said in an in-terview with The ASCO Post, “but I’ve become obsessed with APL.”

Dr. Jillella shares credit with his col-league, Vamsi K. Kota, MD, Assistant Professor of Hematology and Medical Oncology at Emory, who is co–princi-pal investigator with Dr. Jillella on the upcoming ECOG/ACRIN trial.

APL was first described in 1950 as a hyperacute fatal illness associ-ated with a hemorrhagic syndrome. The condition remained highly fatal until its genetic profile was identified and all-trans retinoic acid (ATRA, aka tretinoin) became the established treatment. While APL is now largely curable, too many patients still die, he said.

“Early deaths from APL can and should be prevented. Anything short of this is totally unacceptable,” Dr. Jillella commented.

At the recent Debates and Didactics in Hematology and Oncology confer-

ence in Sea Island, Georgia, Dr. Jillela presented an APL patient-care strat-egy that has two components: use of a simplified algorithm, and prompt and frequent consultation with his team of experts.

Mortality Greatly Underestimated

Dr. Jillella pegged the population-wide survival rate at around 65%—much worse than the generally accept-ed figure of 85% to 90% demonstrated in large cooperative group trials.

“These numbers are for highly se-

lected patients treated under a proto-col and perhaps by experts. This is not what happens to these patients in the real world,” he pointed out.

Misconceptions about APL occur because the condition is uncommon, affecting fewer than 1,000 patients a year in the United States. The average oncologist/hematologist rarely if ever sees these patients, and this lack of ex-perience can be fatal for the patient, he suggested.

“A single mistake can result in the demise of the patient because APL is hyperacute, and there are often nu-ances that need to be identified. If you don’t know what you are doing right away, you can kill the patient,” he noted.

Surveillance, Epidemiology, and End Results (SEER) data, recently analyzed by researchers at The Uni-versity of Texas MD Anderson Can-cer Center, Houston, opened the eyes of the medical community to the seriousness of APL.1 The analy-sis over time showed 5-year survival to be 18% between 1975 and 1990, improving to 52% between 1991 and 1999, and to 64% for the years 2000 to 2008; for the most recent period, 1-year survival was 71%.

“Still, the survival rate of 90% in multicenter trials is not a reflection

of the outcome in the general popula-tion. The death rate of 5% to 10% is a gross underestimate. And mortality is not just a problem in small community practices but also in big, sophisticated cancer centers,” he emphasized.

Risk Greatest in First 30 Days Researchers worldwide have ex-

amined early deaths in APL (days 1 to 30), showing fairly consistent mortali-ty rates in the 30% range. “One in three patients dies within the first month, even in countries with sophisticated health care and good record-keeping, such as the United States and Sweden,” he pointed out.

Patients are most likely to die from internal bleeding (70%), differentia-tion syndrome (ie, treatment toxicity, 20%), and infection (10%). Very few patients die as a result of relapse.

The first 30 days are critical, and risk diminishes thereafter. “If we get patients through the first month, it’s basically a ‘home run,’” he said. He believes that improvements in survival rates will come not through drug de-velopment but through the reduction in early deaths. Success in reducing early mortality could push survival estimates into the 90% range, he predicted.

Finding a Plan of Action Dr. Jillella’s particular interest in

APL began while he was Chief of He-matology/Oncology at the Medical College of Georgia (now Georgia Re-gents University). His team treated 19

patients with APL between 2005 and 2009, of whom 7 died. The 11 sur-vivors are now in remission and pre-sumed cured.

“We admitted we were not doing well with these patients. Our goal in 2009 was to fix the problem that we saw,” he said. “I reviewed the literature and conference abstracts. I attended national meetings. I talked to experts.

I had an external consultant review my death charts, to see if we were doing things right. It seemed no one else was seeing this problem: either they were not looking, or they did not acknowl-edge it,” he continued.

“We found a proactive way of treat-ing APL and preventing complications, rather than worrying about them once they occur,” he said.

Dr. Jillella and colleagues created a “culture of awareness” in the states of Georgia and neighboring South Caro-lina. They simplified what was once a 15-page document, creating a 1.5-page checklist, based on standards of care, to guide management. The strategy involves rapid diagnosis and initiation of therapy, aggressive management of coagulopathy, prevention of differ-entiation syndrome, and prophylaxis and aggressive treatment of infection. What makes this protocol really ef-fective is its emphasis on prompt and frequent consultation with an APL expert.

“We function as a resource for the physician caring for the patient. And we call the doctor; we don’t wait for the doctor to call us. We have gotten good at this, and we can predict what’s going to happen to the patient tomor-row, and 2 days from now. That’s a big help to physicians who infrequently see APL,” he said. “We are currently helping to manage three patients, and we are in constant contact with their doctors.”

Dr. Kota added that this arrange-ment allows very sick patients to be

treated locally. “This is intensive treat-ment, and patients need to be close to their families. Bringing them to a spe-cialized center may not be appropriate from the patient’s point of view.”

APL is a medical emergency that should be immediately treated with ATRA, the physicians emphasized. “If you suspect this diagnosis, there is no downside to treating it immediately.

Debates and Didactics in Hematology and Oncology ConferenceHematology

If you suspect this diagnosis, there is no downside to treating it immediately. You can always step back, but withholding treatment will be detrimental to the patient.

—Anand P. Jillella, MD

By collaborating and co-managing patients, we have done much better in APL. I think we can replicate this model in other diseases.

—Vamsi K. Kota, MD


You can always step back, but with-holding treatment will be detrimental to the patient,” Dr. Jillella added.

The algorithm alone “is not a pana-cea,” he emphasized. “It’s extremely important to call someone who treats APL on a day-to-day basis.”

Implementing the Plan Dr. Jillella and Dr. Kota dissemi-

nated their protocol by actually visit-ing every oncology practice through-out Georgia and South Carolina. They urged any oncologist/hematologist to immediately alert the Emory program when APL is suspected, where they could receive an immediate consulta-tion and frequent telephone follow-up.

“We literally went to every prac-tice, and we mailed out flyers with our protocols and our pictures,” Dr. Jillella said. “We think that 90% of practi-tioners in two states (and a few other practices in Florida and North Caro-lina) know about us, and they call us as soon as a patient is seen—or even before one is transferred to their cen-ter. They have our cell phones and we have been available 24/7 for the past 4 years.” Dr. Kota estimated that the program helps an average of three new patients per month.

The 37% mortality rate that Dr. Jillella observed among his own pa-tients prior to instituting the algo-rithm (median follow-up, 2,358 days) was greatly improved after 2009. He and his colleagues have now treated 61 patients, of whom only 3 died (me-dian follow-up, 255 days), for a mor-tality rate of 4.9%.

Commenting on his protocol, he said, “When we had treated nine pa-tients and none died—while three should have—we knew we were onto something.”

Program Will ExpandDrs. Jillella and Kota have sought

funding to expand his program and to more rigorously validate the inter-vention. They received a grant from the Leukemia & Lymphoma Society through its Therapy Acceleration Pro-gram, for work in two states. That pro-gram began accruing July 1, 2013, and will enroll 120 patients over 3 years.

More recently ECOG/ACRIN signed on to help expand the pro-gram’s scope. The goal of EA9131 is to prospectively assess 30-day mortality and to collect survival data using the ECOG/ACRIN mechanism. Physi-cian education, use of the algorithm, and consultations with national ex-perts in several sites will be key com-

ponents of the study. They hope this study will be expanded nationwide.

“We are tremendously excited about this program and this study,” Dr. Jillella said. “We think it will change the outcome in these patients, and that our model will evolve into a global par-adigm whereby a physician in South Korea, for instance, can text us and get

an immediate reply.”Dr. Kota proposed an even larger

objective: that the APL program serve as a model for other challenging diseas-es. “By collaborating and co-managing patients, we have done much better in APL,” he noted. “I think we can repli-cate this model in other diseases.” n

Disclosure: Drs. Jillella and Kota received

grant funding from the Leukemia & Lymphoma Society.

References1. Chen Y Kantarjian H, Wang H, et al:

Acute promyelocytic leukemia: A popula-tion-based study on incidence and survival in the United States, 1975-2008. Cancer 118:5811-5818, 2012.

Debates and Didactics in Hematology and Oncology Conference

Primary Endpoint: • Objective survival

Secondary Endpoints: • Safety: incidence of adverse events

• Overall response rate

• Progression-free survival

• Duration of response

Key Inclusion Criteria2: • Locally advanced or metastatic NSCLC

(stage IIIB, stage IV, or recurrent)

• Representative FFPE tumor specimens

• Disease progression during or following platinum-containing treatment regimen

• Measurable disease, defined by RECIST v1.1


Key Exclusion Criteria2: • History of autoimmune disease

• Active hepatitis B or hepatitis C

• Prior treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

Patients with locally advanced ormetastatic NSCLC who have failed platinum-containing chemotherapy

Now Enrolling

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.


A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)OAK

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Awards

ASTRO Awards $35,500 in Individual Grants to 43 Researchers

The American Society for Radia-tion Oncology (ASTRO) has se-

lected 43 recipients to receive a total of $35,500 for the 2014 Annual Meeting Abstract Awards. The awardees will be recognized at ASTRO’s 56th An-nual Meeting. ASTRO’s 56th Annual Meeting, takes place San Francisco’s Moscone Center, September 14-17,

2014, and will be led by ASTRO Presi-dent Bruce G. Haffty, MD, FASTRO. The theme of the 2014 Meeting is “Tar-geting Cancer: Technology and Biol-ogy.” Watch future issues of The ASCO Post for coverage of ASTRO 2014.

Resident Clinical/Basic Science Research Abstract Award

The Resident Clinical/Basic Science Research Abstract Award recognizes the top three resident authors of the leading abstracts in radiation and cancer biol-ogy, clinical practice, and radiation phys-ics (one award in each category). Award winners will receive $1,500 and a trophy during the scientific session in which their abstract is presented. Recipients are:Radiation and Cancer Biology• Andrew Sharabi, MD, PhD, Johns

Hopkins University, BaltimoreRadiation Physics• Madhu Sudhan Reddy Gudur,

PhD, Stanford University, StanfordClinical Practice• Stephanie Markovina, MD, PhD,

Washington University School of Medicine, St. Louis

Resident Digital Poster Recognition Award

The Resident Digital Poster Recog-nition Award honors the three highest rated abstracts selected for digital poster discussions by residents who are the lead author. Awards are presented for one abstract in each category: radiation and cancer biology, clinical practice, and ra-diation physics. Awardees are:Radiation and Cancer Biology• Pranshu Mohindra, MD, University

of Wisconsin School of Medicine and

Public Health, Madison, Wisconsin Radiation Physics• Adam Gladwish, MD, University of

Toronto, Toronto Clinical Practice• Kim Cao, MD, Institut Curie, Paris

Resident Poster Viewing Recognition Award

The Resident Poster Viewing Rec-ognition Award recognizes the highest rated, resident-submitted abstracts se-lected for paper poster presentations. The top three resident authors in each category (radiation and cancer biology, clinical practice, and radiation physics) are awarded this recognition. The 2014 Resident Poster Viewing Recognition Award recipients are:Clinical Practice• 1st place: Steven Sckolnik, MD, Uni-

versity of Arizona, Tuscon, Arizona• 2nd place: Jessica Zhou, MD, Uni-

versity of Michigan, Ann Arbor, Michigan

• 3rd place: Thomas Mullen, MD, PhD, University of Washington, Seattle

Radiation and Cancer Biology• 1st place: Nils Nicolay, MD, PhD,

Heidelberg University Hospital, Hei-delberg, Germany

• 2nd place: Kate Barrett, MD, Prin-cess Margaret Cancer Centre, To-ronto

• 3rd place: Chi Zhang, MD, PhD, Columbia University Medical Cen-ter/New York Presbyterian Hospital, New York

Radiation Physics• 1st place: Paul Romesser, MD, Me-

morial Sloan Kettering Cancer Cen-ter, New York

• 2nd place: Roohi Gupta, PhD, Fox Chase Cancer Center, Philadelphia

• 3rd place: Ziad Simon Fawaz, MD, University of Montreal Health Cen-tre, Montreal

Basic Science Abstract Award The Basic Science Abstract Award

recognizes up to 10 basic scientists (lead authors) of abstracts selected for pre-sentation at the 2014 ASTRO Annual Meeting, in the biology or physics cat-egories, with a $1,000 grant and a cer-tificate. Up to five awards are available in each category. Junior investigators must have completed an ACGME-accredited residency or PhD program no more than 4 years prior to the deadline, and senior investigators must be biologists or physicists 4 to 10 years post-PhD or

Board certification, whichever comes later. Recipients of the 2014 Basic Sci-ence Abstract Award are:Radiation and Cancer Biology• Masayuki Matsuo, MD, PhD, Na-

tional Institutes of Health, Bethesda• Everett Moding, BS, Duke Univer-

sity, Durham, North Carolina• Ngoc Pham, BS, The University of

Texas MD Anderson Cancer Center, Houston

• Corey Speers, MD, PhD, University of Michigan Health System, Ann Arbor

• Daniel Spratt, MD, Memorial Sloan Kettering Cancer Center, New York

Radiation Physics• Ganiyu Asuni, PhD, Cancercare

Manitoba, Winnipeg• Jeremy Booth, PhD, Northern Syd-

ney Cancer Centre, Sydney• Fiona Hegi-Johnson, MBBS, Uni-

versity of Sydney, Sydney• Xia Li, PhD, University of Nevada,

Las Vegas• Yana Zlateva, MS, McGill Univer-

sity, Montreal

Annual Meeting Scientific Abstract/Travel Award

The Annual Meeting Scientific Ab-stract/Travel Award recognizes out-standing abstracts submitted by early ca-reer scientists, biologists, and physicists. Up to 15 awards of $1,000 each are given (five in each category) to help offset trav-el expenses to attend ASTRO’s Annual Meeting. Awardees are the lead authors of high-scoring abstracts selected for pre-sentation at the 2014 ASTRO Annual Meeting. They include: Clinical Practice• Kamran Ahmed, MD, H. Lee Mof-

fitt Cancer Center and Research In-stitute, Tampa

• Ben Creelan, MD, H. Lee Moffitt Cancer Center and Research Insti-tute, Tampa

• Clement Ho, MD, MS, University of Calgary, Calgary, Alberta

• Anthony Paravati, MD, MBA, Uni-versity of California, San Diego

• John Vargo, MD, University of Pitts-burgh Cancer Institute, Pittsburgh

Radiation and Cancer Biology• Miran Blanchard, MD, Mayo Clin-

ic, Rochester• Nevine Hanna, MD, MPH, Univer-

sity of California, Irvine• Amanda Walker, MD, Johns Hop-

kins University, Baltimore• Christopher Wright, BS, Thomas

Jefferson Medical School, Philadelphia

• Zachary Zumsteg, MD, Memo-rial Sloan Kettering Cancer Center, New York

Radiation Physics• Olivia Kelada, MS, BS, Yale Univer-

sity School of Medicine, New Haven• Yilin Liu, PhD, Duke University,

Durham• Jan Schuemann, PhD, Massachu-

setts General Hospital, Boston• Almut Troeller, MS, Beaumont

Health System, Royal Oak, Michigan• Stephen Yip, PhD, Brigham and

Women’s Hospital/Dana-Farber Cancer Institute and Harvard Medi-cal School, Boston

International–U.S. Annual Meeting Scientific Abstract Award

The International–U.S. Annual Meet-ing Scientific Abstract Award provides a $4,000 grant to a radiation oncologist from a developing country to attend ASTRO’s Annual Meeting and to spend one week at a comprehensive cancer cen-ter in the United States. The award fosters continuing medical education, assists in career development, and aids in establish-ing relationships with ASTRO members who may serve as scientific mentors to the award winner. Recipients are the lead author of an abstract selected for presen-tation at the 2014 ASTRO Annual Meet-ing and have a letter of support from the Chair/Mentor of the U.S. institution that will host the awardee at their cancer cen-ter. The awardee must submit a written summary of their Annual Meeting par-ticipation and the experience garnered at the host cancer center. The recipient of the 2014 International – U.S. Annual Meeting Scientific Abstract Award is:• Yun Chiang, MD, National Taiwan

University Hospital, Taipei, Taiwan

Annual Meeting Nurse Abstract Award

The Annual Meeting Nurse Abstract Award honors the two highest rated ab-stracts with a nursing designation. Award candidates must be nurses who are the lead author or co-author of an abstract selected for presentation at the 2014 ASTRO Annual Meeting. Awardees will be recognized with a $1,000 grant and certificate at the Nurses’ Luncheon. The 2014 Annual Meeting Nurses’ Abstract Award recipients are:• Chiaki Fujioka, RN, Tane General

Hospital, Osaka, Japan• Diane Serra, MS, RN, Mount Sinai

Beth Israel Medical Center, New York n

Bruce G. Haffty, MD, FASTRO


Expert’s Corner

Identifying Impending Death Helps Patients and CaregiversA Conversation With David Hui, MD, MScBy Ronald Piana

S ignificant weight loss, cachexia, and being bedbound signal that a

cancer patient is dying. However, iden-tifying the specific signs that give physi-cians the ability to predict death is not well described in the literature. To bet-ter understand why predicting death is an important part of the care continu-um, The ASCO Post spoke with pallia-tive care specialist and medical oncolo-gist, David Hui, MD, MSc, Assistant Professor in the Departments of Pallia-tive Care/Rehabilitation Medicine and General Oncology at The University of Texas MD Anderson Cancer Center, Houston. Dr. Hui and his colleagues re-cently completed a study in this under-reported area of palliative care.

Study DetailsPlease describe the trial design.It was a prospective longitudinal

observational cohort study designed to identify the physical signs of impend-ing death. It involved the MD Ander-son Cancer Center in Houston and the Barretos Cancer Hospital in Brazil. We basically followed the cancer patients from the day of admission to an acute palliative care unit.

We documented clinical signs of in-terest twice a day, every day until they were discharged from the unit or they died. We were able to tell how often certain systems occurred prior to death. After aggregating and analyzing the data, we identified a number of physi-cal signs that allow us to predict death within 3 days.

Difficult Clinical SituationWhy is it important to be able to iden-

tify the clinical signs of impending death?For a number of reasons. Clinical de-

cisions at the end of life, such as discharg-ing patients and ending and beginning medication schedules, are dependent on a patient’s prognosis. In patients who are actively dying, we need to focus all our efforts on comfort measures that prevent suffering. The key question becomes: how can we as oncologists tell when our patients are actively dying?

This is not a subject without contro-versy. In many countries, there is an in-tense debate about the medical propriety in the use of integrated care pathways for patients who are imminently dying, such as the United Kingdom’s Liverpool Care Pathway for the Dying Patient.

Part of this controversy stems from the fact that, to date, we still do not have a lot of clinical confidence to de-termine when a patient has entered this irreversible phase and will die within a few days. That lack of knowledge creates

unease about frank discussions about care in this very difficult clinical setting. Plus, if we cannot predict with certainty that the patient is imminently dying, then it opens the door for critics of the pathway to say that option was taken away from patients still eligible for life-sustaining therapy.

Family ConsiderationsHow does having a better way to pre-

dict death affect the patient’s family?Families of terminally ill cancer pa-

tients often want to know when to ex-pect death so they can appreciate the process and understand what their loved one is going through. This infor-mation can also help their efforts as

caregivers, and they can plan their lives around the dying process. For instance, if a father is admitted to the hospital and his son lives in another state, it’s important to be able to know if the pa-tient is in the final days of life so his son can make appropriate travel plans for a peaceful closing and to say goodbye.

Overestimating SurvivalIn your work, you indicate that physicians

tend to overestimate survival time in their ter-minally ill cancer patients. Why is this?

A body of literature from our group at MD Anderson, as well as from other institutions, shows that doctors and nurses routinely overestimate survival, and this is largely due to our lack of ac-curate prognostic tools. Moreover, we often lean on the side of overcaution when breaking bad news to patients and their families; there are so many implications to a diagnosis of immi-nent death that doctors often avoid the conversation altogether. Caution is understandable, but honesty based on

accurate information is needed in this difficult setting.

Role of HospiceIs this an area of inquiry that might

help hospice workers?We looked at patients in MD Ander-

son’s acute palliative care unit, because they are being carefully monitored, in the inpatient setting. We suspect what we learned might be applicable to other settings such as hospice; however, this would need to be further tested. Our next step is to conduct a larger validation study to further confirm our findings. We could then develop a diagnostic tool to help clinicians and caregivers identify the specific signs of impending death.

Key SymptomsWhat were the symptoms that best pre-

dicted impending death?There were 10 clinical signs leading

to the death of patients we followed in the palliative care unit. Built on our findings, we were able to divide the signs into two groups based on the fre-quency of occurrence, their onset rela-tive to death, and their predictive value for impending death.

The early signs are decreased level of consciousness, decreased perfor-mance status, and dysphagia. Most patients who die have these signs, which occur about a week before death. These signs have only moder-ate predictive value in telling us that the patient has 3 days left.

The later signs that we documented were pulselessness of the radial artery, apnea, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, respiration with mandibular movement, and de-creased urine output. These signs occur due to bodily changes seen with very decreased level of consciousness—per-haps activity in the brainstem or de-creased cardiovascular profusion. These signs usually occur in the last 3 days of life. They are not always present in pa-tients who die within 3 days, but when they are present, they are strongly pre-dictive of impending death.

So with simple bedside observa-tions, a clinician can predict what is going to happen to the patient by de-tecting the signs, such as respiration with mandibular movement, which es-sentially means the jaw drops during breathing. This is a telltale sign that the patient will die in the next few days.

Having tools that help predict im-pending death will make the stressful process easier for the patient, the doc-tor, and the family and caregivers who need to prepare for the end. As men-tioned, our next step is more research from which we can design a tool to help clinicians predict when death is imminent. n

Disclosure: Dr. Hui reported no potential conflicts of interest.

Issues in Oncology

David Hui, MD, MSc

Having tools that help predict impending death will make the stressful process easier for the patient,

the doctor, and the family and caregivers who need to prepare for the end.

—David Hui, MD, MSc


Does your ovarian cancer patient have a BRCA mutation?Only testing will tell.

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES:1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 4;2013. 3. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. March 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed June 13, 2014. 4. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identifi ed by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of di� erent ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The e� ects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237.

©2014 AstraZeneca. All Rights Reserved. 3011508 Last Updated 07/14

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity,yet BRCA testing is not as common in women of non-European descent.10

Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a signifi cant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair defi ciencies and therefore are particularly sensitive to DNA-damaging agents.13

Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13

Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefi t for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

71%of patients withovarian cancer and a BRCA mutation areaged 50 or olderat diagnosis.8

39%

32%

29%

<5050-59>60

BRCAm Ovarian Cancer Patients by Age at Diagnosis8

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

NCCN, SGO, and ASCO guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity.2-4

In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients.8,9

Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no signifi cant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCA-

The Society of GynecologicOncology encourages the medical community to offer hereditary cancer risk assessment to all women with ovarian, fallopian tube and peritoneal carcinoma.”- SGO Clinical Practice Statement, March 20143

47%53%

Relevant family history

No relevant family history

BRCAm Ovarian Cancer Patients by Family History Status8

OLAP14AGRX1444_HCP_Unbranded_BRCA_Advertorial_r19.indd All Pages 7/25/14 11:45 AM

Does your ovarian cancer patient have a BRCA mutation?Only testing will tell.

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES:1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 4;2013. 3. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. March 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed June 13, 2014. 4. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identifi ed by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of di� erent ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The e� ects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237.

©2014 AstraZeneca. All Rights Reserved. 3011508 Last Updated 07/14

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity,yet BRCA testing is not as common in women of non-European descent.10

Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a signifi cant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair defi ciencies and therefore are particularly sensitive to DNA-damaging agents.13

Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13

Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefi t for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

71%of patients withovarian cancer and a BRCA mutation areaged 50 or olderat diagnosis.8

39%

32%

29%

<5050-59>60

BRCAm Ovarian Cancer Patients by Age at Diagnosis8

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

NCCN, SGO, and ASCO guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity.2-4

In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients.8,9

Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no signifi cant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCA-

The Society of GynecologicOncology encourages the medical community to offer hereditary cancer risk assessment to all women with ovarian, fallopian tube and peritoneal carcinoma.”- SGO Clinical Practice Statement, March 20143

47%53%

Relevant family history

No relevant family history

BRCAm Ovarian Cancer Patients by Family History Status8

OLAP14AGRX1444_HCP_Unbranded_BRCA_Advertorial_r19.indd All Pages 7/25/14 11:45 AM

http://www.astrazeneca.com/Healthcare-professionals


Book Review

A New Book Explores an Old Subject: AgingBy Ronald Piana

D eath is the universal experience shared by Earth’s 7 billion or so in-

habitants, from street beggars in Mum-bai to Wall Street investment bankers. Another common human experience is our determination to forestall death. However, while humans strive to live as long as possible, there’s also a common dread of losing youthful vigor as life’s journey moves into its later years—the human paradox of wanting to live for-ever but not grow old.

Aside from X’s on a calendar, wrin-kled skin, and forgetfulness, what is ag-ing and why do we fear it? This big phil-osophical question has been tackled in a captivating new book, Lighter as We Go: Virtues, Character Strengths, and Ag-ing, by Mindy Greenstein, PhD, and Jimmie Holland, MD, both of Memo-rial Sloan Kettering Cancer Center in New York.

About the AuthorsIn 1977, Dr. Holland took a position

at Memorial Sloan Kettering, where she developed the first psychological and psychiatric services center in a can-cer center. Her groundbreaking work would mature into the subspecialty of psycho-oncology practice.

Since cancer is largely a disease of ag-ing, Dr. Holland’s life’s work informed the writing of this intriguing book. Sim-ilarly, her coauthor and Memorial Sloan Kettering colleague, Dr. Greenstein, is a clinical psychologist with extensive experience talking with emotionally vulnerable cancer patients facing an un-certain future.

Dr. Holland turned 85 during the writing of this book. Dr. Greenstein is 50, and in the introduction, the readers learn that she is a breast cancer survivor, having been diagnosed at the age of 49.

Book collaboration is difficult and can strain the best of colleagues, but the authors’ voices are seamlessly woven throughout the narrative, and even be-fore finishing the introduction, you will come to like these smart and compas-sionate women. They bring erudition and hard-earned experiential knowl-edge to the pages of their book.

Character-Building Experiences

Lighter as We Go is about social sci-ence and the results of research that shed light on the way people experience life as they move from youth to old age and how, if we pay attention, we can in-

tegrate the character-building lessons of aging into other parts of our society—and into cancer care, too. Also, in the words of the authors, “From our differ-ent vantage points, we can both see how much society needs an attitude adjust-ment when it comes to aging.”

Divided into three sections and 13 chapters, Lighter as We Go asks diffi-cult questions and then explores the answers using anecdotal and research-backed narratives. For instance, in chap-ter 1, “The Oak Tree and The U-Bend,” the authors ask, “So, what is this me?” This me can be defined and realized by the term character, which has fallen into disuse in the contemporary psychiat-ric community. But Drs. Holland and Greenstein argue that character is an es-sential component of the healthy aging process, especially in a youth-oriented society that enforces negative stereo-types that “scare the young and make el-ders feel worse about themselves. Mid-lifers fear becoming old, and young adults fear becoming mid-lifers, like

one long cascading domino effect of the fear of aging.”

For help on this issue, they refer to psychologist James Hillman, who noted that it takes a lot of living to develop character, and it only emerges in elders. “How we age, the patterns we regularly perform, and the style of our image show the character at work. As character di-rects aging, aging reveals character.”

Identity BalanceThe authors’ use of stimulating anal-

ogy is shown early in the book when citing research by Joel Sneed and Susan Whit-

bourne, psychologists who developed what is called “identity balance theory,” which suggests that there are processes that help us keep a balanced sense of who we are, even as we age and change in ap-pearance. They explain that the idea of identity balance comes from the fact that not every new experience leads to chang-ing fundamental qualities or how you define yourself. And even when major

changes in one’s life occur, there is still a core identity underpinning those changes.

Professional athletes, whose personal identity is forged to their sport, experi-ence a radical change of life because their careers are cut so short by age. The au-thors use legendary Cleveland Indians pitcher Bob Feller as an example of how character withstands upheaval and en-hances the aging process. After retiring as one of history’s most notable pitchers, Feller built a successful insurance com-pany and became a licensed pilot, living a long and fulfilling life. “While some core aspects of his identity changed over

the years, other core aspects stayed the same, and he could experience himself as a coherent whole, despite the dramatic changes,” the authors write.

‘U-Bend’ PhenomenonIn an absorbing discussion, Drs. Hol-

land and Greenstein look at a phenom-enon that consistently finds its way into the social science literature called the “U-Bend” of life. According to the au-thors, research has surprisingly shown that the age group that feels the greatest sense of well-being is the 82- to 85-year-old group. Eighteen year olds have a very high sense of enjoyment of life, but those feelings begin sliding, reaching bottom around the early 50s. After that, feelings of well-being bend upward rather rap-idly, peaking in the early 80s—hence, the U-Bend phenomenon, which is not completely understood.

“So, what might be going on, and what can we learn from it?” the authors ask. To that end, they discuss a 2009 Yale study that found people who have negative ste-reotypes of aging when they are young are more likely to have serious chronic illnesses as they get older, compared with those with a more positive view of ag-ing. One possible explanation (that’s ex-amined in chapter 9) is that people with more positive expectations about old age might be more likely to develop healthier lifestyles. Therefore, teaching the young to embrace aspects of their own aging could lead to better health outcomes for future generations of elderly.

Mixing social science with anecdotal forays into the personal experiences of real people can be tricky, and if done with too heavy a hand, downright dead-ly to a serious book such as this. But Drs. Holland and Greenstein are natu-ral storytellers, and they put human

BookmarkTitle: Lighter as We Go: Virtues, Character Strengths, and Aging

Authors: Mindy Greenstein, PhD, and Jimmie Holland, MD

Publisher: Oxford University Press

Publication date: September 2014

Price: $27.95; Hardcover, 320 pages

From our different vantage points, we can both see how much society needs an attitude adjustment when it comes to aging.

—Mindy Greenstein, PhD, and Jimmie Holland, MD


FOR OVERALL SURVIVAL LOOK TO ZELBORAF

Signi� cant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety Information on New Primary MalignanciesCutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF.

The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.

Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% con� dence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

77193ha_a.indd 1 4/22/14 9:18 PM

FOR OVERALL SURVIVAL LOOK TO ZELBORAF

Signi� cant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety Information on New Primary MalignanciesCutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF.

The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.

Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% con� dence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

77193ha_a.indd 1 4/22/14 9:18 PM

http://www.zelboraf.com/oncology

Learn more at Zelboraf.com/EXPERIENCE

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OS (months)ZELBORAF (n=337) Dacarbazine (n=338)

OS at FDA approval (August 2011)†

HR=0.47(95% CI, 0.35-0.62), P<0.0001

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2

† At the time of FDA approval, median follow-up was 6.2 months for ZELBORAF patients.

Indication and UsageZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety InformationNew Primary Malignancies (cont’d)Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF.

Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.

Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms.

Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Con� rm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF.

Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF.

In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval.

Prior to and following treatment initiation or after dose modi� cation of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the � rst 3 months, and then every 3 months thereafter or more often as clinically indicated.

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001)

—78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively

In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months)

—Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Signi� cant improvement in OS in a randomized, open-label Phase III trial*

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-� nding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid).

Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modi� cations for intolerable grade 2 or greater photosensitivity.Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm.

Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

75%of responses to ZELBORAF occurred by 1.6 months, approximately the time of the � rst postbaseline assessment

Baseline assessment

First postbaselineassessment

1 month

Signi� cant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine � rst line2

48.4% of treatment naive patients had con� rmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001)

—There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on � le. Genentech, Inc.

© 2014 Genentech USA, Inc. All rights reserved. BRF0000653206

EXTEND SURVIVAL WITH ZELBORAF

77193ha_a.indd 2-3 4/23/14 3:04 PM


Advocates in Oncology

How Pharmaceutical Companies Are Partnering With Patient Advocates to Ensure Access to Oncology CareA Conversation With Thomas P. Sellers, MPABy Jo Cavallo

Thomas P. Sellers, MPA, has been a tireless advocate for patients’

rights for more than 20 years. A 15-year prostate cancer survivor and only child,

Mr. Sellers said it was his mother’s death from lung cancer when she was 51, fol-

lowed by the death of his father from glioblastoma multiforme that led him to a career in patient advocacy. Over the past 2 decades, Mr. Sellers held the positions of Chief Financial Officer for the American Cancer Society New Eng-land Division and CEO of the National Coalition for Cancer Survivorship. He

faces on each topic they engage. For example, Nancy Miller, a

63-year-retired engineer says, “People over 60 have less to lose. Their striving is over, and now you can take risks. It’s time to be generative. You have to go out of your way to connect with people.” That’s a powerful sentiment, shared by millions of Americans.

The authors seize on the complicated notion of being generative. Citing the psy-chologist Erik Erikson, who in 1950 the-orized that mid-life was the time in our life to generate and nurture the next gen-eration. And quite poetically, psychiatrist George Vaillant “refers to us [mid-lifers] as society’s ‘keepers of meaning,’ a role we will continue into older age.”

Important LessonAlong with deep and thoughtful ex-

plorations of aging that will assuredly en-lighten their audience, the authors give even more, such as chapter 4, “Older Age in the Olden Days: A History of Aging in the Western World.” This chapter details the history of our very complicated rela-tionship with age and mortality, from an-tiquity to present day. The authors sum up this edifying section thusly: “Perhaps one of the most important lessons of his-tory is the importance of learning to rec-oncile the good with the bad, the things we can control with the things we can’t, the older with the younger.”

Lighter as We Go does not glorify old age. But by explaining the multilayered physical and psychological processes of aging, the book defends the old against crass ageists that populate much of our pop culture. More important, without being the least bit didactic, Drs. Holland and Greenstein have open-mindedly ex-plored and discussed a societal topic that still remains sorely misunderstood, partly out of our universal fear of aging. This bold and liberating book should be on ev-eryone’s reading list, regardless of age. n

Book Reviewcontinued from page 68

BRAFP-52627_M5_BrfSmry.indd4-10-2014 3:55 PM Suke Yawata / Arielle Benjoya

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ZELBORAF® (vemurafenib) tablet for oral useInitial U.S. Approval: 2011This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.1 INDICATIONS AND USAGE ZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].5 WARNINGS AND PRECAUTIONS5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)].5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.Institute dose modifications for intolerable Grade 2 or greater photosensitivity.5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONS6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

* Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.

a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2).

† Includes both squamous cell carcinoma of the skin and keratoacanthoma.

# Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysisMusculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysisNeoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinomaInfections and infestations: folliculitisEye disorders: retinal vein occlusionVascular disorders: vasculitisCardiac disorders: atrial fibrillationTable 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)].7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.10 OVERDOSAGEThere is no information on overdosage of ZELBORAF.17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following:• Evidence of BRAF V600E mutation in the tumor specimen with an FDA

approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)].

• ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)].

• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)].

• Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)].

• ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)].

• Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)].

• ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)].

• Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)].

• ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by:Genentech, Inc.1 DNA Way BRF0000422005 South San Francisco, CA Initial U.S. Approval: August 2011 94080-4990 © 2014 Genentech, Inc

Change From Baseline to Grade 3/4

Parameter ZELBORAF (%) Dacarbazine (%)GGT 11.5 8.6AST 0.9 0.4ALT 2.8 1.9Alkaline phosphatase 2.9 0.4Bilirubin 1.9 0

Trial 1: Treatment Naïve Patients Trial 2: Patients with Failure of at Least One Prior

Systemic Therapy

ADRs ZELBORAFn= 336

Dacarbazinen= 287

ZELBORAFn= 132

All Grades

(%)

Grade 3a

(%)

All Grades

(%)

Grade 3

(%)

All Grades

(%)

Grade 3a

(%)Skin and subcutaneous tissue disordersRash 37 8 2 0 52 7Photosensitivity reaction 33 3 4 0 49 3Alopecia 45 < 1 2 0 36 0Pruritus 23 1 1 0 30 2Hyperkeratosis 24 1 < 1 0 28 0Rash maculo-papular 9 2 < 1 0 21 6Actinic keratosis 8 0 3 0 17 0Dry skin 19 0 1 0 16 0Rash papular 5 < 1 0 0 13 0Erythema 14 0 2 0 8 0Musculoskeletal and connective tissue disordersArthralgia 53 4 3 < 1 67 8Myalgia 13 < 1 1 0 24 < 1Pain in extremity 18 < 1 6 2 9 0Musculoskeletal pain 8 0 4 < 1 11 0Back pain 8 < 1 5 < 1 11 < 1General disorders and administration site conditionsFatigue 38 2 33 2 54 4Edema peripheral 17 < 1 5 0 23 0Pyrexia 19 < 1 9 < 1 17 2Asthenia 11 < 1 9 < 1 2 0Gastrointestinal disordersNausea 35 2 43 2 37 2Diarrhea 28 < 1 13 < 1 29 < 1Vomiting 18 1 26 1 26 2Constipation 12 < 1 24 0 16 0Nervous system disordersHeadache 23 < 1 10 0 27 0Dysgeusia 14 0 3 0 11 0Neoplasms benign, malignant and unspecified (includes cysts and polyps)Skin papilloma 21 < 1 0 0 30 0Cutaneous SCC†# 24 22 < 1 < 1 24 24Seborrheic keratosis 10 < 1 1 0 14 0InvestigationsGamma- glutamyltransferase increased

5 3 1 0 15 6

Metabolism and nutrition disordersDecreased appetite 18 0 8 < 1 21 0Respiratory, thoracic and mediastinal disordersCough 8 0 7 0 12 0Injury, poisoning and procedural complicationsSunburn 10 0 0 0 14 0

Safety:7"

Safety:10"

77193ha_a.indd 4 4/22/14 9:18 PM


Advocates in Oncology

is currently Senior Director for Patient Advocacy and Corporate Philanthropy for Millennium, The Takeda Oncology Company.

His overarching goal at Millennium is to ensure that patients have access to the most effective therapies available and that the company develops pro-grams to address the unmet needs of patients with cancer and their caregiv-ers, including giving them a greater role in drug and clinical trial development.

The ASCO Post talked with Mr. Sellers about the increasing collabora-tion among patients, patient advocacy groups, and the pharmaceutical in-dustry in the funding of new oncology therapies and in the facilitation of clini-cal trial design and patient recruitment, and how these relationships are having an impact on drug development and approval.

Advocacy CollaborationsHow does Millennium collaborate with

patient advocates in its drug development process?

We strategize and engage with pa-tient advocacy groups—such as the International Myeloma Foundation (IMF), the Multiple Myeloma Research Foundation (MMRF) and the Leuke-mia & Lymphoma Society (LLS)—that are very involved in and have a significant amount of knowledge and experience in the design of clinical trial concepts and protocols to consult with our oncology research division about patient concerns. We are also currently looking at additional ways to directly in-volve patient advocates who are highly trained in the clinical trial process.

In addition, we convene meetings with patient advocacy leaders in-volved in cancers we do not currently have a lot of drug development in, such as the Ovarian Cancer National Alliance, LUNGevity, Lung Cancer Alliance, and Melanoma Research Foundation, because we want the voices of all active participants in the cancer community around the table.

Several years ago, we formed the Cancer Advocacy Council, which is made up of patient advocates and thought leaders in the patient commu-nity, and each year we convene one or two meetings to address a specific topic of concern to patients, with the goal of advancing our knowledge of patient needs—for example, easier access to therapies or patient education about their cancer. We also want to know about patients’ experience with their

therapies, such as treatment effective-ness and side effects.

We also have meetings with rep-resentatives from the American Can-cer Society and the Patient Advocate Foundation to ensure that we are aware of every concern patients have, includ-ing their financial concerns. We are re-ally focused on building relationships in which there is mutual value for patients, caregivers, and us.

Greatest ConcernsWhat are some of patients’ greatest

concerns?Their number 1 concern is having

access to drugs, and that access can in-clude everything from getting the drug to transportation to and from the can-cer clinic, lodging, and other financial impacts of having cancer, including not being able to work or their caregivers not being able to work.

One of the ways we try to mitigate the financial burden of having cancer is by supporting the patient assistance programs of organizations like the LLS or the Patient Advocate Foundation and CancerCare’s transportation pro-gram.

Therapeutic AdvancesHow is Millennium partnering with

patient advocacy groups to advance cancer therapies?

One example is MMRF’s 10-year CoMMpass study in multiple myeloma. Millennium was the first company to collaborate with MMRF to both fund and participate in the study. But our involvement is more than just writing a check. We want to partner with patient advocacy groups and private founda-tions to be part of the entire process to learn how patients respond to therapies.

Patients and the pharmaceutical industry will greatly benefit from the work that CoMMpass is doing. Millen-nium’s Translational Medicine Depart-ment is involved in that study, but the

relationship grew from having a strong patient advocacy function within Mil-lennium.

Another example is our collabora-tion with the IMF to identify myeloma patient preferences.

Changing RelationshipPlease talk about the evolution of pa-

tient involvement in drug development. How has the relationship changed between

patients and pharmaceutical companies?It has changed significantly and in

multiple ways. Five years ago, the ex-tent of pharmaceutical companies’ in-volvement with patient groups seemed to be limited to the drugs serving the needs of patients involved in those groups. With the advent and emphasis on patient-focused drug development and through initiatives like the U.S. House of Representatives Committee on Energy and Commerce’s 21st Cen-tury Cures, which is studying the gap between the science of cures and drug regulation, patient groups are having more influence across the entire drug development continuum, from discov-ery and U.S. Food and Drug Adminis-tration (FDA) approval to market.

For example, the MMRF’s Mul-tiple Myeloma Research Consortium is serving as an incubator for clinical trials, and the MMRF has invested a lot of money in the development of new myeloma therapies. Other pa-tient organizations such as the LLS are supporting early drug discovery in preclinical and clinical studies. And there are lots of other groups getting involved earlier and earlier in the drug development process.

There is also more patient involve-ment in government regulatory agen-cies, including the FDA and the Pre-scription Drug User Fee Act, which plays an important role in expediting new drug approval. The FDA has start-ed holding a series of public meetings

with patient groups on individual dis-eases to develop a structured approach to evaluating and regulating drugs based on benefit and risk.

Clinical Trial FundingIs there more emphasis now on patient

advocacy groups directly funding specific clinical trials?

Yes. There are many patient groups directly funding clinical trials and en-gaged in helping with the recruitment or the design and organization of clini-cal trials. Patient advocacy groups are also involved in key government agen-cies to present the patient perspective to advance cancer research. For exam-ple, the National Cancer Institute has an Office of Advocacy Relations and also includes patient advocates who sit on clinical trial and grant review com-mittees and have helped write patient-friendly templates for clinical trial con-sent forms, among other things.

Major AccomplishmentsWhat significant accomplishments

have you seen as a result of patient involve-ment in drug development at Millennium?

One of the initiatives that came out of our Cancer Advocacy Council is a more accurate way to measure patient outcomes. We brought a group of pros-tate cancer advocates in to talk about issues they wanted to address in col-lecting patient reported outcomes and improved the clarity, appropriateness, validity, and usefulness of survey ques-tions.

Ethical IssuesWhat are the ethical boundaries phar-

maceutical companies have to adhere to when working with patient groups?

Most importantly, we must have transparent and open communication characterized by integrity and mutual respect, with clear expectations about our shared goals and objectives. Also, patient groups independently develop their own content for patient educa-tion materials or patient education programs that may have costs offset by unrestricted educational grants we provide.

Another way Millennium operates to preserve the integrity of the process is to rarely be the sole sponsor on a proj-ect or program. We prefer to work with other companies to fund work for the benefit of patients in a particular area. n

Disclosure: Mr. Sellers is Senior Director for Patient Advocacy and Corporate Philanthropy for Millennium, The Takeda Oncology Company.

With the advent and emphasis on patient-focused drug development and through initiatives like 21st Century Cures, patient groups are having more influence across the entire drug development continuum, from discovery and approval to market.

—Thomas P. Sellers, MPA

BRAFP-52627_M5_BrfSmry.indd4-10-2014 3:55 PM Suke Yawata / Arielle Benjoya

Client CodeClient

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BRF0000422005Genentech/ZELBORAF

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Helvetica Neue LT Std (77 Bold Condensed, 57 Condensed, 57 Condensed Oblique, 56 Italic), Myriad Pro (Black, Regular, Bold)

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Printed At

ZELBORAF® (vemurafenib) tablet for oral useInitial U.S. Approval: 2011This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.1 INDICATIONS AND USAGE ZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].5 WARNINGS AND PRECAUTIONS5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)].5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.Institute dose modifications for intolerable Grade 2 or greater photosensitivity.5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONS6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

* Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.

a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2).

† Includes both squamous cell carcinoma of the skin and keratoacanthoma.

# Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysisMusculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysisNeoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinomaInfections and infestations: folliculitisEye disorders: retinal vein occlusionVascular disorders: vasculitisCardiac disorders: atrial fibrillationTable 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)].7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.10 OVERDOSAGEThere is no information on overdosage of ZELBORAF.17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following:• Evidence of BRAF V600E mutation in the tumor specimen with an FDA

approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)].

• ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)].

• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)].

• Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)].

• ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)].

• Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)].

• ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)].

• Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)].

• ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by:Genentech, Inc.1 DNA Way BRF0000422005 South San Francisco, CA Initial U.S. Approval: August 2011 94080-4990 © 2014 Genentech, Inc

Change From Baseline to Grade 3/4

Parameter ZELBORAF (%) Dacarbazine (%)GGT 11.5 8.6AST 0.9 0.4ALT 2.8 1.9Alkaline phosphatase 2.9 0.4Bilirubin 1.9 0

Trial 1: Treatment Naïve Patients Trial 2: Patients with Failure of at Least One Prior

Systemic Therapy

ADRs ZELBORAFn= 336

Dacarbazinen= 287

ZELBORAFn= 132

All Grades

(%)

Grade 3a

(%)

All Grades

(%)

Grade 3

(%)

All Grades

(%)

Grade 3a

(%)Skin and subcutaneous tissue disordersRash 37 8 2 0 52 7Photosensitivity reaction 33 3 4 0 49 3Alopecia 45 < 1 2 0 36 0Pruritus 23 1 1 0 30 2Hyperkeratosis 24 1 < 1 0 28 0Rash maculo-papular 9 2 < 1 0 21 6Actinic keratosis 8 0 3 0 17 0Dry skin 19 0 1 0 16 0Rash papular 5 < 1 0 0 13 0Erythema 14 0 2 0 8 0Musculoskeletal and connective tissue disordersArthralgia 53 4 3 < 1 67 8Myalgia 13 < 1 1 0 24 < 1Pain in extremity 18 < 1 6 2 9 0Musculoskeletal pain 8 0 4 < 1 11 0Back pain 8 < 1 5 < 1 11 < 1General disorders and administration site conditionsFatigue 38 2 33 2 54 4Edema peripheral 17 < 1 5 0 23 0Pyrexia 19 < 1 9 < 1 17 2Asthenia 11 < 1 9 < 1 2 0Gastrointestinal disordersNausea 35 2 43 2 37 2Diarrhea 28 < 1 13 < 1 29 < 1Vomiting 18 1 26 1 26 2Constipation 12 < 1 24 0 16 0Nervous system disordersHeadache 23 < 1 10 0 27 0Dysgeusia 14 0 3 0 11 0Neoplasms benign, malignant and unspecified (includes cysts and polyps)Skin papilloma 21 < 1 0 0 30 0Cutaneous SCC†# 24 22 < 1 < 1 24 24Seborrheic keratosis 10 < 1 1 0 14 0InvestigationsGamma- glutamyltransferase increased

5 3 1 0 15 6

Metabolism and nutrition disordersDecreased appetite 18 0 8 < 1 21 0Respiratory, thoracic and mediastinal disordersCough 8 0 7 0 12 0Injury, poisoning and procedural complicationsSunburn 10 0 0 0 14 0

Safety:7"

Safety:10"

77193ha_a.indd 4 4/22/14 9:18 PM


Clinical Trials Resource Guide

Ongoing Clinical Trials Actively Recruiting Patients With Kidney CancerCompiled by Jo Cavallo

KIDNEY CANCER

Study Type: Interventional/single-group assignment

Study Title: A Prospective Pi-lot Study Evaluating Renal Lesions Through Contrast-Enhanced Utra-sound in Patients With Renal Cancer and in Those With a Risk Factor for Re-nal Malignancy

Study Sponsor and Collabora-tors: University of North Carolina Lineberger Comprehensive Cancer Center

Purpose: This pilot study is designed to evaluate the accuracy of contrast-en-hanced ultrasound when used to evalu-ate renal lesions in two different popula-tions: patients with known renal tumors (cohort 1) and patients with a risk fac-tor for renal malignancy in whom their screening ultrasound shows an indeter-minate or possibly malignant renal mass (cohort 2).

Ages Eligible for Study: 18 years and older

Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures:

Feasibility of using contrast-enhanced ultrasound in diagnosing renal malig-nancy in patients with known renal dis-ease and in patients with a risk factor for renal malignancy diagnosed with sus-picious or indeterminate lesions (time frame: 12 months)

Principal Investigator: Kimryn Rathmell, MD, University of North Carolina Lineberger Comprehensive Cancer Center. Contact: Gayle Grig-son, RN; 919-966-4432; [email protected]

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01751529

Study Type: Phase II/intervention-al/nonrandomized

Study Title: A Phase II Multi-Cen-ter Study of Bevacizumab in Combina-tion With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma

Study Sponsor and Collaborators: National Cancer Institute

Purpose: To determine whether the combination of ixabepilone, a member of the class of drugs called epothilones, and bevacizumab (Avastin) is effective in treating kidney cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Re-

sponse rate per RECISTPrincipal Investigator: Antonio T.

Fojo, MD, National Cancer Institute; 301-496-2831; [email protected]


Study Type: Phase II/observationalStudy Title: A Phase II Metastasec-

tomy Study for Patients With Renal Cell Carcinoma

Study Sponsor and Collaborators: MD Anderson Cancer Center

Purpose: To learn if the surgical re-moval of the primary tumor or the parts of the cancer that has spread to other parts of the body is a good method for treating pa-tients with kidney cancer. Only the parts of the cancer that has spread will be removed during the surgery.

Ages Eligible for Study: N/AGenders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: 24-

week progression-free/relapse-free sur-vival time (time frame: every 3 months for the first year; 4 months during the second year; every 6 months in the third through fifth year)

Principal Investigator: Eric Jonasch, MD, The University of Texas MD Ander-son Cancer Center; 713-792-2830


Study Type: Phase II/intervention-al/randomized

Study Title: A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothe-lial Growth Factor Therapy in Patients With Renal Cell Carcinoma Who Have

Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib


Purpose: To investigate how well trebananib (AMG 386) with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients with kidney cancer that has spread to other places in the body



Overall tumor response rate defined as the total number of efficacy-evaluable patients who achieve a complete or par-tial response by Response Evaluation Criteria in Solid Tumors version 1.1 cri-teria (time frame: up to 8 weeks)

Principal Investigator: Thomas J. Semrad, MD, University of California at David Cancer Center; 916-734-3771; [email protected]


Study Type: Interventional/single-group assignment

Study Title: A Prospective Pilot Study Evaluating Renal Lesions Through Contrast-enhanced Utrasound in Patients With Renal Cancer and in Those With a Risk Factor for Renal Malignancy

Study Sponsor and Collaborators: University of North Carolina Lineberg-er Comprehensive Cancer Center

Purpose: This pilot study is designed to evaluate the accuracy of contrast-en-hanced ultrasound when used to evaluate renal lesions in two different populations: patients with known renal tumors (cohort 1) and patients with a risk factor for renal malignancy in whom their screening ultra-sound shows an indeterminate or possibly malignant renal mass (cohort 2).



Feasibility of using contrast-enhanced ultrasound in diagnosing renal malig-nancy in patients with known renal dis-ease and in patients with a risk factor for renal malignancy diagnosed with sus-picious or indeterminate lesions (time frame: 12 months)

Principal Investigator: Kimryn

Rathmell, MD, University of North Carolina Lineberger Comprehensive Cancer Center. Contact: Gayle Grig-son, RN; 919-966-4432; [email protected]



Study Title: A Phase II Study of Bevacizumab Alone or in Combination With TRC105 for Advanced Renal Cell Cancer


Purpose: To evaluate how well bev-acizumab with or without monoclonal antibody therapy works in treating pa-tients with metastatic kidney cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Pro-

gression-free survival (time frame: the duration of time from start of treatment to time of progression or death, assessed at 12 weeks)

Principal Investigator: Tanya B. Dorff, MD, University of South Caroli-na Norris Comprehensive Cancer Cen-ter; 323-865-3900; [email protected]



Study Title: Randomized Phase II Study Comparing Cabozantinib (NSC #761968) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Meta-static Renal Cell Carcinoma


Purpose: To study how well cabozan-tinib-s-malate works compared to suni-tinib malate in treating patients with pre-viously untreated kidney cancer that has spread to nearby areas of the body



gression-free survival (time frame: up to 5 years)

Principal Investigator: Toni K. Choueiri, MD, Alliance for Clinical Tri-

The information in this Clinical Trials Resource Guide includes

actively recruiting clinical stud-ies for patients with kidney can-cer. The list includes a pilot study and observational, randomized, and nonrandomized phase II and phase III studies evaluating new therapies, combination therapies, surgical techniques, and contrast-enhanced ultrasound diagnostics. All of the studies are listed on the National Institutes of Health web-site at ClinicalTrials.go

Genitourinary Oncology

http://clinicaltrials.gov/show/NCT01751529





Clinical Trials Resource Guide

als in Oncology; [email protected]



Study Title: A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal Cell Car-cinoma With Sarcomatoid Features

Study Sponsor and Collaborators: Eastern Cooperative Oncology Group; National Cancer Institute

Purpose: To investigate giving sunitinib malate together with or without gemcitabine hydrochloride to determine how effective they are in treating patients with advanced kid-ney cancer that cannot be removed by surgery


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Re-

sponse rate Principal Investigator: Naomi S.

Balzer-Haas, MD, Abramson Cancer Center of the University of Pennsylva-nia. Contact: Clinical Trials Office of the Abramson Cancer Center of the University of Pennsylvania at 800-474-9892


Study Type: Phase II/intervention-al/single-group assignment

Study Title: A Phase II Efficacy Trial of Pazopanib in Non-Clear Cell Metastatic Renal Cell Cancer (mRCC) PINCR

Study Sponsor and Collaborators: Mayo Clinic

Purpose: To study how well pazo-panib hydrochloride works in treat-ing patients with metastatic kidney cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Over-

all survival time (time frame: 12 months)Principal Investigator: Brian A.

Costell, MD, Mayo Clinic. Contact: Mayo Clinic Clinical Trials Referral Of-fice: 507-538-7623


Study Type: Phase II/intervention-al/single-group assignment

Study Title: Phase II Trial of Mod-erate Dose Bolus Interleukin-1 in Meta-static Kidney Cancer

Study Sponsor and Collaborators: Western Regional Medical Center

Purpose: To determine whether interleukin-2 at the dose and schedule used in this study helps increase tumor shrinkage



gression-free survival of patients with metastatic kidney cancer who have had disease progression on at least one prior therapy or who have not been treated

(time frame: 9 weeks)Principal Investigator: Walter

Quan, MD, Western Regional Medi-cal Center. Contact: Marci Pierog, RN, 623-207-3000; [email protected]

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01702909 n

Proceed with confidence

Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy.

Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.

© 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today.

• Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1

Confidence begins with a highly accurate risk assessment

For HR+, early-stage invasive breast cancer

18434_nanpro_fa2_ascopst_ad.indd 1 3/24/14 1:43 PM


http://prosigna.com


Gynecologic Cancer Care: Collaboration With Resource-Challenged EthiopiaBy Ronald Piana

O ver the past 40 years, largely be-cause of universal Pap screen-

ing, cervical cancer deaths have been drastically reduced in the United States and other wealthy industrialized coun-tries. However, cervical cancer is still a leading cause of cancer death among women in resource-challenged areas of the developing world, such as sub-Saharan Africa. The ASCO Post recently spoke with Eva J. Kantelhardt, MD, a gynecologist at Martin Luther Univer-sity of Halle-Wittenberg, Halle (Saale), Germany, whose clinical research focus is on gynecologic oncology and breast cancer. Among other things, she spoke about her ongoing research in cervical cancer in Ethiopia.

Rewarding BeginningsPlease tell the readers a bit about your-

self, where you were born and raised.I was born in Mount Kisco, New

York. My parents are both German, but my father, a physicist, was in the United States doing a 1-year postdoctoral pro-gram at the IBM research laboratories in New York State. My early schooling was mainly in the western part of Ger-many in the small town of Schwerte, as well as high school in Göttingen.

Since my father had sabbatical leaves every 4 years, we spent 6-month pe-riods in different parts of the United States as a family. This was a great expe-rience as a child, as I discovered the cul-tural differences and learned English. It is a rewarding situation to begin school as the new foreigner in class and to then be welcomed and make new friends.

Path to a Medical CareerPlease describe your early education

and college, as well as any influences on your decision to pursue a career in medi-cine.

My grandmother studied medicine in the 1920s in Germany and Austria, one of the first women to do so. Having Jewish family members and given the growing political turmoil in Germany, in 1938 she applied to work as a doc-tor in Latin America. Her request was denied, however, since the organization coordinating this effort thought women were unable do this type of work.

Fortunately, the family found an-other opportunity to emigrate from Germany to Brazil, where my grand-mother practiced obstetrics. I still have her notes and some of her instruments. Even though I never met her person-ally, her example encouraged me to go into medicine. My mother was born in Brazil, and parts of the family still live there. My cousin is a plastic surgeon in São Paulo.

When I was 16, I saw a report from a pediatrician who was a missionary in South Africa and worked there during the Apartheid era. This impressed me

very much. I asked her, if I study medi-cine, might I go and spend half a year working with her. She said yes, but not to come before the fourth year of studies.

From the Lab to the ClinicPlease describe medical school and

what influences led you to specialize in gy-necologic oncology.

The medical school at Georg-August University in Göttingen is known for very good natural sciences and preclini-cal education. I decided to spend time in the biochemistry laboratory of Kurt von Figura, MD, who later became the University President. Our group worked with one of the first transgenic mice, which I had to take care of even on weekends. Seeing accurate lab re-search and vigorous collaboration was very memorable.

After finishing the thesis before my internship, I decided not to stay in the lab full-time, but rather to work with patients and do clinical research as well. I did my residency at a university hos-pital to make sure research would be included. It’s worth noting that doing a residency in Germany is also possible

in smaller regional hospitals, without a research background.

When I had finally finished my first 4 years of medicine, I went to the South African North West province, for an ex-tended 6-month elective. The pediatri-cian, Angelika Krug, MD, arranged for me to start my elective where life starts: in the obstetrics ward of a small rural hospital. This was a very positive ex-perience, but I also saw three maternal deaths in only 2 months. I realized that the accumulation of small mistakes can lead to catastrophes and that medicine does have its limitations.

Altogether, the experience there en-couraged me to become a gynecologist and to focus on improving health care for women in settings with limited re-sources. I learned that this could only be done by analyzing the situation, gen-erating evidence, and finding ways to improve the situation as a team.

Ethiopian ExperiencePlease tell us about your current career

and your epidemiologic research in cervi-cal cancer in Ethiopia.

In 2007, a very good Ethiopian nurse friend of mine was diagnosed with breast cancer during her pregnancy. This led me to Solomon Bogale, MD, the only oncologist in Addis Ababa at the only oncologic center (with one cobalt radiotherapy machine) in the country at that time. In the end, we treated my friend in Germany because there was less of a wait there. However, I started visiting Dr. Bogale and collabo-rating with him.

He was very open to collaboration, since few people were interested in his work in cancer. As we discovered, research funding was available mainly for HIV, tu-

berculosis, and malaria. We started with three German students in Addis Ababa in 2010. They documented pathology re-ports and patients’ disease course, and did interviews in the countryside.

One by one, colleagues from pa-thology, public health, surgery, and gynecology at Addis Ababa University joined the group to collect data on fe-male cancer in Ethiopia. More students from Germany and Ethiopia worked together. Visiting conferences like the AORTIC (African Organization for Re-search and Treatment in Cancer) raised spirits on the interdisciplinary team.

We somehow convinced the Ger-man Ministry for Research and Educa-tion to provide a grant for our activities, including the start of a population-based cancer registry in Addis Ababa in 2011. Now there are three radiation on-cologists working there, and Mathewos Assefa, MD, is our main collaborator.

We often faced bureaucratic chal-lenges, technical problems, lack of es-sentials like water or Internet access, and many other unexpected events. But after working together for some time, I can quote my colleague Adamu Addissie, MD, MPH, MA, from the public health sector: “This is part of the experience!” And it truly is a wonderful experience and a privilege to work with my colleagues from Ethiopia and Ger-many to improve female cancer care.

No Quick-Win StrategiesAs an oncologic specialist and global re-

searcher, what is your outlook for reducing the cancer burden in developing nations?

The World Health Organization says: “Do not drink, do not smoke, par-ticipate in sports, and maintain a nor-mal weight.” These recommendations are of course essential, but there are difficulties in promoting them even in countries with highly educated people. For female cancer in Africa, we need more evidence-based strategies.

Much progress has been made in surveillance, with 20 African countries currently submitting data to the Interna-tional Agency for Research in Cancer, for example, in the GLOBOCAN Project (led by Donald Maxwell Parkin, MD). Prevention measures, such as HPV vac-


Forming a collaborative team is the only way forward to tackle a complex issue like oncologic care in these resource-challenged areas.

—Eva J. Kantelhardt, MD


cination and optimization of early-detec-tion strategies for cervical cancer, have been started nationwide now in Rwanda, with other countries following suit.

Downstaging breast cancer through awareness campaigns is on the way. Hospital-based care must be expanded as well, since there is no option for pre-venting breast cancer, for example. On-cology centers must become available throughout these countries. The fact that about half the countries in Africa do not offer radiotherapy represents a serious health-care gap.

For noncommunicable diseases

like cancer, there will be no quick-win strategies. A multidisciplinary approach requiring tertiary-level institutions needs, first of all, political commitment with careful and wise planning. When governments start thinking about buy-ing linear accelerators, they also have to think about stable electrical current and radiotherapy technicians who can handle the machines.

Looking AheadAny last thoughts about your future

direction?My future direction is to continue in

clinical work and research, with a focus on Africa, striving to realize benefits for patients from translational medicine and transnational collaborative efforts. I am sure that high-quality research can be done in resource-challenged coun-tries like Ethiopia. Having joint projects at an eye-to-eye level with colleagues in Africa is the basis for progress in the laboratory and the clinic.

I am aiming to continue surveil-lance and epidemiologic studies, look at best practices, do operational re-search, and in the long term, set up ca-pacities for conducting clinical trials in

Africa. Several international collabora-tions for improving oncologic care in Ethiopia are working together with the Addis Ababa University and the Ethio-pian Ministry of Health.

Forming a collaborative team is the only way forward to tackle a complex issue like oncologic care in these re-source-challenged areas. This will be to the benefit of colleagues in Africa who are the ones facing such a magnitude of patients, and who will ultimately change patients’ lives for the better. n

Disclosure: Dr. Kantelhardt reported no potential conflicts of interest.

NIH Awards Two New Grants to Explore the Understanding of Genomics Research in Africa

Two grants totaling more than $300,000 will support studies on

genomic literacy among Africans as it relates to research conducted in Af-rica by African investigators. The 3-year grants are part of the Human Heredity and Health in Africa (H3Africa) pro-gram, funded by the National Institutes of Health’s Common Fund in partner-

ship with Britain’s Wellcome Trust. One of the grants will support a re-

search project to understand cultural and language concepts of genomics in Nigeria. The goal is to develop a partici-pant consent form for a diabetes study that better relays genetic concepts in terms that people from both rural and urban environments in Nigeria under-stand. The other grant will support a project to determine Ethiopians’ un-derstanding of gene-environment in-teractions, with a goal of also increasing awareness about disease susceptibility.

Both grants are part of the Ethical, Le-gal and Social Implications (ELSI) com-ponent of H3Africa. The program has dis-bursed approximately $78 million to date.

“These grants will help us begin to get a better sense of what people in two different African countries under-stand about genomics concepts,” said H3Africa Program Director Ebony Madden, PhD, an Epidemiologist in the Division of Genomic Medicine at the National Human Genome Re-search Institute (NHGRI), part of

NIH. “We hope that what we learn from this work will lead to more effec-tive informed consent discussions with potential research participants and to new culturally appropriate educational strategies about genomics.”

Institute of Human Virology, Nigeria

The Institute of Human Virology, Nigeria, has been awarded a grant of $162,000, with Clement Adebayo Adebamowo, MD, ScD, serving as Principal Investigator. Dr. Adebamowo and his colleagues will conduct inter-views with community leaders and focus groups in rural and urban popu-lations to gauge how concepts on heri-

tability and genomics are understood in local languages. They will assess the participants’ perception and satisfac-tion with the informed consent form currently in use, and compare it to a new consent form the researchers will develop. The new form will include language that they hope will better ex-plain genomics terms based on feed-back they receive from the interviews and focus groups. The researchers plan to test this on participants enrolling in a diabetes study. The Nigeria project could impact how consent forms for genomics-related projects are written, especially for populations unfamiliar with the concepts of heritability and genomics.

Addis Ababa University, Ethiopia

Addis Ababa University, Ethiopia, has been awarded a grant of $161,151, with Getnet Tadele, PhD, serving as Principal Investigator. Dr. Tadele and his colleagues are assessing young peo-ple’s (ages 15 to 24 years) understand-ing of how genes and the environment interact to cause podoconiosis, an in-fectious condition prevalent in north-

ern Ethiopia. The disease is caused when people with certain genetic vari-ants are exposed to volcanic soil. An estimated one-fifth of Ethiopians carry the genetic variants that result in the debilitating disease. Researchers will then develop educational strategies and a resource to improve the under-standing of these concepts in African communities.

Dr. Madden said both research proj-ects could lead to broader applications.

“Both studies will increase our

knowledge of how to tailor informed consents and educational materials based on linguistic and cultural needs so that genomic concepts are better understood,” Dr. Madden said. “Many times, even though we try to write on a young elementary school student lev-el, we are still using terms that certain cultures may not be able to relate to. These studies will teach us how to truly inform participants and/or educate the public about genetic concepts that they may only have a vague idea about.” n

Disclosure: These awards are supported by NIH grants 1U01HG007654-01 and 1U01HG007628-01.

Both studies will increase our knowledge of how to tailor informed consents and educational materials based on linguistic and cultural needs so that genomic concepts are better understood.

—Ebony Madden, PhD

Getnet Tadele, PhD

Clement Adebayo Adebamowo, MD, ScD

For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection)

single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based � rst-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

See the complete data at ALIMTAhcp.com/data

Select Important Safety InformationWarnings and PrecautionsALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modi� cations, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities.

Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the Important Safety Information and Brief Summary for ALIMTA on thefollowing pages.

a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.

b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Clinically relevant differences in survival probability as compared with placebo in certain patients* with advanced nonsquamous† NSCLC 1,4,5

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Data on � le, Eli Lilly and Company. ONC20120911A.

For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection)

single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.



Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

See the complete data at ALIMTAhcp.com/data

Select Important Safety InformationWarnings and PrecautionsALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modi� cations, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities.

Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the Important Safety Information and Brief Summary for ALIMTA on thefollowing pages.

a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.

b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Clinically relevant differences in survival probability as compared with placebo in certain patients* with advanced nonsquamous† NSCLC 1,4,5

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Data on � le, Eli Lilly and Company. ONC20120911A.

http://www.alimtahcp.com/Pages/index.aspx

ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5 PRINTER VERSION 1 OF 4

ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.

75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose

75% of previous dose

Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)

Indications for ALIMTA® (pemetrexed for injection)ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small celllung cancer.



Important Safety Information for ALIMTAMyelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPrior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insuf� ciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insuf� ciency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug InteractionsSee Warnings and Precautions for speci� c information regarding NSAID administration in patients with renal insuf� ciency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Speci� c Patient Populations

It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Ef� cacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration GuidelinesComplete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapyThe most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

PM_HCP_ISI_NSCLC1M_17OCT2012

PM90247 04/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.ALIMTA® is a registered trademark of Eli Lilly and Company.


Announcements

September Is Prostate Cancer Awareness Month

In recognition of September as Prostate Cancer Awareness Month, The ASCO

Post is pleased to share the following re-minders, adapted in part from the Ameri-can Cancer Society:• Prostate cancer is the second most

common cancer among men, behind

skin cancer, and it affects one in seven men in his lifetime.

• Prostate cancer is the second leading cause of cancer death in American men, behind only lung cancer.

• In 2014, approximately 233,000 new cases will be diagnosed in the United

States; about 29,480 men will die of prostate cancer this year in the U.S.

• Prostate cancer occurs mainly in older men. The average age at the time of di-agnosis is about 66.

• Most men diagnosed with prostate cancer do not die from it.

• African American men have the highest prostate cancer incidence in the world.

• Over 90% of all prostate cancers are dis-covered while they are localized or re-gional. The 5-year survival rate for men diagnosed with prostate tumors discov-ered at these stages is nearly 100%. n



ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.


Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose


Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)


Announcements

Peter Pisters, MD, Appointed President and Chief Executive Officer, University Health Network, Canada

Mr. John Mulvihill, Chair of the Board of Trustees of University

Health Network (UHN), Canada, and Chair of the Board’s Selection Commit-tee for the President and CEO, recently

announced that Peter Pisters, MD, will serve as UHN’s next President and CEO, beginning January 1, 2015.

Dr. Pisters is currently Vice President of The University of Texas MD Anderson

Cancer Center’s Regional Care System and Professor of Surgery. He has held a number of clinical, administrative, and leadership positions at MD Anderson from 1994 to the present, with his most

recent executive responsibilities being the management of six MD Anderson centers for care across metropolitan Houston. Prior to his current role, he was Medical Director of the regional can-



Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%Cardiovascular — supraventricular arrhythmiaDermatology/Skin — erythema multiformeGeneral Disorders — febrile neutropenia, allergic reaction/hypersensitivityNeurology — motor neuropathyRenal — renal failure

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction TherapyTable 6 provides the frequency and severity of adverse reactions reported in >5%

of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.

The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.

Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

Adverse Reaction Organ System and Term

ALIMTA(N=333)

Placebo(N=167)

All Gradesa

Toxicity (%)Grade 3-4a

Toxicity (%)All Gradesa

Toxicity (%)Grades 3-4a

Toxicity (%)

All Adverse Reactions 53 17 34 4.8

Laboratory Hematologic Anemia Neutropenia

159

4.83.9

4.80.6

0.60

Clinical Constitutional Symptoms Fatigue 18 4.5 11 0.6

Gastrointestinal Nausea Vomiting Mucositis/stomatitis

1265

0.30

0.3

2.41.82.4

000

General Disorders Edema 5 0 3.6 0

a Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo

b NCI CTCAE Criteria version 3.0

Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

Incidence 1% to 5%Blood/Bone Marrow — thrombocytopeniaGeneral Disorders — febrile neutropenia

Incidence Less than 1%Cardiovascular — ventricular tachycardia, syncopeGeneral Disorders — painGastrointestinal — gastrointestinal obstructionNeurologic — depressionRenal — renal failureVascular — pulmonary embolism

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Additional Experience Across Clinical TrialsSepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients.

6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of

ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions occurred with ALIMTA when used as a single-agent and in combination therapies.

Blood and Lymphatic System – Immune-mediated hemolytic anemiaGastrointestinal — colitis, pancreatitisGeneral Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitisSkin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal

necrolysis. Some cases were fatal.

7 DRUG INTERACTIONS

7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Although ibuprofen (400 mg four times a day) can decrease the clearance of

pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.

In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic DrugsALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration

and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].Based on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

8.3 Nursing MothersIt is not known whether ALIMTA or its metabolites are excreted in human

milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric UseEfficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was

administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric UseALIMTA is known to be substantially excreted by the kidney, and the risk of adverse

reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients



platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category DBased on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse

reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with CisplatinTable 4 provides the frequency and severity of adverse reactions that have been

reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

ReactionbALIMTA/cisplatin

(N=839)Gemcitabine/cisplatin

(N=830)

All Grades Toxicity (%)

Grade 3-4 Toxicity (%)



All Adverse Reactions 90 37 91 53

Laboratory Hematologic Anemia Neutropenia Leukopenia Thrombocytopenia

33291810

61554

46382127

10278

13

Renal Creatinine elevation 10 1 7 1

Clinical Constitutional Symptoms Fatigue 43 7 45 5

Gastrointestinal Nausea Vomiting Anorexia Constipation Stomatitis/Pharyngitis Diarrhea Dyspepsia/Heartburn

5640272114125

7621110

5336242012136

4610020

Neurology Neuropathy-sensory Taste disturbance

98

00c

129

10c

Dermatology/Skin Alopecia Rash/Desquamation

127

0c

0218

1c

1

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported

as Grade 1 or 2.No clinically relevant differences in adverse reactions were seen in patients based

on histology.In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin

arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%Body as a Whole — febrile neutropenia, infection, pyrexiaGeneral Disorders — dehydrationMetabolism and Nutrition — increased AST, increased ALTRenal — creatinine clearance decrease, renal failureSpecial Senses — conjunctivitis

Incidence Less than 1%Cardiovascular — arrhythmiaGeneral Disorders — chest painMetabolism and Nutrition — increased GGTNeurology — motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction TherapyTable 5 provides the frequency and severity of adverse reactions reported in >5% of

the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.

All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy

ReactionbALIMTA (N=438)

Placebo (N=218)






Laboratory Hematologic Anemia Neutropenia Leukopenia

1566

332

601

101

Hepatic Increased ALT Increased AST

108

00

44

00


Gastrointestinal Nausea Anorexia Vomiting Mucositis/stomatitis Diarrhea

1919975

12011

65123

10000

Infection 5 2 2 0

Neurology Neuropathy-sensory 9 1 4 0

Dermatology/Skin Rash/Desquamation 10 0 3 0


b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients

based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.

Incidence 1% to 5%Dermatology/Skin — alopecia, pruritus/itchingGastrointestinal — constipationGeneral Disorders — edema, fever (in the absence of neutropenia)Hematologic — thrombocytopeniaRenal — decreased creatinine clearance, increased creatinine, decreased

glomerular filtration rate










ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS
























6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

1027813




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0












Announcements

cer centers, Clinical Consultant for the Center for Global Oncology (now known as MD Anderson Cancer Network), and Section Chief for Sarcoma Surgery.

Dr. Pisters was with Memorial Sloan Kettering Cancer Center’s Depart-ment of Surgical Oncology from 1985 to 1992. He completed his internship and residency at New York University

School of Medicine Center, Bellevue Hospital. He holds an MSc degree in Health Care Management from Har-vard University.

“I know I speak for everyone on the Board and all members of the Se-lection Committee when I say how delighted we are that Dr. Pisters has agreed to return home to Canada to

take on the role of President and CEO of UHN,” said Mr. Mulvihill. “His background as a clinician-researcher and his commitment to patients as part-ners in their care will ensure that Dr. Pisters will feel at home at UHN and that the organization will continue to grow, innovate, and lead health care in Canada and beyond our borders.” n Peter Pisters, MD










ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS
























6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

10278

13




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS
























6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

1027813




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0












Announcements

Mark Del Beccaro, MD, Named Senior Vice President, Chief Medical Officer of Seattle Children’s Hospital

Seattle Children’s has announced that Mark Del Beccaro, MD, has been

appointed as Senior Vice President and Chief Medical Officer (CMO) effec-tive October 1, 2014. Dr. Del Beccaro,

who currently serves as Vice President of Medical Affairs, will replace David Fisher, MD, who is retiring.

“Mark has made many significant contributions to Seattle Children’s

over the course of his career,” said Thomas N. Hansen, MD, CEO of Se-attle Children’s.

Dr. Del Beccaro started his career at Seattle Children’s in 1979 after gradu-

ating from Stanford University. He moved to Seattle with the intention of attending the University of Wash-ington School of Medicine. Having a desire to work in pediatrics, and want-ing to become a Washington state resi-dent, Dr. Del Beccaro started working as a nursing aid at what was then Chil-dren’s Orthopedic Hospital. He later transitioned to the position of mental health specialist within the Inpatient Psychiatric Unit.

Long History at Seattle Children’s

Dr. Del Beccaro entered medical school at the University of Washing-ton in 1981 and started his pediatric residency at Seattle Children’s in 1985. Three years later, he was appointed chief resident. He joined the faculty of Seattle Children’s Emergency Depart-ment in 1989 and was appointed Pedi-atrician-in-Chief in 2007. A professor at the University of Washington School of Medicine, Del Beccaro became Vice President of Medical Affairs in 2012. During his time at Seattle Children’s, Dr. Del Beccaro played an integral role in the design, preparation, and comple-tion of Building Hope, the hospital’s new state-of-the-art cancer, critical and emergency care building.

In his new role, Dr. Del Beccaro said he will continue the work that Dr. Fisher started, namely the support of hospital medical staff and faculty, and efforts to continually improve patient safety. He also will advocate for com-pletion of a fully electronic medical re-cord that reaches community partners and families, further the development and integration of clinical standard work, and ensure the care provided is affordable and of the highest quality. “Mark’s passion, dedication, leader-ship and commitment to our patients, families and his colleagues make him an outstanding candidate to serve as CMO,” Dr. Hansen said. “He is in a great position to lead Seattle Children’s into the next era.” n

Mark Del Beccaro, MD


ALIMTA® (pemetrexed for injection) PV 8927 AMP

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics

of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function

will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderOf 3,946 patients (Male 70.5% ) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 RaceOf 3,946 patients (Caucasian 78.6%) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included

neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was

clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA- Approved Patient Labeling (PPI)Instruct patients to read the patient package insert before initiating ALIMTA.• Instructpatientsontheneedforfolicacidandvitamin B12 supplementation to

reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them toimmediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instructpatients tocontact theirphysician if persistent vomiting,diarrhea,orsigns of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescriptionor over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013


Patient’s Corner

Cancer Has Given Me CourageDespite enduring three cancers over 3 decades, I know how lucky I am and I’m grateful for every day.By Lori Piggott, as told to Jo Cavallo

In 1986, I was pregnant with my third child and excited to be interviewing

for a job on the assembly line at a General Motors plant near my home in Brodhead, Wisconsin. Hiring requirements included a physical examination and a chest x-ray, which was done by my obstetrician to avoid any radiation harm to the fetus. I was young, just 29, and thought I was in excellent health, so when I got a call from my doctor telling me I had a large mass in the middle of my chest and that he thought it was cancer, I was shocked. A bi-opsy of a swollen lymph node confirmed I had Hodgkin lymphoma.

I saw an oncologist at a large medical center and was advised to terminate my pregnancy and start treatment immedi-ately. But by then I was 5 months preg-nant and refused the advice. My cancer treatment would have to wait.

I knew the next few months would be difficult. The cancer made it impos-sible for me to take the job at General Motors, and that meant that my hus-band Tom, who was already working 6 to 7 days a week as a mechanic, would be under even greater pressure to pro-vide for our growing family. My illness also meant that he would have to take on the additional responsibility of car-ing for our children once I started treat-ment.

Although I had some fearful mo-ments, once I made the decision not to be treated until after the baby was born, I felt at peace and had a sense that I was going to be fine. I had no way of know-

ing that I would be struggling with can-cer for the next 3 decades.

Facing Recurrent CancerAfter my daughter Kimberly was

born, I had thoracic surgery to remove the mass in my chest and 33 rounds of radiation to my mediastinum, which put me in remission for 4 years. Two weeks before I was scheduled to see my on-

cologist for my final checkup, I noticed a mass behind my left ear, which was later diagnosed as Burkitt’s lymphoma, possibly the result of all the radiation therapy to my chest and lower face.

I had surgery to remove the mass and was prescribed a regimen of five che-motherapies, but despite the aggressive treatment, the cancer progressed rap-idly. My only chance to halt the cancer, said my oncologist, was an autologous bone marrow transplant. There were seven of us on the transplant unit, but I was so sick from the induction therapy, I didn’t get to know any of them very

well, which I’ve always regretted. I had my transplant in January 1992 and was cancer-free for 18 years.

Then, in the fall of 2010, I began feeling lethargic, I was having trouble breathing, and my voice grew hoarse. I knew something was seriously wrong. I made an appointment with my primary care physician, who found a small mass on the back of my tongue. A biopsy de-

termined that it was diffuse large B-cell lymphoma. My oncologist treated me with four cycles of rituximab (Rituxan), and I’m currently in remission.

Coping With the Aftermath of Cancer

My history with cancer has extend-ed over so many years, and for a while I struggled with severe panic attacks. People think once you’re through with treatment, the terror of having cancer is over and it’s time to move on. But that’s not how it works, especially when you have recurrent disease. I have been with

my oncologist and medical team for so long, we are on a first-name basis, and their constant kindness and continual support have helped me overcome any lingering fear of what might lie ahead.

Despite all that I’ve endured, I know how fortunate I am, and I’m grateful for every day. Soon after my bone marrow transplant I learned that I was the only one of the seven of us on the transplant unit to survive the treatment.

Legacy of CourageHaving cancer has given me the

gift of courage, which I have passed down to my children, now 31, 29, and 27. Because I have been ill for most of their lives, I’ve instilled in my children the importance of finding happiness in whatever they choose to do and the confidence to pursue their dream. So profound was cancer on their lives, Kimberly became a cytotechnologist studying cancer cells, and my older daughter Beverly is a cancer researcher who recently received a Damon Run-yon Cancer Fellowship Award.

Perhaps Beverly’s research will re-sult in breakthroughs that protect other mothers, fathers, and children from this dreaded and unforgiving disease.

I know sometimes the world can be a depressing place, but having cancer has taught me how precious life is and the importance of making a contribu-tion to the happiness of others. n

Lori Piggott lives in Brodhead, Wisconsin.

I know sometimes the world can be a depressing place. But having cancer has taught me how precious life is and the importance of making a contribution to the happiness of others.

—Lori Piggott

Patient Guides Available Through ASCO University Bookstore• ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including

health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to in-formation on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

The ASCO Post Wants to Hear

From YouWe encourage readers to share

their opinions and thoughts on issues of interest to the

oncology community.

Write to The ASCO Post at [email protected]


ALIMTA® (pemetrexed for injection) PV 8927 AMP

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics

of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function

will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderOf 3,946 patients (Male 70.5% ) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 RaceOf 3,946 patients (Caucasian 78.6%) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included

neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was

clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA- Approved Patient Labeling (PPI)Instruct patients to read the patient package insert before initiating ALIMTA.• Instructpatientsontheneedforfolicacidandvitamin B12 supplementation to

reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them toimmediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instructpatients tocontact theirphysician if persistent vomiting,diarrhea,orsigns of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescriptionor over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013


Journal Spotlight

EXPERT POINT OF VIEW

Information on the drivers of can-cer care is important in helping to

deliver higher-quality and potentially less costly cancer treatments, noted Richard L. Schilsky, MD, ASCO’s Chief Medical Officer, in a commen-tary accompanying the study by Dotan et al.1 Moreover, practice change can be a complex process, and there is probably more to the story than the three important factors pointed out by the investigators, he wrote.

More to the StoryWhile new medical evidence is fun-

damental to practice change, it may take a year or two for policy to recali-brate, Dr. Schilsky said in an interview with The ASCO Post. And during that time, there is uncertainty, which makes life complicated for many parties—cli-nicians, pharmaceutical companies, laboratories, insurers, and others.

The reimbursement policies of differ-ent insurers, for instance, may begin to change following new data. That almost certainly was the case with KRAS testing and the use of cetuximab (Erbitux) and panitumumab (Vectibix), Dr. Schilsky wrote. For instance, Aetna announced a

policy change in April 2009, and a local Medicare carrier in Florida announced a change in February 2009—both in line with the ASCO guidance.

Rates of change may also depend on the clinical context. In this case,

one factor could have been how quickly KRAS tests became available. After the ASCO presentation, many laboratories began to develop their own tests, but it was a year before a

U.S. Food and Drug Administration–approved test became available.

Other potential drivers of prac-tice change, Dr. Schilsky wrote, are quality assessment and improvement activities, including changes in re-

quirements for provider licensing or certification. Also, public reporting of physician reimbursement or transfers of value from pharmaceutical compa-nies to physicians, such as required by

the Physician Payments Sunshine Act, may contribute.

“The effect may be subtle,” he said, “but there is increased awareness that some interactions of clinicians with pharmaceutical companies are now subject to public reporting. These kinds of things can affect behavior.”

Fundamental DriversRegardless of which factors play a

role, the fundamental drivers remain the same. “Whether driven primarily by guideline revisions, regulatory ac-tions, or changes in reimbursement policies,” Dr. Schilsky wrote, “chang-es in clinical practice result primarily from the generation of new medical evidence through well-designed re-search studies and from the commit-ment of every oncologist to deliver the highest quality care to his or her patients.” n

Disclosure: Dr. Schilsky is Chief Medical Officer of ASCO.

Reference1. Schilsky RL: Drivers of change in

cancer care. J Oncol Pract. July 22, 2014 (early release online).

Whether driven primarily by guideline revisions, regulatory actions, or changes in reimbursement policies, changes in clinical practice result primarily from the generation of new medical evidence through well-designed research studies and from the commitment of every oncologist to deliver the highest quality care to his or her patients.

—Richard L. Schilsky, MD

Chase Cancer Center, looked spe-cifically at whether and how much the use of the two agents, both epidermal growth factor receptor (EGFR) inhibi-tors, declined after each event. The first

was ASCO’s Annual Meeting in June 2008, where the evidence was pre-sented. The following February, ASCO issued a Provisional Clinical Opinion recommending that the drugs be used only in patients with wild-type KRAS, and in August 2009, the FDA changed

the drugs’ labels to reflect the new evidence.

Significant ChangesUsing a commercial insurance

claims database, the authors found that at the time of the ASCO pre-sentation, 59.4% of colorectal cancer patients had received one of the anti-EGFR agents as part of second-line therapy, or beyond. That dropped to 46.2% following the publication of the Provisional Clinical Opinion by ASCO and to 35.2% at the time of the FDA label change. Eight months after the FDA action, only 16.2% of pa-tients received the drugs. The great-est decline occurred after the label change, but the decrease in use was

statistically significant at all points.“These results suggest the atten-

tiveness of the oncologic community to clinical presentations at national meetings and ASCO guidance,” the authors wrote. “It is also evidence that oncologists change their practice promptly in the face of highly publi-cized data, even years after a drug’s original approval.” n

Disclosure: Dr. Dotan reported no potential conflicts of interest. For full disclosures of all study authors, visit jop.ascopubs.org.

Reference1. Dotan E, Li T, Hall MJ, et al: Oncolo-

gists’ response to new data regarding the use of epidermal growth factor receptor in-hibitors in colorectal cancer. J Oncol Pract. July 22, 2014 (early release online).

Oncology Practicecontinued from page 1

Drivers of Cancer Care

■ New medical evidence is the fundamental driver of practice change, but other factors may influence how long it takes clinical practice to reflect new findings.

■ Public presentation of new data, issuance of professional guidelines, and an FDA label change each had a significant impact on prescriptions for anti-EGFR agents in colorectal cancer.

■ Other factors may also be involved, such as reimbursement policy and quality assurance activities.


78589-R1-V2_AmgAssist_CKingSize_ASCOPost_July_V2.indd 1 5/27/14 5:45 PM

78589-R1-V2_AmgAssist_CKingSize_ASCOPost_July_V2.indd 1 5/27/14 5:45 PM

http://www.amgenassist.com/index.jsp


In the News

Survival Benefit of Contralateral Prophylactic Mastectomy Less Than 1% at 20 Years, but Numbers of Procedures Have Increased By Charlotte Bath

For women with stage I and II breast cancer without BRCA mutations,

the absolute 20-year survival benefit from contralateral prophylactic mastectomy was less than 1%, regardless of age, es-trogen receptor status, and cancer stage, according to a decision analysis study us-ing a Markov model to simulate survival outcomes with or without the procedure. The study, published in the Journal of the National Cancer Institute,1 also noted that the 10-year cumulative risk of contralat-eral breast cancer is about 4% to 5% but may be even lower for women diagnosed with breast cancer today.

These figures are at odds with the es-timated risks of contralateral breast can-cer and expected benefits of contralateral prophylactic mastectomy reported by pa-tients. Todd M. Tuttle, MD, MS, Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medical Director of the University of Minnesota Breast Center, and one of three study authors, told The ASCO Post “A few years ago, we conducted a prospec-tive study in our institution of women with unilateral breast cancer who didn’t have a BRCA mutation. We asked them to estimate their 10-year risk of getting a contralateral breast cancer. The mean per-ceived risk was over 30%, which is about the same as what it is for a BRCA muta-tion.”

Dr. Tuttle also cited another survey study of women under 40 diagnosed with breast cancer, published in 2013.2 “They also substantially overestimated their risk of developing a contralateral breast cancer,” he noted. “In that study, a large proportion of women said the reason that they chose to have a [contralateral pro-phylactic mastectomy] was to improve their survival; it was one of the most com-mon reasons women cited for having a contralateral prophylactic mastectomy. However, our data clearly show that the vast majority of women will not have a meaningful survival benefit from this op-eration.”

Complex Modelling, High Sensitivity

Asked if the finding of an overall sur-vival benefit of less than 1% surprised him and his coauthors, Dr. Tuttle replied, “No, it actually didn’t. We had previously performed crude estimations, and this is the number that kept coming up. But this study is a much more rigorous analy-

sis, with sensitivity analysis and complex modeling.” He added that the Markov model “is a well accepted methodology when a randomized clinical trial cannot be performed. We used the highest qual-ity of resources that were available.”

The model simulates the long-term prognosis of hypothetical cohorts of women with newly diagnosed unilateral breast cancer according to two scenarios: (1) contralateral prophylactic mastec-tomy (ie, double mastectomy) and (2) no contralateral mastectomy (assuming that women undergo either lumpectomy with radiation therapy or unilateral mas-tectomy), the authors explained in the JNCI article. “We projected the benefit of

[contralateral prophylactic mastectomy] for cohorts of women defined by age at breast cancer diagnosis (40, 50, or 60 years), stage of primary breast cancer (I, II), and estrogen receptor status (positive, negative).”

Stage-specific breast cancer mortality rates were derived from relative survival curves reported in the Surveillance, Epi-demiology, and End Results (SEER) data. Probabilities for developing contralateral breast cancer, dying from contralteral and primary breast cancer, and age-specific mortality rates were estimated from pub-lished studies. Those studies included me-ta-analyses of large numbers of random-ized clinical trials, sometimes spanning 10 to 15 years, Dr. Tuttle noted.

Explaining the use of the model, the researchers contended that prospective randomized trials of contralateral pro-phylactic mastectomy vs no contralateral prophylactic mastectomy are not feasible, and “retrospective studies evaluating a po-tential survival benefit with [contralateral prophylactic mastectomy] are limited by short follow-up, potential selection bias, and lack of important clinical informa-tion.”

In retrospective studies comparing the outcomes of women who have had

a contralateral prophylactic mastectomy vs those who have not, the patients who undergo the procedure have better sur-vival rates, primarily because women who undergo contralateral prophylactic mas-tectomy are younger, healthier, and often have better access to health-care insur-ance, Dr. Tuttle noted.

Stage and Age Differences Contralateral prophylactic mastec-

tomy was more beneficial among women with stage I than those with stage II can-cer, according to the model. Predicted life expectancy gains from contralateral prophylactic mastectomy “ranged from 0.13 to 0.59 years for women with stage

I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer,” the results showed.

“We focused on stage I and II dis-ease because as the stage goes up, your chances of dying from your known can-cer go markedly up as well. So if you have a stage III breast cancer, there is going to be no benefit at all, because almost all the survival risk is due to the known cancer,” Dr. Tuttle explained.

Contralateral prophylactic mastec-tomy was also more beneficial among women with estrogen receptor–nega-tive breast cancer and younger women. For example, a 60-year old woman would gain less than 2 months life ex-pectancy from contralateral prophy-lactic mastectomy, while a 40-year-old woman would gain as much as 7 months, according to the model.

Dr. Tuttle said that older women fre-quently opt for contralateral prophylactic mastectomy, but not as often as younger women. “Young age is consistently associ-ated with having a [contralateral prophy-lactic mastectomy].”

Overall Exaggerated RiskWomen with BRCA mutations were

excluded from the study. Women who do not have BRCA mutations have a lower risk of breast cancer and “don’t have con-tralateral prophylactic mastectomies as frequently as those women who do have a BRCA mutation,” Dr. Tuttle said, but the rate has been rising.

“Numerous studies in the United States have shown that the rates of [con-tralateral prophylactic mastectomy] use among all women, but also including women who don’t have BRCA mutations, is markedly increased,” he added. Those studies include one that Dr. Tuttle coau-thored in 2007 that found the use of con-tralateral prophylactic mastectomy had doubled in a 6-year period.3

“In the United States, there is an over-all exaggerated risk for breast cancer,” Dr. Tuttle said. “For example, women who do not have breast cancer substantially over-estimate their chances of getting breast cancer. Women who have early breast cancer, or ductal carcinoma in situ, sub-stantially overestimate their risk of getting a recurrence or dying from that cancer. And, as we found, women who have can-cer in one breast substantially overesti-mate the risk of getting cancer in the op-posite breast.”

The reason for the exaggerated risk is unclear, he said. It could be due to the prevalence of breast cancer themes in movies and on television, or races and other fundraising events, “or maybe the unintended consequence of increased breast cancer awareness.” n

Disclosure: Dr. Tuttle reported no potential conflicts of interest.

References1. Portschy PR, Kuntz KM, Tuttle

TM: Survival outcomes after contra-lateral prophylactic mastectomy: A decision analysis. J Natl Cancer Inst 106(8):dju160, 2014.

2. Rosenberg SM, Tracy MS, Meyer ME, et al: Perceptions, knowledge, and satisfaction with contralateral prophy-lactic mastectomy among young women with breast cancer: A cross-sectional sur-vey. Ann Intern Med 159:373-381, 2013.

3. Tuttle TM, Haberman EB, Grund EH, et al: Increasing use of contralateral prophylactic mastectomy for breast can-cer patients: A trend toward more ag-gressive surgical treatment. J Clin Oncol 25:5203-5209, 2007.

Breast Cancer

Our data clearly show that the vast majority of women will not have a meaningful survival benefit from this operation.

—Todd M. Tuttle, MD, MS


In the News

Expect Questions and Perhaps Unrealistic ExpectationsBy Charlotte Bath

A recent study reporting the ab-solute 20-year survival ben-

efit from contralateral prophylactic mastectomy was less than 1% for women with stage I and II breast cancer without BRCA mutations runs counter to common percep-tions about the risk of contralateral breast cancer among these women and the benefits of contralateral prophylactic mastectomy.1 (Earlier studies about perceptions of con-tralateral breast cancer and contra-lateral prophylactic mastectomy are referenced in the current study.)

The less than 1% survival benefit was found among all subgroups studied—by age, estrogen receptor status, and cancer stage—although contralateral prophy-lactic mastectomy was more beneficial among younger women, those with stage I disease, and those with estrogen receptor–negative breast cancer, ac-cording to the report, published in the Journal of the National Cancer Insti-tute.1 The stated aim of the study was “to provide projected long-term sur-vival information by using a stimulated Markov model for physicians and their patients when discussing breast cancer risk-reduction strategies.”

In an interview with The ASCO Post, study coauthor Todd M. Tuttle, MD, MS, noted that those risk-reduc-tion strategies could include standard follow-up and tamoxifen or an aro-

matase inhibitor. “There is a growing body of research looking at alternative ways to reduce risk as well by diet and exercise,” he added, although “there are not really strong data on that yet.” Dr. Tuttle is Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medi-cal Director of the University of Min-nesota Breast Center.

More and Better Information The article concludes that the “sur-

vival estimates derived from our model may be useful for physicians and breast cancer patients to arrive at evidence-

based informed decisions regarding [contralateral prophylactic mastecto-my].” While the study’s impact cannot yet be gauged, Dr. Tuttle said, “What I hope it does is at least provides women with better information.”

Information about the study ap-peared in reports in both the medical and popular press, including a New York Times Sunday Review opinion article that included comments from

Dr. Tuttle. In that opinion article, ti-tled “The Wrong Approach to Breast Cancer,” New York Times Magazine contributing writer Peggy Orenstein discussed the study and personal ex-periences with breast cancer, writing, “Treatment decisions are ultimately up to the individual. But physicians can frame options and educate patients in a way that incorporates psychology as well as statistics. Beyond that, doctors are not obliged to provide treatment that is not truly necessary.” 2

The study report noted that “the use of accurate and easily understood decision aids may reverse some of the

mastectomy trends recently observed in the United States.” Still in the de-velopment phase and intended to be used in addition to patient-physician discussions, those decision aids could include online tools to provide wom-en with information on what they can expect from risk of recurrence, risk of death, risk of complications, and side effects from having these different procedures, Dr. Tuttle explained.

Other Potential BenefitsThe JNCI authors acknowledged

that survival “is only one potential benefit of a cancer risk-reduction strat-egy; effects on cancer-related anxiety, cosmesis, and self-image are also im-portant in decision-making processes. For some women, the negative impact of contralateral prophylactic mastec-tomy on quality of life may outweigh a potential survival benefit. For others who are very anxious about [contralat-eral breast cancer], [contralateral pro-phylactic mastectomy] may result in a psychological benefit even if survival benefits are minimal.”

An accompanying editorial points out, “The balance between harm and benefit depends on the patient’s prefer-ences and highlights the importance of capturing the patient’s values and ex-pectations before considering [contra-lateral prophylactic mastectomy].”3 n

References1. Portschy PR, Kuntz KM, Tuttle TM:

Survival outcomes after contralateral pro-phylactic mastectomy: A decision analysis. J Natl Cancer Inst 106(8):dju160, 2014.

2. Orenstein P: The wrong approach to breast cancer. New York Times, July 26, 2014.

3. Pauker SG, Alseiari M: How big is big enough? Thinking about contralateral prophylactic mastectomy. J Natl Cancer Inst 106(8):dju175, 2014.

Treatment decisions are ultimately up to the individual. But physicians can frame options and

educate patients in a way that incorporates psychology as well as statistics.

—Todd M. Tuttle, MD, MS

Editorial CorrespondenceJames O. Armitage, MD

Editor-in-Chief e-mail: [email protected]

Cara H. Glynn Director of Editorial

e-mail: [email protected]: 631.935.7654

Andrew Nash Assoc. Director of Editorial

e-mail: [email protected] Phone: 631.935.7657

Editorial OfficeHarborside Press

37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com

HarborsidePress.com

Rights & Permissionse-mail:

[email protected]

Advertising Rates, reprints, or supplements

Leslie Dubine-mail: [email protected]

Phone: 631.935.7660

Contact The ASCO Post


Awards

Royal Society Presents 2014 Royal Medal to Tony Hunter, PhD, FRS, Salk Professor

Tony Hunter, PhD, FRS, has been awarded the 2014 Royal

Medal for Biological Sciences by the Royal Society, an international fellow-ship of scientists based in the United Kingdom. The award recognizes Dr.

Hunter, Director of Salk Institute Cancer Center in San Diego, for his contributions to the understanding of cellular signaling transduction. Dr. Hunter discovered a master “switch” for this cell growth signaling that ul-timately led to the development of a number of new cancer drugs.

Dr. Hunter is also a Professor in the Molecular and Cell Biology Lab-oratory at the Salk Institute.

Research Changed Cancer Treatment Landscape

“Tony Hunter’s discoveries have changed the landscape for the treat-ment of cancer and other related diseases and underscores the impor-tance of basic science,” said William Brody, MD, PhD, President of the Salk Institute. “All of us at the Salk Institute are thrilled that the Royal Society is recognizing Dr. Hunter’s groundbreaking discoveries with the award of the Royal Medal.”

Each year, the Royal Society, which was founded in 1660 and is the oldest scientific academy in continuous existence, awards three Royal Medals, also referred to as the “Queen’s Medals,” for the most im-portant contributions in the physical, biological, and applied sciences. The medal will be presented at the Soci-ety’s Anniversary Day meeting on December 1, 2014.

“I am delighted to have been se-lected to receive the 2014 Royal Medal of the Royal Society of Lon-don, and I am extremely honored to join the scientific luminaries who

make up the list of past biological sci-ences medal winners,” says Dr. Hunt-er, who is also an American Cancer Society Professor and the holder of Salk’s Renato Dulbecco Chair.

Dr. Hunter, a Fellow of the Royal Society (FRS) and a member of the National Academy of Sciences stud-ies how mutations in genes that con-trol growth lead to the unchecked

proliferation of cancer cells. In 1979, his lab uncovered an

entirely new mechanism of protein regulation in cells by discovering that the addition of a phosphate group to

Tony Hunter, PhD, FRS

When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH

• CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA

• Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration

• Monitor electrolytes periodically

• Avoid drugs known to prolong the QT interval

• Only prescribers and pharmacies certifi ed with the restricted distribution program are able to prescribe and dispense CAPRELSA

To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certifi cation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

FDA-approved in April 2011 as the fi rst medication for advanced MTC.1

CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA

Lead the way

with

Lead / Forward


Awards

the amino acid tyrosine in proteins affects how cells multiply. This semi-nal discovery of a cellular “master switch” opened the door to the study of the dozens of proteins that act as enzymes to add the phosphate to tyrosine—known as tyrosine kinas-es—and their important role in can-cer and other human diseases. This

knowledge has resulted in the devel-opment of new cancer treatments, such as imatinib for leukemia.

Dr. Hunter received his PhD from the University of Cambridge, Eng-land, and completed his postdoctoral fellowship at The Salk Institute and University of Cambridge.

Other recipients of this year’s

Royal Medals are Professor Howard Morris, FRS, and Professor Ter-ence Tao, FRS. Professor Morris was awarded the 2014 Royal Medal for his pioneering work in biomo-lecular mass spectrometry including strategy and instrument design and for outstanding entrepreneurship in biopharmaceutical characteriza-

tion. Professor Terence Tao, FRS, was awarded the 2014 Royal Medal for his many deep and varied contri-butions to mathematics, including harmonic analysis, prime number theory, partial differential equations, combinatorics, computer science, statistics, representation theory, and much more. n

When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),


• CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA

• Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration

• Monitor electrolytes periodically

• Avoid drugs known to prolong the QT interval

• Only prescribers and pharmacies certifi ed with the restricted distribution program are able to prescribe and dispense CAPRELSA

To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certifi cation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

FDA-approved in April 2011 as the fi rst medication for advanced MTC.1

CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA

Lead the way

with

Lead / Forward


News

Postmenopausal Breast Cancer Risk Decreases Rapidly After Starting Regular Physical Activity

Postmenopausal women who in the past 4 years had undertaken

regular physical activity equivalent to at least 4 hours of walking per week had a lower risk for invasive breast cancer

compared with women who exercised less during those 4 years, according to data published recently in Cancer Epide-miology, Biomarkers & Prevention.1

“Twelve MET-h [metabolic equiva-

lent task-hours] per week corresponds to walking 4 hours per week or cycling or engaging in other sports 2 hours per week, and it is consistent with the World Cancer Research Fund recom-

mendations of walking at least 30 min-utes daily,” said Agnès Fournier, PhD, a Researcher in the Centre for Research in Epidemiology and Population Health at the Institut Gustave Roussy in Ville-

Breast Cancer

HR=0.35 (95% CI: 0.24, 0.53) P<.0001

Median PFS not reached

(95% CI: 22.6 months,

non-estimable)

16.4 months median PFS

(95% CI: 8.3, 19.7)

CAPRELSA 300 mg

59/231Events/Patients

Placebo

41/100

2

Risk of Progression Overall Survival (OS)

Subgroup analysis showed similar PFS results for2:

• Symptomatic patientsHR=0.31 (95% Cl: 0.19, 0.53)

• Patients who had progressed within 6 months prior to ZETA study enrollmentHR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2

• Further OS analysis will take place when ≥50% of patients have died3

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signifi cantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2

Results from a phase 3,

international, randomized,

double-blind, placebo-

controlled trial in adult

patients (N=331) with

unresectable locally

advanced or metastatic

MTC. At disease progression,

patients had the option

to receive open-label

CAPRELSA.2,3

65% Relative Reduction in Risk of Progression2

Additional Important Safety Information for CAPRELSA (contd)

• Do not use in patients with congenital long QT syndrome

• CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA

• Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction

• Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA canthen be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above

• Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions

• Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

0.0

0.25

0.50

0.75

Pro

gre

ssio

n-f

ree

su

rviv

al

60 12 2418 30 36

1.0

Months

173231 145 33118 1 0

CAPRELSA300 mg

Number at Risk

47100 30 624 0 0Placebo

www.LeadWithCAPRELSA.com

Additional Important Safety Information for CAPRELSA

• Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed

• Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event

• Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage

• Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA

• Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose

• Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly

• Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS

• Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval

• Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis

• CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established

• CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA

• The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%)

• CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

* PFS is defi ned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.2

CAPRELSA is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 2977331 4/14

References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information,

including Boxed WARNING, on adjacent pages.

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS)

For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com


News

juif, France. “So, our study shows that it is not necessary to engage in vigorous or very frequent activities; even walking 30 minutes per day is beneficial.”

Rapid Impact on RiskPostmenopausal women who in the

previous 4 years had undertaken 12 or more MET-h of physical activity each

week had a 10% decreased risk of inva-sive breast cancer compared with wom-en who were less active. Women who undertook this level of physical activity between 5 and 9 years earlier but were less active in the 4 years prior to the final data collection did not have a de-creased risk for invasive breast cancer.

“Physical activity is thought to de-

crease a woman’s risk for breast cancer after menopause,” said Fournier. “How-ever, it was not clear how rapidly this as-sociation is observed after regular phys-ical activity is begun or for how long it lasts after regular exercise stops.

“Our study answers these questions,” Fournier continued. “We found that rec-

continued on page 94Agnès Fournier, PhD

HR=0.35 (95% CI: 0.24, 0.53) P<.0001

Median PFS not reached

(95% CI: 22.6 months,

non-estimable)

16.4 months median PFS

(95% CI: 8.3, 19.7)

CAPRELSA 300 mg

59/231Events/Patients

Placebo

41/100

2

Risk of Progression Overall Survival (OS)

Subgroup analysis showed similar PFS results for2:

• Symptomatic patientsHR=0.31 (95% Cl: 0.19, 0.53)

• Patients who had progressed within 6 months prior to ZETA study enrollmentHR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2

• Further OS analysis will take place when ≥50% of patients have died3

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signifi cantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2

Results from a phase 3,

international, randomized,

double-blind, placebo-

controlled trial in adult

patients (N=331) with

unresectable locally

advanced or metastatic

MTC. At disease progression,

patients had the option

to receive open-label

CAPRELSA.2,3

65% Relative Reduction in Risk of Progression2

Additional Important Safety Information for CAPRELSA (contd)

• Do not use in patients with congenital long QT syndrome

• CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA

• Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction

• Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA canthen be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above

• Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions

• Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

0.0

0.25

0.50

0.75

Pro

gre

ssio

n-f

ree

su

rviv

al

60 12 2418 30 36

1.0

Months

173231 145 33118 1 0

CAPRELSA300 mg

Number at Risk

47100 30 624 0 0Placebo

www.LeadWithCAPRELSA.com

Additional Important Safety Information for CAPRELSA

• Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed

• Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event

• Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage

• Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA

• Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose

• Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly

• Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS

• Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval

• Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis

• CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established

• CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA

• The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%)

• CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

* PFS is defi ned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.2

CAPRELSA is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 2977331 4/14

References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information,

including Boxed WARNING, on adjacent pages.

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS)

For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com

http://www.caprelsa.com/hcp/index.aspx


News

reational physical activity, even of mod-est intensity, seemed to have a rapid im-pact on breast cancer risk. However, the decreased breast cancer risk we found as-sociated with physical activity was atten-uated when activity stopped. As a result, postmenopausal women who exercise

should be encouraged to continue and those who do not exercise should con-sider starting because their risk of breast cancer may decrease rapidly.”

Fournier and colleagues analyzed data obtained from biennial question-naires completed by 59,308 postmeno-pausal women who were enrolled in E3N, the French component of the Eu-

ropean Prospective Investigation Into Cancer and Nutrition (EPIC) study. The mean duration of follow-up was 8.5 years, during which time, 2,155 of the women were diagnosed with a first pri-mary invasive breast cancer. n

Disclosure: Dr. Fournier reported no potential conflicts of interest. This study was supported by funds from Institut National du

Cancer, the Fondation de France, and the Institut de Recherche en Santé Publique. The E3N cohort is financially supported by the Institut National du Cancer, the Mutuelle Générale de l’Education Nationale, the Institut de Cancérologie Gustave Roussy, and the Institut National de la Santé et de la Recherche Médicale.

Reference1. Fournier A, et al: Cancer Epidemiol Bio-

markers. August 11, 2014 (early release online).

Breast Cancer Riskcontinued from page 93

CAPRELSA®

(vandetanib) Tablets for Oral Use

BRIEF SUMMARY. Before prescribing, please see full Prescribing Information.


CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients

receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagne-

semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to

CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT

interval. Only prescribers and pharmacies certified with the restricted distribution program are able to

prescribe and dispense CAPRELSA [see Warnings and Precautions].

INDICATIONS AND USAGECAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with

unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or

slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

DOSAGE AND ADMINISTRATIONThe recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable

toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the

next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for

approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immedi-

ately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can

also be administered through nasogastric or gastrostomy tubes.

Dosage AdjustmentFor adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg

for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities.

Interrupt CAPRELSA for the following:

• Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns

to less than 450 ms.

• CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.

For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade

1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a

prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions].

For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine

clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings

and Precautions and Use in Specific Populations].

For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe

hepatic impairment [see Use in Specific Populations].

CONTRAINDICATIONSDo not use in patients with congenital long QT syndrome [see Boxed Warning].

WARNINGS AND PRECAUTIONSQT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) in

full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in

patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than

450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT

syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with

ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired

renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and

monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline,

2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor

electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT

prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain

serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium

levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to

prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients

already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more

frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than

450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration].

Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients

treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage

and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after

treatment discontinuation.

Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with

CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the

randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently

with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy

after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who

experience a severe ischemic cerebrovascular event.

Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer

CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA

in patients with severe hemorrhage.

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of

heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be

reversible upon stopping CAPRELSA.

DiarrheaDiarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC

study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early

detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for

severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration].

Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of

thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-

treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after

starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur,

examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients

for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be

controlled, do not resume CAPRELSA [see Dosage and Administration].

Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema

diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any

patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical

studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue

CAPRELSA treatment in patients with RPLS.

Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone,

disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but

not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and

pimozide) [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in

patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information

available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and

Administration, Use in Specific Populations and Clinical Pharmacology (12.3) in full Prescribing Information ].

Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and

efficacy have not been established [see Dosage and Administration].

Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In

nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or

lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female

fertility, embryofetal development, and postnatal development of pups. If this drug is used during pregnancy, or if

the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a

fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they

must use effective contraception during CAPRELSA treatment and for at least four months following the last dose

of CAPRELSA [see Use in Specific Populations].

CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only

through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies

certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS require-

ments and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the label:

• QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions]

• Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions]

• Interstitial Lung Disease [see Warnings and Precautions]

• Ischemic Cerebrovascular Events [see Warnings and Precautions]

• Hemorrhage [see Warnings and Precautions]

• Heart Failure [see Warnings and Precautions]

• Diarrhea [see Warnings and Precautions]

• Hypothyroidism [see Warnings and Precautions]

• Hypertension [see Warnings and Precautions]

• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions]

• Embryofetal Toxicity [see Warnings and Precautions]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect

the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer

were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58%

male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to

CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of

CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency:

diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection,

decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109

(47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of

231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions

leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia

(1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation

(0.9%), and hypertension (0.9%).

Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence inCAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1]

System Organ Class CAPRELSA 300 mg PlaceboPreferred Term N=231 N=99

All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%)

Gastrointestinal Disorders

Diarrhea/Colitis 57 11 27 2

Nausea 33 1 16 0

Abdominal Pain2 21 3 11 0

Vomiting 15 1 7 0

Dyspepsia 11 0 4 0

Dry Mouth 9 0 3 0

Skin and Cutaneous Disorders

Rash3 53 5 12 0

Dermatitis Acneiform/Acne 35 1 7 0

Dry Skin 15 0 5 0

Photosensitivity Reaction 13 2 0 0

Pruritus 11 1 4 0

Nail abnormalities4 9 0 0 0

Alopecia 8 N/A 0 N/A

Vascular Disorders

Hypertension/Hypertensive

Crisis/Accelerated Hypertension 33 9 5 1

Nervous System Disorders

Headache 26 1 9 0

Dysgeusia 8 0 3 0

General Disorders

Fatigue5 24 6 23 1

Infections

Upper Respiratory Tract Infections6 23 0 16 0

Metabolic and Nutritional Disorders

Decreased Appetite 21 4 12 0

Hypocalcemia 11 2 3 0

Investigations

ECG QT Prolonged7 14 8 1 1

Eye Disorders

Corneal Abnormalities8 13 0 1 0

Blurred Vision 9 0 1 0

Renal Disorders

Proteinuria 10 0 2 0

Psychiatric Disorders

Depression 10 2 3 0

Endocrine Disorders

Hypothyroidism 6 0 0 0

Musculoskeletal Disorders

Muscle Spasms 6 0 1 0

1. CTCAE version 3 was used to grade adverse events.2. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort.3. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis,

dermatitis bullous, generalized erythema, and eczema.4. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.5. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.6. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and

tracheitis.7. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction.8. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits,

acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients whoreceived placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was morecommon in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer(9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) intreated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination,including slit lamp examination, in patients who report visual changes.Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibitionof VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSAtreated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% inpatients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroidcancer (MTC) study.

Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at aHigher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1]

Laboratory Abnormalities CAPRELSA 300 mg PlaceboN = 231 N = 99


Chemistries


ALT Increased 51 2 19 0

Hypoglycemia 24 0 7 1

Creatinine Increased 16 0 1 0

Hypomagnesemia 7 <1 2 0

Hematologic

Neutropenia 10 <1 5 2

Thrombocytopenia 9 0 3 01. CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.DRUG INTERACTIONSEffect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use ofknown strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John’s Wort because it candecrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transportertype 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that aretransported by OCT2 [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on DigoxinCAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities whenadministering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) in full Prescribing Information].Drugs that Prolong the QT IntervalAvoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions].USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnantwoman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to thoseexpected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patientbecomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancyat a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax),there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of liveembryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times thehuman exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embry-ofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study.Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax inpatients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of theheart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicatingdelayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity(1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natalpup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactatingrats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of thedrug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk andbecause of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established.Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determinewhether they respond differently compared to younger patients.Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg inpatients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min)renal impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology (12.3) infull Prescribing Information].Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8),moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild(Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment hadcomparable mean AUC and clearance values to those with normal hepatic function. There are limited data inpatients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is notrecommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have notbeen established. [see Dosage and Administration and Warnings and Precautions].Females and Males of Reproductive PotentialContraception Females of reproductive potential should avoid pregnancy. Use effective contraception duringtreatment and up to 4 months after the last dose of CAPRELSA.Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate thatvandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information].OVERDOSAGEIn the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adversereactions may not resolve quickly.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850CAPRELSA is a registered trademark of the AstraZeneca group of companies© AstraZeneca 2014. All Rights Reserved. 3/14 2975903 5/14

CAPRELSA® (vandetanib) Tablets 2


Announcements

NIH Announces Launch of Precision Medicine Trials in Early-Stage Lung Cancer

The National Institutes of Health (NIH) recently announced the

launch of the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST. The purpose of the trial, which has three components, is to identify patients with

early-stage lung cancer whose tumors harbor certain uncommon genetic mu-tations and evaluate whether drug treat-ments targeted against those mutations can lead to improved survival.

The three component trials of ALCHEMIST are:

• screening component (A151216), coordinated by the Alliance for Clin-ical Trials in Oncology; Principal In-vestigators: Pasi A. Jänne, MD, PhD, and Geoffrey Oxnard, MD, Dana-Farber Cancer Institute, Boston. www.cancer.gov/clinicaltr ials/

NCT02194738• EGFR treatment component

(A081105), coordinated by the Alliance for Clinical Trials in On-cology; Principal Investigator: Ramaswamy Govindan, MD, Washington University, St. Louis. www.cancer.gov/clinicaltr ials/NCT02193282

• ALK treatment component (E4512), coordinated by ECOG-ACRIN; Prin-cipal Investigator: David E. Gerber, MD, University of Texas South-western Medical Center at Dallas. www.cancer.gov/clinicaltr ials/NCT02201992

Study Objectives“We believe that the findings from

ALCHEMIST will not only help an-swer an important question about the addition of targeted therapies in earlier-stage disease but will also help us in un-derstanding the prevalence and natural history of these genomic changes in earlier-stage lung cancer. We also hope to gain a better understanding regard-ing the genetic changes in the tumor at the time of recurrence,” said Shakun Malik, MD, Head of Thoracic Cancer Therapeutics in the Clinical Investiga-tions Branch of the National Cancer Institute (NCI).

In the ALCHEMIST screening trial, surgically removed tissue will be tested in a central laboratory for certain genetic changes in two genes, ALK and EGFR. Participants with tumors found to har-bor EGFR mutations or rearrangement of the ALK gene will then be referred to one of two randomized, placebo-con-trolled ALCHEMIST treatment trials. These studies will evaluate the value of adding therapy with erlotinib (Tarceva) (targeted against EGFR) and crizotinib (Xalkori) (targeted against ALK), in the postoperative setting.

Support for the TrialALCHEMIST is supported by the

NCI, with coordination of the compo-nent trials by the Alliance for Clinical Tri-als in Oncology and the ECOG-ACRIN Cancer Research Group. All of the NCI-supported National Clinical Trials Net-work (NCTN) groups collaborated in the development of ALCHEMIST and are participating in the component trials.

ALCHEMIST is the second preci-sion medicine clinical trial to launch as part of the new NCTN. The first trial, Lung-MAP, for patients with ad-vanced squamous cell lung cancer, was launched in June 2014. n

Thoracic Oncology

CAPRELSA®

(vandetanib) Tablets for Oral Use

BRIEF SUMMARY. Before prescribing, please see full Prescribing Information.


CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients

receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagne-

semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to

CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT

interval. Only prescribers and pharmacies certified with the restricted distribution program are able to

prescribe and dispense CAPRELSA [see Warnings and Precautions].

INDICATIONS AND USAGECAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with

unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or

slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

DOSAGE AND ADMINISTRATIONThe recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable

toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the

next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for

approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immedi-

ately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can

also be administered through nasogastric or gastrostomy tubes.

Dosage AdjustmentFor adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg

for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities.

Interrupt CAPRELSA for the following:

• Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns

to less than 450 ms.

• CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.

For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade

1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a

prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions].

For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine

clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings

and Precautions and Use in Specific Populations].

For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe

hepatic impairment [see Use in Specific Populations].

CONTRAINDICATIONSDo not use in patients with congenital long QT syndrome [see Boxed Warning].

WARNINGS AND PRECAUTIONSQT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) in

full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in

patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than

450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT

syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with

ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired

renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and

monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline,

2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor

electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT

prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain

serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium

levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to

prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients

already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more

frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than

450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration].

Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients

treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage

and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after

treatment discontinuation.

Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with

CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the

randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently

with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy

after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who

experience a severe ischemic cerebrovascular event.

Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer

CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA

in patients with severe hemorrhage.

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of

heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be

reversible upon stopping CAPRELSA.

DiarrheaDiarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC

study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early

detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for

severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration].

Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of

thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-

treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after

starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur,

examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients

for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be

controlled, do not resume CAPRELSA [see Dosage and Administration].

Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema

diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any

patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical

studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue

CAPRELSA treatment in patients with RPLS.

Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone,

disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but

not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and

pimozide) [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in

patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information

available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and

Administration, Use in Specific Populations and Clinical Pharmacology (12.3) in full Prescribing Information ].

Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and

efficacy have not been established [see Dosage and Administration].

Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In

nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or

lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female

fertility, embryofetal development, and postnatal development of pups. If this drug is used during pregnancy, or if

the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a

fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they

must use effective contraception during CAPRELSA treatment and for at least four months following the last dose

of CAPRELSA [see Use in Specific Populations].

CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only

through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies

certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS require-

ments and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the label:

• QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions]

• Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions]

• Interstitial Lung Disease [see Warnings and Precautions]

• Ischemic Cerebrovascular Events [see Warnings and Precautions]

• Hemorrhage [see Warnings and Precautions]

• Heart Failure [see Warnings and Precautions]

• Diarrhea [see Warnings and Precautions]

• Hypothyroidism [see Warnings and Precautions]

• Hypertension [see Warnings and Precautions]

• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions]

• Embryofetal Toxicity [see Warnings and Precautions]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect

the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer

were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58%

male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to

CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of

CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency:

diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection,

decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109

(47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of

231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions

leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia

(1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation

(0.9%), and hypertension (0.9%).

Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence inCAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1]

System Organ Class CAPRELSA 300 mg PlaceboPreferred Term N=231 N=99


Gastrointestinal Disorders

Diarrhea/Colitis 57 11 27 2

Nausea 33 1 16 0

Abdominal Pain2 21 3 11 0

Vomiting 15 1 7 0

Dyspepsia 11 0 4 0

Dry Mouth 9 0 3 0

Skin and Cutaneous Disorders

Rash3 53 5 12 0

Dermatitis Acneiform/Acne 35 1 7 0

Dry Skin 15 0 5 0

Photosensitivity Reaction 13 2 0 0

Pruritus 11 1 4 0

Nail abnormalities4 9 0 0 0

Alopecia 8 N/A 0 N/A

Vascular Disorders

Hypertension/Hypertensive

Crisis/Accelerated Hypertension 33 9 5 1

Nervous System Disorders

Headache 26 1 9 0

Dysgeusia 8 0 3 0

General Disorders

Fatigue5 24 6 23 1

Infections

Upper Respiratory Tract Infections6 23 0 16 0

Metabolic and Nutritional Disorders

Decreased Appetite 21 4 12 0


Investigations

ECG QT Prolonged7 14 8 1 1

Eye Disorders

Corneal Abnormalities8 13 0 1 0

Blurred Vision 9 0 1 0

Renal Disorders

Proteinuria 10 0 2 0

Psychiatric Disorders

Depression 10 2 3 0

Endocrine Disorders

Hypothyroidism 6 0 0 0

Musculoskeletal Disorders

Muscle Spasms 6 0 1 0

1. CTCAE version 3 was used to grade adverse events.2. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort.3. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis,

dermatitis bullous, generalized erythema, and eczema.4. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.5. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.6. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and

tracheitis.7. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction.8. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits,

acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients whoreceived placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was morecommon in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer(9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) intreated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination,including slit lamp examination, in patients who report visual changes.Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibitionof VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSAtreated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% inpatients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroidcancer (MTC) study.

Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at aHigher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1]

Laboratory Abnormalities CAPRELSA 300 mg PlaceboN = 231 N = 99


Chemistries


ALT Increased 51 2 19 0

Hypoglycemia 24 0 7 1

Creatinine Increased 16 0 1 0

Hypomagnesemia 7 <1 2 0

Hematologic

Neutropenia 10 <1 5 2

Thrombocytopenia 9 0 3 01. CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.DRUG INTERACTIONSEffect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use ofknown strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John’s Wort because it candecrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transportertype 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that aretransported by OCT2 [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on DigoxinCAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities whenadministering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) in full Prescribing Information].Drugs that Prolong the QT IntervalAvoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions].USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnantwoman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to thoseexpected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patientbecomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancyat a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax),there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of liveembryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times thehuman exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embry-ofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study.Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax inpatients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of theheart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicatingdelayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity(1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natalpup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactatingrats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of thedrug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk andbecause of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established.Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determinewhether they respond differently compared to younger patients.Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg inpatients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min)renal impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology (12.3) infull Prescribing Information].Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8),moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild(Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment hadcomparable mean AUC and clearance values to those with normal hepatic function. There are limited data inpatients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is notrecommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have notbeen established. [see Dosage and Administration and Warnings and Precautions].Females and Males of Reproductive PotentialContraception Females of reproductive potential should avoid pregnancy. Use effective contraception duringtreatment and up to 4 months after the last dose of CAPRELSA.Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate thatvandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information].OVERDOSAGEIn the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adversereactions may not resolve quickly.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850CAPRELSA is a registered trademark of the AstraZeneca group of companies© AstraZeneca 2014. All Rights Reserved. 3/14 2975903 5/14

CAPRELSA® (vandetanib) Tablets 2


2014-2015 Oncology Meetings 2014-2015September

American Society for Radiation Oncology Annual MeetingSeptember 14-17 • San Francisco, California For more information: www.astro.org

Cancer Medicine and Hematology 2014September 14-19 • Boston, Massachusetts For more information: www.hmscme.com/cancermedicine

18th Annual Meeting: Collaborative Group of the Americas on Inherited Colorectal CancerSeptember 15-16 • New Orleans, Louisiana For more information: www.clevelandclinicmeded.com/live/courses/cga/default.asp

Academy of Oncology Nurse and Patient Navigators 5th Annual ConferenceSeptember 18-21 • Orlando, Florida For more information: www.aonnonline.org

NCCN 9th Annual Congress: Hematologic Malignancies™September 19-20 • New York, New York For more information: www.nccn.org/professionals/meetings/hematological/

Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/meetings--workshops/special-conferences/advances-in-melanoma-from-biology-to-therapy.aspx

European Society for Medical Oncology 2014 CongressSeptember 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO-2014-Congress

2nd International Conference on Hematology & Blood DisordersSeptember 29–October 1 • Linthicum, Maryland For more information: omicsgroup.com/hematology-blood-disorders-conference-2014/index.php

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to BiomarkersSeptember 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

OctoberACCC 31st National Oncology ConferenceOctober 8-11 • San Diego, California For more information: www.accc-cancer.org

International Cancer Imaging Society Meeting and 14th Annual Teaching CourseOctober 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index.cfm?task=meetings&meetingid=37

11th Meeting of the European Association of NeuroOncology (EANO)October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php

2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/breastcancer/pages/index.aspx

18th SIS World Congress on Breast HealthcareOctober 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home.aspx

2014 Quality Care SymposiumOctober 17-18 • Boston, Massachusetts For more information: quality.asco.org

Atlanta Lung Cancer SymposiumOctober 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014

16th World Congress of Psycho-Oncology and Psychosocial AcademyOctober 20-24 • Lisbon, Portugal For more information: www.ipos2014.com

14th Annual Conference of SIOGOctober 23-25 • Lisbon, Portugal For more information: www.siog.org

11th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO)October 23-24 • Arlington, Virginia For more information: www.isgio.org

ASCO’s Palliative Care in Oncology SymposiumOctober 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org

11th International Conference of the Society for Integrative OncologyOctober 26-28 • Houston, Texas For more information: www.integrativeonc.org

American College of Surgeons Clinical CongressOctober 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/future_congress/future

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/home/programs/physicians

2014 Chicago Multidisciplinary Symposium in Thoracic OncologyOctober 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

3rd Annual Global Biomarkers Consortium ConferenceOctober 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

NovemberChemotherapy Foundation SymposiumNovember 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org


There is no cure for multiple myeloma. That’s why we’ve dedicated ourselves to three guiding principles: a relentless commitment to scientifi c advances, a persistent focus on patient needs, and a progressive approach to collaboration.

Celgene has put these beliefs into practice for more than 15 years. And we’re not done yet.

DO WE.

MULTIPLE MYELOMA

NEVER GIVES UP.BUT NEITHER

www.celgene.com© 2013 Celgene Corporation 02/13 US-CELG130012c

C M Y K


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24166a 02.13.13 133

Q1 Q2

S:9.5”

S:13”

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B:10.75”

B:14.25”

There is no cure for multiple myeloma. That’s why we’ve dedicated ourselves to three guiding principles: a relentless commitment to scientifi c advances, a persistent focus on patient needs, and a progressive approach to collaboration.

Celgene has put these beliefs into practice for more than 15 years. And we’re not done yet.

DO WE.

MULTIPLE MYELOMA

NEVER GIVES UP.BUT NEITHER

www.celgene.com© 2013 Celgene Corporation 02/13 US-CELG130012c

C M Y K


4js

24166a 02.13.13 133

Q1 Q2

S:9.5”S:13”

T:10.5”T:14”

B:10.75”B:14.25”

https://www.celgene.com


2014-2015 Oncology Meetings 2014-2015Diagnostic Error in Medicine 5th International ConferenceNovember 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail.aspx/80028747

CNS Anticancer Drug Discovery/Development ConferenceNovember 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

Multidisciplinary Update in Breast Disease 2014November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgical-specialties-2014s306

19th Annual Meeting of the Society for Neuro-OncologyNovember 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer TherapeuticsNovember 18-21 • Barcelona, Spain For more information: www.aacr.org

European Multidisciplinary Colorectal Cancer Congress (EMCCC)November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl

RSNA 2014: Radiological Society of North AmericaNovember 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

DecemberAmerican Association for Cancer Research: Tumor ImmunologyDecember 1-4 • Orlando, Florida For more information: www.aacr.org

UICC World Cancer CongressDecember 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

24th World Congress of the International Association of Surgeons, Gastroenterologists and OncologistsDecember 5-7 • Vienna, Austria For more information: iasgo2014.org

ASH Annual Meeting and ExpositionDecember 6-9 • San Francisco, California For more information: hematology.org

37th Annual San Antonio Breast Cancer SymposiumDecember 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

11th Annual Clinical Breakthroughs and Challenges in Hematologic MalignanciesJanuary 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

The Society of Thoracic Surgeons 51st Annual MeetingJanuary 24-28 • San Diego, California For more information: www.sts.org/education-meetings/educational-meetings-activities/future-meetings

February2015 BMT Tandem Meeting American Society for Blood and Marrow TransplantationFebruary 11-15 • San Diego, California For more information: www.asbmt.org

5th International Conference on Innovative Approaches in Head & Neck OncologyFebruary 12-14 • Nice, France For more information: www.estro.org/congresses-meetings/items/5th-ichno

The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer ResearchFebruary 19-21 • San Diego, California For more information: www.imedex.com/anti-angiogenesis-and-immune-therapies/

Genitourinary Cancers SymposiumFebruary 26-28 • Orlando, Florida For more information: www.gucasym.org

32nd Annual Miami Breast Cancer Conference®February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/meetings/32nd-Annual-Miami-Breast-Cancer-Conference

March13th International Congress on Targeted Anticancer TherapiesMarch 2-4 • Paris, France For more information: www.tatcongress.org

16th European Congress: Perspectives in Lung CancerMarch 6-7 • Torino, Italy For more information: www.imedex.com/lung-cancer-congress-europe/index.asp

Advanced Prostate Cancer Consensus ConferenceMarch 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

NCCN Annual Conference: Advancing the Standard of Cancer CareMarch 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/meetings/annual_conference.asp

continued from page 96

A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2ndLoews Royal Pacific Hotel at Universal Orlando, FL

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For Your NPs and PAs

More streamlined navigation and a fresh design

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Tell Your Patients About ASCO’s Enhanced Cancer.Net Website

Visit the new www.cancer.net today!

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Spanish translation toggle tool, including a new Spanish translated home page

New videos and podcasts with experts to help illustrate complex subject matters

More streamlined navigation and a fresh design

http://www.mydisneymeetings.com/cri14

Tell Your Patients About ASCO’s Enhanced Cancer.Net Website

Visit the new www.cancer.net today!

Finding Trusted Cancer Information Just Got Easier

A new blog to communicate timely information to patients and caregivers

Spanish translation toggle tool, including a new Spanish translated home page

New videos and podcasts with experts to help illustrate complex subject matters

http://www.cancer.net


Lab Notes

Ongoing Molecular Research in the Science of Oncology

TARGETED THERAPY

BET Bromodomain Inhibition Highly Active in Castration-Resistant Prostate Cancer

Progression to castration-resistant prostate cancer after androgen ablation therapy is primarily due to deregulated androgen receptor signaling. Treatment with agents that target such signaling, such as abiraterone (Zytiga) and enzalutamide (Xtandi), has been successful. However, durable response is infrequently achieved, likely reflecting development of acquired resistance.

BRD4 is a member of the BET fam-ily of bromodomain-containing proteins that influence transcription by binding to acetylated histones. Recently, selec-tive small-molecule inhibitors (JQ1 and I-BET762) that target the amino-termi-nal bromodomains of BRD4 have been found to exert antiproliferative effects in several cancers.

In a study reported in Nature, Asan-gani and colleagues showed that andro-gen receptor signaling–competent hu-man castration-resistant prostate cancer cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. JQ1 was shown to inhibit the physical interaction of BRD4 with the N-terminal domain of the androgen receptor and, like enzalutamide, disrupt androgen receptor recruitment to target gene loci. Unlike enzalutamide, JQ1 was found to function downstream of the androgen receptor and to more effectively inhibit both BRD4 localization to receptor tar-

get loci and androgen receptor–mediated gene transcription, with effects including inhibition of TMPRSS2-ERG gene fusion and its oncogenic activity.

BET bromodomain inhibition was found to be more effective in reducing tumor growth than direct androgen re-ceptor inhibition in castration-resistant prostate cancer xenograft mouse models.

The investigators concluded, “Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in ad-vanced prostate cancer.”

Asangani IA, et al: Nature 510:278-282, 2014.

IMMUNOTHERAPY

Fusion Protein Improves Dendritic Cell Penetration, Raising Prospect of Efficient Cancer Vaccine

Immunotherapy with dendritic cells in combination with cytotoxic chemo-therapy may eliminate minimal disease burden by generating cytotoxic T lym-phocytes (CTLs). Improving the cy-tosolic bioavailability of tumor-specific antigens to improve access to HLA class I molecules would result in better genera-tion of cytotoxic T lymphocytes. Numer-ous cell-penetrating domains (CPDs) are known to carry linked heterologous anti-gens through the plasma membrane into the intracellular compartment.

In a study reported in JAMA Surgery, Batchu and colleagues assessed whether

fusing melanoma antigen family A,3 (MAGE-A3), a tumor-specific cancer-testis antigen, with a cell-penetrating domain would increase the cytosolic bio-availability of MAGE-A3. MAGE-3 was amplified by polymerase chain reaction and cloned in frame with a cell-penetrat-ing domain (YARKARRQARR) at the amino-terminal end and hexahistidine at the carboxy-terminal end to generate CPD–MAGE-A3.

Western blot analysis with MAGE-A3 antibodies recognized both MAGE-A3 and CPD–MAGE-A3 proteins, whereas analysis with cell-penetrating domain an-tibodies recognized only CPD–MAGE-A3. Purified CPD–MAGE-A3 exhibited improved dendritic cell membrane pen-etration vs MAGE-A3 alone. The finding on flow cytometry of high expression of unique dendritic cell markers (CD80, CD83, CD86, and HLA-DR) on den-dritic cells was consistent with a mature dendritic cell phenotype, indicating that pulsing with CPD–MAGE-A3 did not alter the repertoire of cell-surface antigens required for T-cell activation.

The investigators concluded, “We have demonstrated for the first time, to our knowledge, that cloning and purifica-tion of MAGE-A3 with CPD enhances its cytosolic bioavailability in [dendritic cells] without altering cell-surface anti-gens, potentially making it a more potent therapeutic cancer vaccine compared with existing MAGE-A3 protein and pep-tide vaccines.”

Batchu RB, et al: JAMA Surg 149:451-457, 2014.

NOVEL MECHANISMS

Dysregulated Cell-Cycle Progression and Akt Hyperactivation in Cancer

Akt plays important roles in cell pro-liferation, survival, and metabolism. Akt hyperactivation contributes to tumori-genesis and is associated with poor prog-nosis and resistance to chemotherapy and radiotherapy. It is known that activation of Akt results from phosphorylation at S473 and T308, but it is unclear whether other mechanisms are involved in full Akt activation. It is also unclear whether Akt hyperactivation is associated with dysreg-ulated cell-cycle progression, which is also involved in tumorigenesis.

In a study reported in Nature, Liu and colleagues found that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. They showed that

phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2 promoted Akt activation by facilitating or functionally compensating for S473 phosphorylation. Deletion of the cyclin A2 allele in the mouse olfac-tory bulb resulted in reduced S477/T479 phosphorylation and increased apoptosis. Cellular apoptosis in mouse embryonic stem cells induced by cyclin A2 deletion was partly inhibited by S477D/T479E-Akt1, supporting a physiologic role for cyclin A2 in controlling Akt activation.

The investigators concluded, “To-gether, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiologi-cal functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactiva-tion in cancer.”

Liu P, et al: Nature 508:541-545, 2014.

Small Molecule Induces Catastrophic Vacuolization and Death of Glioblastoma Cells

In a study reported in Cell, Kitambi and colleagues screened patient-derived glioblastoma cells to identify targetable cellular processes gained by these cells that are not necessarily involved in ma-lignancy. They found that a quinine de-rivative (NSC13316) selectively com-promised viability of glioblastoma cells.

Structure-activity relationships of the derivative were identified and exploited to produce analogs (vacquinols) with increased potency. The vacquinols were shown to induce death of glioblastoma cells via membrane ruffling, cell round-ing, massive macropinocytic vacuole accumulation, ATP depletion, and cyto-plasmic membrane rupture.

Short hairpin RNA screening identi-fied the MAP kinase MKK4 as a critical signaling node, with the kinase being required for vaquinol-induced vacuoliza-tion. In a glioblastoma multiforme ani-mal model, vacquinol-1 had good phar-macokinetics and brain exposure and was associated with reduced disease pro-gression and prolonged survival.

The investigators concluded, “These results identify a vulnerability to mas-sive vacuolization that can be targeted by small molecules and point to the pos-sible exploitation of this process in the design of anticancer therapies.”

Kitambi SS, et al: Cell 157:313-328, 2014.©P.C. Vey/The New Yorker Collection/www.cartoonbank.com


Lab Notes

BIOMARKERS

15-PGDH Expression in Normal Mucosa May Be Biomarker for Aspirin Prevention of Colorectal Cancer

Aspirin use reduces the risk of colorec-tal cancer at least in part via inhibition of prostaglandin-endoperoxide syn-thase 2 (PTGS2, COX-2) pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide; 15-PGDH, HPGD) is a metabolic antag-onist of PTGS2 and is downregulated in colorectal cancer.

In a study reported in Science Trans-lational Medicine, Fink and colleagues investigated whether the effect of aspirin in reducing risk of colorectal cancer is an-tagonized by low 15-PGDH expression in normal colon mucosa. The study involved analysis of data on aspirin use collected every 2 years and occurrence of colorectal cancer among 127,865 participants in the Nurses’ Health Study and the Health Pro-fessionals Follow-Up Study.

A total of 270 colorectal cancer cases in which 15-PGDH expression could be assessed were identified. Compared with nonuse, regular aspirin use was as-sociated with lower risk of development of colorectal cancer in normal colonic mucosa with high 15-PGDH expression (multivariate hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.34–0.71) but not in normal colonic mucosa with low 15-PGDH expression (multi-variate HR = 0.90, 95% CI = 0.63–1.27, P = .018 for heterogeneity).

The investigators concluded, “Regular aspirin use was associated with lower in-cidence of colorectal cancers arising in as-sociation with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal co-lon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.”

Fink SP, et al: Sci Transl Med 6:233re2, 2014.

TARGETED THERAPY

Spleen Tyrosine Kinase Inhibition Has Promise in High-Risk Precursor B-Cell ALL

In a study reported in Science Translational Medicine, Perova and colleagues found that pre–B-cell recep-tor–independent spleen tyrosine kinase signaling was necessary for leukemic B-cell survival and proliferation in a mouse model. Investigation of samples from

pediatric and adult B-cell acute lym-phoblastic leukemia (ALL) showed that spleen tyrosine kinase and downstream targets were phosphorylated indepen-dently of pre–B-cell receptor expression or genetic subtype.

Studies with two small-molecule spleen tyrosine kinase inhibitors showed reduced growth in vitro of B-cell ALL

subtypes, including high-risk subtypes. Treatment of immunodeficient mice with one of the inhibitors reduced disease bur-den in high-risk B-cell ALL xenografts and decreased dissemination of leukemia into the spleen, liver, kidney, and central nervous system.

The investigators concluded, “[Spleen tyrosine kinase] activation sustains the

growth of multiple [high-risk] B-ALL subtypes, suggesting that [spleen tyrosine kinase] inhibitors may improve outcomes for [high-risk] and relapsed B-ALL.” n

Perova T, et al: Sci Transl Med 6:236ra62, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Perspective

patients to realize the goal of personal-ized medicine. I believe the best clini-cal results are achieved for each patient when the patient’s personal values and goals are met. That is really what quality of care is all about: achieving outcomes that matter to patients.

I plan to focus on several areas this year, but they all center on strengthen-ing our Society and supporting mem-bers in their daily work. One of the goals I would like to achieve this year is to use our accumulating knowledge base in the application of more effec-tive patient-centered care to achieve the goals the patient desires.

Another important priority of mine is to meet and exceed the needs of our membership to ensure that ASCO re-mains a leader in the oncology com-munity. I have been traveling in the United States, Asia, and Europe to meet with domestic and international mem-bers (who now make up 30% of ASCO membership) as well as our sister pro-fessional societies, to learn about their needs and concerns.

I’m finding that the problems con-fronting them are not that different from practice to practice or country to country and that we all share com-mon goals and values. Overly bureau-cratic health-care systems, unafford-able cancer care, and the challenges of financing medical education and ongoing professional development are issues every ASCO member is confronting. Although many of the solutions will be different depending on the local resources and political realities of each country, many will be the same and we can learn from each other.

Membership DiversityDomestically, I am concentrating

on the diversity between our members at academic centers and in community practices to understand the challenges they face. Although their career goals are somewhat different—academic oncologists are generally more focused on discovering new therapies for can-cer, whereas community oncologists tend to be more focused on learning how to apply those discoveries in the clinic—they are really based on one principle: to generate new knowledge

and apply that knowledge to improve patient care.

Recently, we have seen a dramatic shift in the size and number of many community practices as smaller prac-tices merge with another practice, an academic medical center, or a commu-nity hospital, or have to shutter their doors completely. This is a particularly troubling trend since these practices see more than one-third of new patients and play a critical role in the nation’s cancer care system.

ASCO is dedicated to supporting the viability of community practices and finding solutions to help them re-main solvent. This issue will be a main focus of mine this year.

Harnessing Big DataAfter several years of development,

in 2015, ASCO through its subsidiary, the ASCO Institute for Quality, will launch its rapid learning health informat-ics system called CancerLinQ™. ASCO is developing CancerLinQ to monitor, coordinate, and improve the quality of

care provided to cancer patients through the collection, aggregation, and analysis of data extracted from electronic health records of patients from participating oncology practices. The system will rev-olutionize how we care for people with cancer—improving quality and value and accelerating research.

The initial launch of CancerLinQ will take place in a small group of 12 or more “vanguard practices,” which will vary from small community practices to major academic cancer centers to capture the diversity of different mod-els of care delivery. The initial version of CancerLinQ will be followed by rapid releases with expanding func-tionality into the larger oncology eco-system.

We anticipate that CancerLinQ will provide insights into the design of new models of cancer care delivery that are sustainable and that address societal objectives, provide supportive mecha-nisms to sustain a thriving community practice base, and allow the voice of the physician to be resonant, while speed-ing progress in the development and delivery of better treatment options for patients.

High-Value Cancer CareThe drive for health-care reform in

the United States has led ASCO to ex-amine the complex concept of value in cancer care. The rising prices of cancer drugs are creating a difficult situation for patients and oncologists, and ASCO is investigating the integration of cost of care into evidence-based medicine, policy, and research.

We know our members have a diffi-cult enough task dealing with medically complex cancer patients. To have to dis-cuss with patients not only the scientific evidence that shows which treatments

are most likely to improve survival and enhance quality of life, but also issues regarding cost of treatment and the impact it may have on their financial security, raises the demands on already limited time available for patient inter-action. But these are the factors that de-fine high-quality oncology care.

Ultimately, what is of value to one patient may not be the same for an-other, and we have to take that factor into account when attempting to de-fine value. We are not proposing that the determination of value is the same for all patients, but we believe that we need to start having this conversation with our patients.

Currently, ASCO’s Value in Cancer Care Task Force is developing a value

algorithm to help define and assess the value of cancer treatment options. Once the prototype is completed, we will share it with our members and others in the oncology community and get their input.

Palliative Care EndeavorsProviding our patients with opti-

mal oncology care and improving their quality of life at every stage of their disease and survivorship is of such critical importance to ASCO, the So-ciety is launching a Palliative Care in Oncology Symposium this fall. The scientific meeting will be held October 24–25, 2014, in Boston, and will focus on innovative strategies in the manage-ment of treatment- and disease-related symptoms and models of integrated health-care delivery during every stage of disease.

Together with the Academy of Hospice and Palliative Care Medicine, ASCO is working on defining the pal-liative care skill set every oncologist needs to be familiar with to manage patients’ symptoms. Another initia-tive is a virtual learning collaborative that brings together 25 community and academic oncology practices from around the country to design, execute, present, and evaluate quality improve-ment projects with the goal of opti-mizing palliative care delivery. The program, which began earlier this year, will be in place for 2 years.

Common Ground and Diversity

All of the goals I have outlined here relate to one overarching focus of my presidential term, and that is to address the needs of all our mem-bers—domestic and international, in private and academic practices—and to look for common ground and com-mon solutions to the issues confront-ing all of us.

That said, it is our members’ di-versity that makes our Society strong and will define our place in the global effort to improve the lives of patients with cancer. The initiatives we are un-dertaking to study new models of pro-viding high-quality, high-value cancer care will hold us in good stead during these challenging times and enable us to continue to be at the forefront of innovation. n

The initiatives we are undertaking to study new models of providing high-quality, high-value cancer care will hold us in good stead during these challenging times and enable us to continue to be at the forefront of innovation.

—Peter P. Yu, MD, FASCO

The Year Aheadcontinued from page 1


In the Literature

Emerging Clinical Data on Cancer Management

RISK FACTORS

Prolonged TV Viewing, Other Sedentary Behaviors Linked to Increased Risk of Particular Cancers

“Prolonged TV viewing and time spent in other sedentary pursuits is as-sociated with increased risks of certain types of cancer,” concluded a meta-anal-ysis of data from 43 observational stud-ies including more than 4 million people and 68,936 cancer cases. A positive as-sociation with overall sedentary behav-ior was found for colon, endometrial, and lung cancer.

“The primary finding from our meta-analysis is that prolonged TV viewing and time spent in other sedentary pur-suits is associated with increased risks of colon and endometrial cancer. Each 2-hour per day increase in sedentary time was related to a statistically sig-nificant 8% increase in colon cancer risk and 10% increase in endometrial cancer risk,” Daniela Schmid, PhD, MSc, and Michael F. Leitzmann, MD, DrPH, Department of Epidemiology and Pre-ventive Medicine, University of Regens-burg, Germany, wrote in the Journal of the National Cancer Institute. “Sedentary behavior was unrelated to cancers of the breast, rectum, ovaries, prostate, stom-ach, esophagus, testes, renal cell, and non-Hodgkin lymphoma.”

The authors noted that sedentary behavior is emerging as an indepen-dent risk factor for chronic disease and mortality. Television viewing was sin-gled out because it “is accompanied by increased consumption of unhealthy foods, such as sugar-sweetened beverag-es, sweets, and fast food and it is related to enhanced smoking initiation,” the in-vestigators stated.

“We performed a comprehensive electronic literature search in Cochrane, EMBASE, Medline, and SciSearch data-bases through February 2014 for pub-lished articles investigating sedentary behavior in relation to cancer incidence. Because randomized controlled trials are difficult to perform on this topic, we focused on observational studies that met uniform inclusion criteria,” the re-searchers explained. Data in the studies had been obtained with self-adminis-tered questionnaires and interviews.

“Comparing the highest vs lowest levels of sedentary time, the relative risks (RRs) for colon cancer were 1.54 (95% confidence interval [CI] = 1.19 to 1.98) for TV viewing time, 1.24 (95% CI =

1.09 to 1.41) for occupational sitting time, and 1.24 (95% CI = 1.03 to 1.50) for total sitting time. For endometrial cancer, the relative risks were 1.66 (95% CI = 1.21 to 2.28) for TV viewing time and 1.32 (95% CI = 1.08 to 1.61) for

total sitting time. A positive association with overall sedentary behavior was also noted for lung cancer (RR = 1.21; 95% CI = 1.03 to 1.43),” the authors wrote.

Among the biologic mechanisms that “may mediate the observed posi-

tive association between sedentary behavior and cancer,” the investigators listed decreased energy expenditure ac-companied by weight gain and obesity, and vitamin D deficiency. The authors


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In the Literature

pointed out that while sedentary behav-ior was strongly associated with colon cancer and endometrial cancer, “tumors that are considered obesity-related,” sedentary behavior was not associated with breast cancer and renal cell cancer, “even though obesity is positively as-sociated with those malignancies. This suggests that sedentary behavior and obesity mediate risk for certain cancers (eg, colorectal cancer and endometrial cancer) through shared mechanisms, whereas other cancers (eg, breast can-cer and renal cell cancer) show distinct obesity-specific pathways.”

The authors called for stronger in-dividual and public health efforts to re-duce time spent on sedentary behavior.

“Given the strength of the data, the dose–response relation, and the lack of heterogeneity among studies, these data support a causal relation between sedentary behavior and both colon and endometrial cancers. For other cancers that are related to obesity (breast, kid-ney), the association for sitting may op-erate through obesity-specific pathways,” noted an accompanying editorial by Lin Yang and Graham A. Colditz, MD, DrPH, of the Siteman Cancer Center and Department of Surgery, Washington University School of Medicine, St. Louis.

“Cancer prevention requires a suf-ficient evidence base, political will to fund programs to address the preven-tion potential, and a social strategy or plan by which we apply our knowledge to initiate or improve programs,” the editorialists continued. They mentioned several possible interventions including worksite modifications to reduce seden-tary time and “replacing sedentary time in transport with active commuting.”

Schmid D, Leitzmann MF: J Natl Can-cer Inst 106(7):dju098, 2014.

Yang L, Colditz GA: J Natl Cancer Inst 106(7):dju135, 2014.

COLORECTAL CANCER

Patient, Tumor Characteristics Associated With BRAF and KRAS Mutations

KRAS and BRAF V600E mutations were nearly mutually exclusive and as-sociated with specific patient and tumor characteristics, such as age and smoking status, according to an analysis of data from the N0147 phase III trial for stage III colon cancer.

Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair status,

Wilson I. Gonsalves, MD, of the Mayo Clinic, and colleagues explained in the Journal of the National Cancer Institute. That information was merged with clini-cal characteristics collected at the time of randomization, and patient charac-teristics, including activity level, smok-ing, alcohol intake, and family history of colorectal cancer, obtained from the 2,326 (93%) of the 3,397 enrolled pa-tients who completed questionnaires.

“Specifically, age of 70 years or older, smoking, high-grade histology, and [de-fective mismatch repair] status were as-sociated with a lower incidence of mu-tant KRAS tumors but a higher incidence of BRAF [V600E]-mutated tumors. Both mutations tend to [occur in right-sided tumors] and were nearly mutually exclusive, but BRAF [V600E]-mutated tumors are more common in females, non-Hispanic white patients, those hav-ing four or more positive lymph nodes, stage T4 disease, and those with a histo-ry of gastrointestinal conditions. Finally, within KRAS mutant tumors, those with a KRAS Gly13Asp mutation tend to be associated with [defective mismatch re-pair] status and high-grade histology,” the researchers reported.

“The presence of a KRAS mutation is predictive for resistance to anti-[epidermal growth factor receptor (EGFR)] mono-clonal antibodies in advanced colon can-cer,” the authors noted, although “it has been suggested that patients whose tu-mors harbor a KRAS Gly13Asp mutation may benefit from anti-EGFR [monoclo-nal antibody] therapy. BRAF activating mutations, specifically V600E, occur in less than 10% of patients with sporadic co-lon cancer and are a strong negative prog-nostic marker; however, their predictive value for efficacy of anti-EGFR [mono-clonal antibody] treatment is less certain.”

In the current study, there were 783 tumors (35%) that had KRAS muta-tions, “of which 191 (24%) were KRAS Gly13Asp, whereas 310 (14%) tumors had a BRAF [V600E] mutation. Of 2,231 tumors analyzed for [mismatch repair] status, 279 (13%) were charac-terized as [defective mismatch repair],” according to the study report.

“KRAS mutations were more likely to be present in patients without a fam-ily history of colon cancer and never smokers. Tumors with KRAS mutations [excluding those with KRAS Gly13Asp mutation] were less likely to have [defec-tive mismatch repair] (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001),” the investigators stated. “Tumors with BRAF [V600E] mutations

were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men.”

The authors noted that further stud-ies are warranted to explain the associa-tion between the mutations and the cit-ed epidemiologic and clinicopathologic characteristics.

Gonsalves WI, et al: J Natl Cancer Inst 106(7):dju106, 2014.

SKIN CANCER

Simple Bedside Assessment of Pain and Itch Is Valuable Tool for the Evaluation of Suspicious Skin Lesions

A prospective, clinicopathologic study involving 268 patients with biop-sy-proven basal cell carcinoma, squa-mous cell carcinoma, malignant mela-noma, or melanoma in situ “revealed that pain is associated with histologic features that involve deeper dermal pro-cesses in [squamous cell carcinoma] le-sions, such as ulceration and depth of invasion, whereas itch is linked with the more superficial [basal cell carcinoma] lesions.” The study by Gil Yosipovitch, MD, of the Department of Dermatol-ogy and Temple Itch Center, Temple University School of Medicine, Phila-delphia, and colleagues was published in JAMA Dermatology.

The authors concluded, “These find-ings support the theory that itch emanates from the upper layers of the skin, whereas pain is associated with deeper processes.” The investigators also stated that the study “highlights the importance of a simple bedside evaluation for the presence and intensity of pain and itch as an easily implementable tool for physicians to use when evaluating suspicious skin lesions.”

Drawn from the patient population presenting to the Department of Derma-tology surgical unit at Wake Forest Uni-versity Baptist Medical Center in Win-ston-Salem, North Carolina, from July 1, 2010, through March 31, 2011, the study participants represented 339 histologi-cally confirmed cutaneous neoplasms: 166 basal cell carcinomas, 146 squamous cell carcinomas, and 27 melanomas. The participants completed questionnaires assessing itch and pain intensity of their skin tumors at the time of excision. His-topathologic analysis for each neoplasm included assessment of the amount and type of inflammation, ulceration, peri-neural invasion, and depth of invasion.

Across all types of skin cancers,

itch was prevalent in 36.9% and pain in 28.2%. “The prevalence of itch was greatest in [squamous cell carcinoma] (46.6%), followed by [basal cell carcino-ma] (31.9%) and melanoma (14.8%). Pain prevalence was also greatest in [squamous cell carcinoma] (42.5%), again followed by [basal cell carcino-ma] (19.9%) and melanoma (3.7%). The prevalence of itch and pain was significantly greater in [squamous cell carcinomas] (P = .002) and [basal cell carcinomas] (P < .001) compared with melanoma,” the researchers reported.

Grouping all skin cancers together, the mean depth of invasion was highest in the most painful lesions and lowest in the painless lesions. “Pain intensity was significantly associated with the degree of inflammation (mild or none vs mod-erate or marked; P < .001), presence of neutrophils in the inflammatory infil-trate (predominantly mononuclear vs mixed or neutrophilic; P = .003), pres-ence of eosinophils (present vs absent; P = .007), ulceration (yes vs no; P = .003), perineural invasion (yes vs no; P < .001), depth of invasion (P = .001), and largest diameter length of skin lesion (P < .003), the researchers reported.

“Itch intensity was significantly asso-ciated with the degree of inflammation (mild or none vs moderate or marked; P = .001) and the presence of eosinophils (present vs absent; P = .02),” they added.

The authors acknowledged that the relatively small sample size of mela-noma cases “does not allow us to draw firm conclusions about the association between pain and itch and histopatho-logic features of melanoma. However, it is clear that melanomas have a signifi-cantly decreased prevalence of pain and itch compared with nonmelanoma skin cancer, a finding confirmed by a similar study that examined itch and tenderness in patients with melanoma,” the investi-gators noted.

Yosipovitch G, et al: JAMA Dermatol. July 23, 2014 (early release online).

LYMPHOMA

First Prospective Study of Rare Lymphoma Shows Promising but Inconclusive Results With DA-EPOCH-R

Presenting “the first prospective study” of mediastinal gray zone lympho-ma, researchers from the National Can-cer Institute reported that DA-EPOCH-R (infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and ritux-imab (Rituxan) and filgrastim (Neupo-

Emerging Clinical Datacontinued from page 103


In the Literature

gen) in untreated mediastinal gray zone lymphoma produced event-free survival of 62% and overall survival of 74% at 59 months median follow-up.

“DA-EPOCH-R alone produced du-rable remissions in most patients indicat-ing it is an effective treatment for these relatively resistant lymphomas,” the au-thors wrote. While the results of the trial, which involved 24 patients, were consid-ered promising, “we cannot rigorously determine if DA-EPOCH-R is optimal treatment for [mediastinal gray zone lymphoma] given the limited number of cases and absent a randomized study de-sign,” Wyndham H. Wilson, MD, PhD, and colleagues wrote in Blood.

Mediastinal gray zone lymphoma is extremely rare, the investigators noted, and has pathologic features intermedi-ate between the more common types of mediastinal B-cell lymphomas, nodu-lar sclerosis Hodgkin lymphoma and primary mediastinal B-cell lymphoma. “The indeterminate pathobiology of [mediastinal gray zone lymphoma] has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been character-ized,” the researchers wrote.

Study participants had a median age of 33 years (range, 14–59) years and 46% had mediastinal masses ≥ 10 cm. “All pa-tients had histological and/or phenotyp-ic features intermediate between [pri-mary mediastinal B-cell lymphoma] and [nodular sclerosis Hodgkin lymphoma]. Usually, the tumors have a predominant morphology, which was either [pri-mary mediastinal B-cell lymphoma]-like in 33% (8/24), or more frequently Hodgkin-like in 63% (15/24) of cases, and one case was classified as composite [nodular sclerosis Hodgkin lymphoma] and [primary mediastinal B-cell lym-phoma],” the researchers noted.

“All patients responded with 19 com-plete and 5 partial remissions,” the inves-tigators reported. Nine patients were di-agnosed with active disease at a median of 3 months (range, 1–6) after complet-ing therapy. Based on positron-emission tomography/computed tomography evaluation showing disease limited to the mediastinal area, all nine patients re-ceived involved-field salvage radiothera-py “and four are in continuous remission at 3, 73, 91, and 128 months,” according to the study report.

“The occurrence of treatment failure in one third of [mediastinal gray zone lymphoma] patients and the curative potential of salvage radiotherapy makes early identification of treatment failure important,” the authors noted. Indica-tors of worse outcome include low ab-

solute lymphocyte count, the presence of tumor-associated dendritic/macro-phage cells, and CD15 expression on the malignant cells.

Results of the study were compared to a cohort of patients with primary me-diastinal B-cell lymphoma prospectively treated with DA-EPOCH-R. “Patient eligibility was identical for both groups

except patients with [primary mediasti-nal B-cell lymphoma] were required to have a mediastinal mass at least 5 cm. Treatment and follow-up were identical in both groups,” the investigators stated. “Compared with [primary mediastinal B-cell lymphoma], [mediastinal gray zone lymphoma] patients were more likely to be male, express CD15, have

lower expression of CD20 and to have a worse outcome.”

The trial was registered at ClinicalTri-als.Gov (NCT00001337).n

Wilson WH, et al: Blood. July 14, 2014 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

2015 Young Investigator Award (YIA)Young Investigator Award (YIA) — A one-year, $50,000 grant that provides funding to

promising physicians to support their transition from the final years of training to a faculty

appointment, and to encourage and promote quality research in clinical oncology.

The Conquer Cancer Foundation accepts applications in ALL areas of cancer research,

from physician-scientists all around the globe. For 2015, CCF also has funds restricted

to certain areas including Breast Cancer, Cholangiocarcinoma, Kidney Cancer, Pediatric

Cancer, Sarcoma, and to researchers based in Florida.

All applications must be received by 11:59 PM (EST) September 25, 2014.

www.conquercancerfoundation.org/YIA

Applications Due September 25th

http://www.conquercancerfoundation.org


In Memorium

Pioneer in Fight Against Tobacco, Emanuel Farber, MD, PhD, Dies at 85By Ronald Piana

On December 11, 1969, a soft-spoken pathologist wearing outsized spec-

tacles answered a long and complex series of questions by the legal team represent-ing Liggett & Myers Tobacco Company, the maker of Chesterfield cigarettes. The tobacco lawyers contended that one Les-lie Thayer—a lifelong smoker of Ches-terfields—had died of lung cancer due to “misuse” of their product. The expert witness, Emanuel Farber, MD, PhD, dis-mantled that contention, demonstrating that years of smoking Chesterfield ciga-rettes had caused Leslie Thayer’s death of lung cancer. Dr. Farber’s groundbreaking research in carcinogenesis was instrumen-tal in the paradigm shift in American atti-tudes toward smoking. Dr. Farber died on August 3, 2014, at the age of 95.

Early LifeDr. Emmanuel Farber was born in

Toronto in 1918. His lifelong interest

in science blossomed during his early schooling, leading him to the Faculty of Medicine, University of Toronto, in 1936, where he received his MD degree in 1942. Having completed his residency train-ing in pathology at the Hamilton General Hospital in Ontario, Canada, Dr. Farber served in the Royal Canadian Army Medi-cal Corps. After his military service, Dr. Farber entered the University of Califor-nia Graduate School, Berkeley, obtaining his doctorate in biochemistry in 1949.

Dr. Farber developed an early interest in liver disease that can be traced to a 1950 fel-lowship awarded by the American Cancer Society. There he worked with Hans Pop-per, MD, who was the driving force behind the founding of the American Association for the Study of Liver Diseases. During this exciting period of study, Dr. Farber wrote several papers dealing with early theories on the etiology of liver diseases.

Pathologist, Biochemist, and Educator

Although Dr. Farber was a renowned pathologist and biochemist, he was also an educator. When he was elected as an hon-orary member of the Society of Toxicolog-ic Pathologists, his colleague Felix A. de la Iglesia, MD [now Chief Enterprise Officer of the Michigan Technology & Research Institute at Wayne State University School of Medicine, Ann Arbor, Michigan] wrote, “Those who are fortunate enough to work

near or under Dr. Farber’s guidance enjoy the feeling of continuing mental probing, the intense research intellectual exercise, and the amazing flow of energy that ema-nates from his personality.”

He began his academic teaching career as an instructor in pathology at Tulane University in New Orleans, serving as As-sociate Professor from 1950 to 1959. He later became the American Cancer Soci-ety Research Professor of Pathology and Biochemistry from 1959 to 1961.

After leaving the American Cancer Society, Dr. Farber became Professor and Chair of the Pathology Department and Professor in the Biochemistry De-partment at the University of Pittsburg School of Medicine, serving from 1961 to 1970. From 1970 through 1975, Dr. Farber was at the Fels Research Insti-tute in Philadelphia, where he was ap-pointed as Director.

Emanuel Farber, MD, PhD

Jesse L. Steinfeld, MD, Past Surgeon General, ASCO President, Dies at 87By Ronald Piana

The 1964 Surgeon General’s Report on Smoking and Health started a cul-

ture change in the way Americans viewed tobacco and their health, and has saved countless million of lives. But the 1964 Re-port remained scientifically ambiguous on certain vital issues, such as the effect smok-ing had on the unborn child. This was a crucial issue, as Big Tobacco had targeted America’s women as a growing source of new smokers, playing down harms associ-ated with smoking while pregnant.

In 1971, then Surgeon General Jesse L. Steinfeld, MD, took Big Tobacco to task, stating, “Let me suggest that certain purveyors of cigarettes stop making re-marks about how some young mothers in childbirth might welcome smaller babies. The mother who smokes is subjecting the unborn child to the adverse effects of to-bacco, and as a result we are losing babies and possibly handicapping babies.”

Dr. Steinfeld died on August 5, 2014, at the age of 87.

Education and Early CareerThe son of Jewish immigrants from

Hungary, Dr. Steinfeld was born on Jan-uary 6, 1927, in the Pittsburgh suburb of West Aliquippa, deep in coal country. When he was 5 years old, his father, a lifelong smoker, died of lung cancer.

Boys in his social class were routine-

ly placed in vocational tracks that often led to the coal mines. However, Dr. Steinfeld persuaded his counselor to put him on an academic track instead; he graduated high school with honors at age 16 and received his bachelor’s de-gree 19 months later from the Univer-sity of Pittsburgh in 1945.

Dr. Steinfeld earned his MD in 1949 from Western Reserve University, now called Case Western Reserve University, in Cleveland. He then did his internship at Cedars of Lebanon Hospital in Los An-geles and his residencies at the Veterans Administration Hospital in Long Beach, California, and at the University of Cali-fornia, where he studied oncology.

In 1954, Dr. Steinfeld took a position at the National Cancer Institute (NCI), serving as Director of the Radioisotope Laboratory until 1958. In 1959, he re-turned to California, where he joined the faculty of the University of Southern California School of Medicine, serving as Assistant Professor of Medicine, rising to Associate Professor in 1963, and full professorship in 1967. During this period, most of his research focused on cancer.

Dr. Steinfeld returned to the NCI in 1968, serving as Associate Director for Programs. Later that same year, he was appointed Deputy Assistant Secretary for Health and Scientific Affairs, and

on December 18, 1969, he became the U.S. Surgeon General. During his tenure

as Surgeon General, Dr. Steinfeld also served as ASCO’s seventh President, from 1970 to 1971.

Antismoking PassionFor various political reasons prior

to his appointment, the Surgeon Gen-eral’s position had been watered down, operating without a clear line of author-ity. But that changed with Dr. Steinfeld, who embraced the role of public-figure activist. His antitobacco stance was bold and unequivocal, leading him to become Big Tobacco’s worst enemy. Remarkably, his two predecessors had been smokers. Dr. Steinfeld removed all the ashtrays and placed no-smoking signs in his offices, an unheard of move against the status quo in that era.

Dr. Steinfeld’s antismoking passion led him into uncharted waters. Citing numer-

ous studies showing that women were less likely than men to quit smoking, he spearheaded a campaign to reduce the number of female smokers. He spoke lib-erally without mincing words about how Big Tobacco cleverly marketed cigarettes to women, even pregnant women, despite the deleterious effects on the fetus.

He was also at an unpopular vanguard, warning against the dangers of second-hand smoke. Many of his ideas about banning smoking on airplanes, trains, restaurants, the workplace, and other public places would take hold decades later as antismoking activists lobbied for and achieved smoke-free zones. But at the time, they were considered radical.

Not surprisingly, Big Tobacco at-

It is high time to ban smoking from all public places…. It is time we interpret the Bill of Rights for the nonsmoker as well as the smoker.

—Jesse L. Steinfeld, MD, in 1971




In Memorium

In Memoriam

Jesse L. Steinfeld, MDJanuary 6, 1927 – August 5, 2014

Emanuel Farber, MD, PhDOctober 19, 1918 – August 3, 2014

Jesse L. Steinfeld, MD, and The War on Cancer

In “Stories on the History of Cancer,” available on ASCO’s Cancer .Progress.Net, past ASCO presidents and other oncology luminaries

discuss the founding of ASCO, the early days of cancer treatment, and the notable changes that have occurred since then—both in the care of people with cancer and in our understanding of the disease. In one such interview, Dr. Jesse Steinfeld recalls the excitement surrounding the 1971 National Cancer Act. To view Dr. Steinfeld’s interview, visit http://cancerprogress .net/story/war-cancer. n

tacked him. In 1972, the President of R.J. Reynolds wrote to Elliot Richard-son, the Secretary of Health, Educa-tion, and Welfare: “The results of pub-lic misinformation are evident. Public transportation, for example, is beset with no-smoking policies on the ba-sis of the Surgeon General’s arbitrary campaign to ban all smoking.”

Undaunted ZealDr. Steinfeld remained undaunted in

his zeal for public health. Besides his non-stop vigorous antismoking campaign, he also spoke out about what he regarded as a negative influence on children—vio-lence on television. His call for networks to impose certain types of self-censorship or to at least give parental warnings about

violent programs drew heavy criticism, which also attracted the ire of the Nixon administration.

His superiors ordered him not to testify before Congress on the televi-sion violence issue, but true to form, Dr. Steinfeld testified without clearing his remarks first. This latest move against the industry created a firestorm. When Nixon was reelected in 1972, he asked certain members of his administration to submit letters of resignation. Dr. Stein-feld’s letter, which needed to be rewrit-ten several times to dilute its power, was finally accepted.

Following his forced resignation, Dr. Steinfeld spent a year at the Mayo Clinic and 2 years at the University of California, Irvine. From 1976 to 1983, Dr. Steinfeld served as Dean at the Medical College of Virginia School of Medicine. He became

President of the Medical College of Geor-gia in 1983.

Health-related issues led to his retire-ment in 1987, but he remained a strong public advocate for nonsmoker’s rights. In 1971, Dr. Steinfeld publically stated before Congress, “It is high time to ban smoking from all public places…. It is

time we interpret the Bill of Rights for the nonsmoker as well as the smoker.”

Lest we forget, our public health has greatly improved because of courageous physicians like Dr. Steinfeld. He is sur-vived by three daughters, two grandchil-dren, and his wife of more than 61 years, the former Gen M. Stokes. n

Jesse L. Steinfeld, MDcontinued from page 106

In 1975, Dr. Farber returned to his native city of Toronto, to serve as Chair-man of the Department of Pathology at the University of Toronto. Later, Dr. de la Iglesia, would write, “Dr. Farber’s aca-demic career and research achievements

are the proof that pathologists must seek with interdisciplinary knowledge and profound biochemical insight into the bi-ological processes they study through the microscope. At an early age, Dr. Farber de-voted himself to this discipline; thus, his leading role in developing experimental and biochemical pathology.”

Early in Dr. Farber’s career, he was the recipient of the Parke-Davis Award in Experimental Pathology, a prize giv-en to an investigator under age 40 who has shown a promising career in pathol-ogy. The Parke-Davis Award would be the first of many bestowed on Dr. Far-ber. In 1984, he was made a Fellow of

the Royal Society of Canada, an award that recognizes outstanding Canadians.

Legacy WorkDr. Farber’s work in illuminating the

public health disaster associated with smoking was his legacy work. His ground-breaking studies in experimental pathol-

ogy confirmed that chemical carcinogens are capable of binding to nucleic acids, in turn generating specific DNA adducts.

These early findings led to the ob-servation that chemical carcinogenesis is a sequential process. Dr. Farber later substantiated this theory by showing that cancer could be induced through a series of step-by-step chemical treat-ments in the liver.

Dr. Farber served on the Surgeon General’s first Advisory Committee on Smoking and Health from 1961 to 1964. The committee was responsible for issu-ing the landmark 1964 Surgeon General’s Report, which has now done more to pre-vent tobacco-related disease than any oth-er public health document, and is credited with saving tens of millions of lives.

Moreover, Dr. Farber promoted the concept that to understand carcinogene-sis, one must also understand the cellular, genetic, metabolic, and molecular chang-es that are occurring during the process. This conviction, along with Dr. Farber’s energy and enthusiasm in exploring the nature of cancer, has inspired the guid-

ance for cancer researchers worldwide. In addition to his academic and re-

search contributions, Dr. Farber was a very active member of the American As-sociation for Cancer Research (AACR), serving as Vice President from 1971 to 1972 and President from 1972 to 1973. He was a member of the AACR Board of Directors and served as Associate Editor of Cancer Research; he was elected as an inaugural Fellow of the AACR Academy in 2013.

Unmatched TenacityAs news of Dr. Farber’s death became

public, colleagues uniformly remembered him as researcher of unmatched tenacity and devotion to scientific exploration. A remark by Dr. de la Iglesia in 1985 cap-tures the essence of the scientific com-munities that Dr. Farber touched: “For us he represents a guiding example of a life devoted to serving his fellow man and scientific colleagues with unmatched qualities of integrity, humbleness, deep reasoning, and an exquisite no-nonsense … approach to science.” n

Emanuel Farber, MD, PhDcontinued from page 106

[H]e represents a guiding example of a life devoted to serving his fellow man and scientific colleagues

with unmatched qualities of integrity, humbleness, deep reasoning, and an exquisite no-nonsense …

approach to science. —Felix A. de la Iglesia, MD

http://cancerprogress.net/story/war-cancer

http://cancerprogress.net/story/war-cancer

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