best practices in treatment selection for patients with advanced nsclc · 2018-08-16 · strategies...

cancercontroljournal.org Vol. 23, No. 4, October 2016 Supplement

H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER

Best Practices in Treatment Selection for

Patients With Advanced NSCLC

Mark A. Socinski, MD, and Nathan Pennell, MD, PhD

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H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE INC12902 Magnolia DriveTampa FL 33612-9416

Cancer Control is included inIndex Medicus/MEDLINE

October 2016, Vol. 23, No. 4 Supplement Cancer Control 1

Table of Contents

Article

About the art in this issue:

Bryan Whitney is a photographer based in New York City. His experimental, architectural, and fine-art work have been featured in many magazines and books, and his work has been exhibited in the United States and Europe. He was awarded a Fulbright lecture grant and currently teaches at the International Center for Photography. To view more of Bryan’s work or to contact him, please visit www.x-rayphotography.com or www.bryanwhitney.com.

Cover: Nasturtium

Article: Tulip

Jointly Provided by:

Introduction 2

Scope of the Problem 3

Clinical Controversies and Challenges 3

Therapeutic Targets 3

Practical Considerations in Biomarker Testing 5

Case Study: Treatment of Stage IVb Nonsquamous Disease 5

Case Study: Treatment of Stage IVb Squamous Disease 7

Case Study: Second-Line Therapy 8

Case Study: Treatment of EGFR Mutation-Positive Disease 10

Conclusions 12

Continuing Medical Education Activity

CME Instructions 15

This activity is supported by an independent educational grant from Boehringer Ingelheim, Genentech, and Lilly.

Best Practices in Treatment Selection for Patients With Advanced NSCLC 2Mark A. Socinski, MD, and Nathan Pennell, MD, PhD

2 Cancer Control October 2016, Vol. 23, No. 4 Supplement

IntroductionNon–small-cell lung cancer (NSCLC) represents a het-erogeneous group of malignancies that constitutes 80% to 85% of lung cancers.1 Adenocarcinoma is the most common subtype of NSCLC and accounts for nearly 50% of cases.1 Worldwide, lung cancer repre-sents the most common type of cancer: 1.8 million new

cases of lung cancer were diagnosed in 2012 alone, and it is estimated to be responsible for 1 in 5 can-cer-related deaths each year.2 It remains the most com-mon cancer in men.2

Death rates from lung cancer in the United States have declined by 38% in men since 1990 and by 12% in women since 2002, primarily due to the decrease in smoking prevalence.3 Nonetheless, lung cancer re-mains the second most common cancer in both men and women in the United States, with 117,920 and 106,470 estimated new cases diagnosed in men and women, respectively, in 2016.3 Lung cancer is the lead-ing cause of cancer-related death in the United States, with an estimated 85,920 deaths occurring in men and 72,160 deaths among women.4 This is partly because 16% of lung cancers are diagnosed at a localized stage when the 5-year survival rate is 55%; however, the overall 1- and 5-year survival rates for lung cancer are 44% and 17%, respectively.3

From the Florida Hospital Cancer Institute (MAS), Orlando, Flori-da, and the Cleveland Clinic (NP), Taussig Cancer Institute, Cleve-land, Ohio.

Address correspondence to Mark A. Socinski, MD, Florida Hospi-tal Cancer Institute, Executive Offices, 11th Floor, 601 E. Rollins Street, Orlando, FL 32803. E-mail: [email protected]

Dr Socinski has received grants/research support from Bristol-Myers Squibb, Clovis, Genentech, Lilly, Pfizer, and Synta, and has served on the speakers’ bureaus for Bristol-Myers Squibb, Celgene, and Genentech. Dr Pennell serves as a consultant/independent contractor for AstraZeneca and Boehringer Ingelheim.

This monograph is supported by independent educational grants from Boehringer Ingelheim, Genentech, and Lilly.

Leading experts discuss treatment

strategies for advanced NSCLC.

Best Practices in Treatment Selection for Patients With Advanced NSCLC

Mark A. Socinski, MD, and Nathan A. Pennell, MD, PhD

Tulip. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com.

Summary: Worldwide, lung cancer is the most prevalent form of cancer, and its non–small-cell subtype consti-tutes up to 85% of cases. Overall, lung cancer is the most common cause of cancer-related death in the United States for both sexes, and its 5-year survival rate is 17%. It is a heterogeneous disease characterized by a variety of biomarkers and differing histologies. Non–small-cell lung cancer may be squamous or nonsquamous in nature and fueled by a number of oncodrivers. Obtaining sufficient tissue during biopsy to perform thorough biomarker testing is a challenge but essential for the modern, targeted therapeutic environment. Although platinum-based doublets still play a major role in first-line treatment, novel therapeutic agent targeting BRAF, EGFR, ALK, and ROS1, as well as agents targeting the T790M mutation, may offer options for patients whose disease fails to re-spond to initial therapy or relapses following an initial response. The emergence of immunotherapy as second-line standard therapy has changed the treatment paradigm. Some patients will have more favorable outcomes in the first-line setting with immunotherapy. However, managing lung cancer has become more complex than it was 15 years ago when the challenge of treatment was seen as being only binary, ie, small-cell vs non–small-cell disease.

Cancer Control 3October 2016, Vol. 23, No. 4 Supplement

The following report presents highlights from a roundtable discussion between 2 leading medical on-cology experts in NSCLC, Mark A. Socinski, MD, and Nathan A. Pennell, MD, PhD. The panel members share insights into the validity and clinical implications of a variety of NSCLC biomarkers, first- and second-line therapies for NSCLC of squamous or nonsquamous origin, and promising novel therapies on the horizon. Case studies are used to demonstrate selected thera-peutic strategies in real-world clinical scenarios.

Scope of the ProblemDr Pennell: Lung cancer is the second most common cancer in both men and women in the United States, but more Americans die of lung cancer than the next 4 most common cancers combined.4 Despite the fact that death rates have been dropping in men for sometime and, more recently, in women, it is still far and away the most important cancer from a morbidity and mor-tality perspective in the United States and worldwide.2,3 Despite excitement over treatment advances and the onset of screening in lung cancer, the 5-year survival rate remains at 18%.3,4

Dr Socinski: I might also mention here that, in com-parison with breast cancer, we have a different stage demographic. At the time of diagnosis, most patients with lung cancer present with stage III/IV disease, whereas, because of awareness and screening, most patients with breast cancer present with stage I/II disease.4 Right out of the gate, we are disadvantaged with regard to long-term survival. Stage IV disease is treatable but not curable; with stage III disease, even though we approach it in some subset as curative, the majority of patients are not cured.5

Dr Pennell: It is heartening that smoking rates in American adults overall have dropped below 20%.6 It will take several decades for this change in behavior to be reflected in falling death rates from lung cancer. While we finally have Centers for Medicare & Medicaid Services coverage for the screening of lung cancer in high-risk patients, the process has not yet been widely enough adopted for us to see any real impact on lung cancer–related deaths.

Clinical Controversies and ChallengesDr Socinski: One of the challenges we face in this population is getting an initial diagnosis and all that entails. Historically, we have approached this disease as a single entity. About 15 or 20 years ago the distinc-tion we asked pathologists to make was to differenti-ate between small cell lung cancer and NSCLC, and that was pretty much it. We believed all NSCLCs were similar from a treatment perspective. This perspective changed with bevacizumab and pemetrexed when we

decided it was important to distinguish between squa-mous and nonsquamous histologies. With the advent of modern molecular testing, obtaining adequate tissue for testing can be a challenge in the individual patient, particularly as the initial specimen on biopsy is often acquired before the patient sees an oncologist.

Dr Pennell: I completely agree. The biggest challenge is obtaining sufficient tissue and having enough insti-tutional expertise in the pathology department where the biopsy is performed as well as good communica-tion with those performing the biopsy. Going forward, nonsquamous NSCLC patients will need to have a fair-ly broad panel of molecular tests performed. This re-quires far more extensive testing, which represents a fairly high burden of need for sufficient tissue.7 Now we may even be talking about biomarkers such as pro-grammed death ligand 1 (PD-L1). Meanwhile, a large number of individuals are diagnosed based on a brush-ing from bronchoscopy with a few cells and that is all you get. In many of these patients, it is fairly high risk to obtain tissue. This consideration is an issue I think does not receive nearly enough attention.8

Dr Socinski: This need for tissue is particularly true for adenocarcinoma patients in whom the number of mark-ers we are testing for seems to be increasing yearly. We are rapidly entering an era where immunotherapy will be the preferred first-line treatment for a subset of pa-tients. But you select those patients based on a biomark-er performed from core biopsy.7 Most of the decision-making is made without consultation from a medical oncologist. Instead, pulmonologists, thoracic surgeons, and primary care physicians refer patients to interven-tional radiology. Those subspecialties may not know or have an appreciation of all the demands on tissues. The word needs to spread to these other disciplines.

Therapeutic TargetsWhat would you say is the standard of care today for the minimal number of genotypes that we should be testing?

Dr Pennell: We have consensus guidelines from the International Association for the Study of Lung Can-cer and the College of American Pathologists that have recommended for years that every nonsqua-mous NSCLC or adenocarcinoma or suspected adeno-carcinoma be tested for EGFR mutations as well as for ALK rearrangements.9

However, most of us recognize that current guide-lines require updating. At a minimum, I think that EGFR mutations and ALK and ROS1 rearrangements should be tested for in every newly diagnosed patient with adenocarcinoma or select squamous cell patients with a minimal smoking history.9,10 However, I would argue that there are a number of other markers that


should routinely be tested for if those 3 are negative. At the most recent annual meeting of the American Society of Clinical Oncology (ASCO), mature data on the combination of the B-raf proto-oncogene inhibitor dabrafenib and the mitogen-activated protein kinase (MEK) inhibitor trametinib were presented that might argue for the testing of those biomarkers and the BRAF V600E mutation in NSCLC.10

Dr Socinski: What about the clinical significance of the data presented on MET alteration at ASCO?

Dr Pennell: I think MET is the next big target. Now that we have recognized the phenomenon of these driver mutations and have demonstrated, even in relatively small numbers of patients, that agents targeting these mutations lead to high response rates with durable dis-ease control, I do not think we need to wait for a major phase 3 trial to start saying that these are genetic rear-rangements for which we need to start testing.

In the past few years, we have also identified the exon 14–skipping mutation, which appears to be a real driver mutation present in about 4% of adenocar-cinomas.11 These mutations are probably as common as ALK rearrangements and seem to respond to MET inhibitors like crizotinib, which is typically used for ALK and ROS1 rearrangements but also works well as a MET inhibitor.12

Dr Socinski: I agree. We have evidence in patients with EGFR mutations and ALK-positive disease that tar-geted oral tyrosine kinase inhibitors (TKIs) are superior to chemotherapy on the basis of their rate of progres-sion-free survival (PFS) and their toxicity profile.13-15 We also have a drug approved by the US Food and Drug Ad-ministration (FDA) for ROS1 rearrangements — crizo-tinib — yet we do not have any randomized data.16 However, I would not be in favor of conducting a 300- to 400-patient randomized trial of dabrafenib plus trametinib vs a platinum-based doublet as the control arm to prove that targeting the oncogenic driver is better than nonspecific cytotoxic chemotherapy.

Dr Pennell: I agree. When you have 2 small phase 2 trials and you show a response rate of 70% and PFS in the 10- to 12-month range, which is basically double what we see with chemotherapy, and there is a favor-able toxicity profile and enough experience with safety to know that it is something reasonable for patients, then I think the FDA needs to be more flexible in how it is conducting approvals (Table 1).17,18 It can be very challenging to conduct randomized trials targeting a mutation present in 1% to 2% of lung-cancer patients.10 Furthermore, it is not ethical to randomly assign a pa-tient to chemotherapy when one knows that there are other agents that are active against in their disease.

Dr Socinski: What about ERBB2 (formally known as HER2/neu) mutations?

Dr Pennell: These are present in about 1% to 2% of ad-

Table 1. — Select Adverse Events Associated With Crizotinib or Dabrafenib Plus Trametinib

Adverse Event Crizotinib, % Dabrafenib + Trametinib, %

All Grades

Grade 3/4

All Grades

Grade 3/4

Gastrointestinal

Diarrhea 44 0 34 2

Nausea 40 0 40 0

Constipation 34 0 18 0

Vomiting 34 2 35 0

Dysgeusia 18 0 11 0

Dyspepsia/upper abdominal pain 10 0 12 0

Decreased appetite — — 30 0

Hematological

Neutropenia 12 10 20 9

Febrile neutropenia — — 2 2

Anemia — — 18 6

Thrombocytopenia — — 7 2

Leukopenia — — 8 4

Neurological

Visual impairment 82 0 4 2

Dizziness/vertigo 16 0 11–14 0

Headache — — 11 0

Cardiovascular

Sinus bradycardia 10 0 — —

Hypertension — — 6 4

Change in Laboratory Value

Elevated aspartate aminotransferase 22 2 7 2

Elevated alanine transaminase 14 4 6 2

Elevated blood alkaline phosphatase — — 16 0

Other

Peripheral edema 40 0 23 0

Fatigue 20 0 18 2

Decreased testosterone 14 0 — —

Hypophosphatemia 14 10 7 2

Asthenia — — 32 4

Hypercalcemia — — 4 4

Hyponatremia — — 11 7

Pyrexia — — 46 2

Data from references 17 and 18.


enocarcinoma patients.19-21 I do not know why there has not been more attention given to clinical trials in this population, because these mutations seem to be as com-mon as others, and there are a lot of agents available that target ERBB2. Some European cohorts have evaluated broad genetic testing and off-label use of anti-ERBB2 agents, suggesting that there can be activity with both TKIs and a monoclonal antibody like trastuzumab.20,22

Dr Socinski: I would not say ERBB2 needs routine test-ing, but, if it is identified, then I would probably reserve any off-label use until patients have exhausted proven therapies. What role does KRAS have currently?

Dr Pennell: We routinely test for KRAS, but it is a bit of a holdover from our initial approach where we test-ed for EGFR, ALK, and KRAS. If KRAS tests positive — which it does in about 15% to 25% of adenocarcino-ma patients — we do not feel it is necessary to test for other potential drivers.23 I think it is still useful in that setting. It is also useful to know in terms of selecting patients for clinical trials. However, in terms of deter-mining treatment outside of a clinical trial, testing for KRAS mutations is not really all that helpful, other than you no longer have to worry about looking for other potential drivers.

Dr Socinski: What about RET alterations? We have a number of small phase 2 trials suggesting that various ret proto-oncogene (RET) inhibitors have activity.24,25 However, the level of activity in these alterations does not seem to be as impressive as the other markers we have discussed. At the ASCO annual meeting, Reck-amp et al26 presented data on targeting RET alterations: response rates were 20% to 40% and the durability of response was not highly impressive. I might place RET in the same category as ERBB2.

Dr Pennell: I think we have a little more data with various available agents for RET than ERBB2.27-31 However, the data are disappointing.27,30-33 It is a prov-en driver oncogene, but I agree with you. I would not treat someone with a RET fusion with a RET inhibitor as first-line therapy.

Dr Socinski: As for DDR2, the data we have are very immature; however, this is a potentially attractive tar-get in patients with squamous histology.34,35

Dr Pennell: I think we all want to find targets that we can exploit in squamous cell carcinoma (SCC), and am-plifications and mutations of DDR2 or FGFR1 occur in a significant percentage of patients with SCC.34-36 How-ever, the actionability of those targets and the clinical activity of the agents that we have targeting them are unproven at this point.

I do think we need to support the LUNG-MAP pro-tocol to try to put squamous-cell patients on some of these targeted agents so that we can actually get a bet-ter idea of how active they are.37 I know that DDR2 is also part of the NCI-MATCH study.38

Practical Considerations in Biomarker TestingDr Socinski: If I were advising a large community hospital in terms of testing practices, I would suggest being as cost effective as possible and identifying those patients who would receive a major benefit from tar-geted therapy. I would test for EGFR, ALK, MET am-plification, exon 14 mutation, ROS1, BRAF, and KRAS. At the University of Pittsburgh Medical Center, 31% of the population of adenocarcinomas had a KRAS alter-ation.39 As for other drivers beyond those I just men-tioned, you are in the 1% to 2% range, and, for many of the other alterations, we do not yet have robust clinical data that indicate a targeted agent has an impact.40

Dr Pennell: I want to address the cost effectiveness of testing. In the past we would test for EGFR mu-tations and ALK rearrangements, and we now have ROS1-approved agents. Although getting insurance coverage is not difficult for the majority of those in-dividual tests, we now have so many tests that really should be considered standard of care that it is much more cost effective to do a single broad test.41 It con-serves tissue, gives you information faster, and it is cheaper to pay for 1 test than it is to pay for 6 indi-vidual tests.

Dr Socinski: Yes, I agree. Panels and next-generation sequencing strategies are probably going to end up be-ing the most cost effective. One of the issues I struggle with is just how much information is necessary. Some-times it is confusing to figure out the impact of testing in an individual patient. We do not know if all of the targets identified are valid.

Dr Pennell: Extremely broad testing of hundreds of potential genes does not have much clinical validity. I think guided molecular testing for proven targets makes sense. Broader testing from a purely research stand point makes sense; however, I would not recommend broader testing be routinely performed for patients who have no intention of enrolling in a clinical trial.

Case Study: Treatment of Stage IVb Nonsquamous DiseaseA 65-year-old man presents with a good Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0–1 and no comorbidities) and a diagnosis of stage IVb NSCLC. The patient is tested for all common oncogenic biomarkers, including EGFR, ALK, ROS1, MEK, MET, BRAF V600E, and KRAS, but no oncogenic


driver is identified. Histological testing reveals adeno-carcinoma.

This individual is a healthy patient eligible for anything that we might want to use. An upfront, targeted agent would not be appropriate outside of a clinical trial for this patient, so platinum-combination chemotherapy would be the standard of care.

There are 2 established regimens in this setting. A carboplatin and paclitaxel doublet with the anti–vas-cular endothelial growth factor antibody bevacizumab has been established for more than 10 years now and is effective as first-line therapy.42,43 A second regimen that is becoming more common these days is the combina-tion of a platinum agent with pemetrexed. There are head-to-head data from a phase 3 trial showing that, in the nonsquamous NSCLC setting, this regimen is more effective and tolerable than a platinum doublet-con-taining regimen.44-46 I am not a fan of adding bevaci-zumab to pemetrexed. We do not have any randomized evidence suggesting that adding bevacizumab results in any meaningful clinical benefit. However, there are adequate safety data on that combination and it is com-monly used.47-49 My personal preference is to use carbo-platin and pemetrexed in an otherwise healthy patient with adenocarcinoma who has no comorbidities.

Dr Socinski: The PointBreak trial showed us that, whether you use bevacizumab with carboplatin and pa-clitaxel or carboplatin and pemetrexed, the outcomes in terms of response and survival are equivalent.45,46 It makes me uncomfortable that we are accepting that a 2-drug regimen is as good as the 3-drug regimen. The PRONOUNCE trial did not demonstrate the superiority of carboplatin and pemetrexed followed by pemetrexed maintenance vs carboplatin and paclitaxel plus bevaci-zumab followed by bevacizumab maintenance.50 How-ever, I do not see that as a definitive phase 3 trial.

My tendency is to try to figure out what is the best doublet for the patient. If carboplatin with peme-trexed is a reasonable choice for the patient — and there are some clear advantages for pemetrexed51 — I would use that agent. However, I do not want to por-tray pemetrexed as being without toxicity. Common adverse events associated with pemetrexed include fatigue, nausea, and anorexia.52 When combined with a platinum agent, vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation are common.52 The next question is: Am I going to add a biologic agent to it? There are phase 3 data from large trials suggesting that, wheth-er you add bevacizumab to pemetrexed or a taxane, the outcomes are equivalent.45

Dr Pennell: If you are using a taxane, then bevacizum-ab is necessary. I do not think there is anything wrong

with using bevacizumab in a healthy patient who does not have any contraindications. However, the field seems to be moving away from using bevacizumab so commonly. Perhaps we have better subsequent thera-pies and maybe we have become a little less concerned about trying to squeeze every possible ounce of efficacy out of our first-line regimen. But there is a little more discomfort now that we have had years of experience and we have seen some rare, but potentially serious tox-icities associated with bevacizumab.53,54 I am surprised, however, that we have not seen at least 1 small phase 3 trial of a platinum agent plus pemetrexed with or with-out bevacizumab. That would probably answer most people’s criticism of that regimen.

Dr Socinski: Once you have decided on a regimen, how many cycles do you administer?

Dr Pennell: With chemotherapy, the established standard of care is 4 cycles of platinum-based dou-blet therapy.7 I almost never give more than 4 cycles of platinum-based doublet therapy because we have very good evidence that 3 or 4 cycles vs 6 or continu-ation to progression does not seem to confer any ad-ditional survival benefit.55 Furthermore, after 4 cycles of therapy, most patients have had enough in terms of toxicity and could use a treatment break. However, I have given 6 cycles in patients who have continued to respond after 4 cycles and who are tolerating therapy very well. However, I am not sure I am really help-ing them with that, especially now in an era where I routinely continue with maintenance therapy when I use first-line doublet therapy with pemetrexed. I do not think that continuing the platinum agent beyond 4 cycles adds much benefit.

Dr Socinski: If you were using carboplatin and a tax-ane with bevacizumab as your choice for this patient, then it sounds as if you would be in favor of mainte-nance therapy if a response was evident.

Dr Pennell: I was surprised that the results from the PointBreak trial — comparing carboplatin, paclitaxel, and bevacizumab followed by maintenance bevaci-zumab with carboplatin, pemetrexed, and bevacizum-ab followed by maintenance bevacizumab and peme-trexed — showed there was no difference in overall survival (OS).45 I think if you are going to use a taxane, platinum-based, bevacizumab regimen, continuing the bevacizumab as maintenance therapy is appropriate.

Dr Socinski: Yes, I agree. If there were contraindica-tions to bevacizumab and the patient was receiving carboplatin and pemetrexed and was either stable or responding and tolerating therapy well, would you continue with pemetrexed maintenance?


Dr Pennell: Yes, that is the standard of care now. We have a couple of good phase 3 trials supporting a sur-vival benefit through either continuation or a switch to maintenance with pemetrexed if you have a non-beva-cizumab regimen for first-line therapy.44,45,56

Case Study: Treatment of Stage IVb Squamous DiseaseA 65-year-old man presents with a good ECOG PS (0–1 and no comorbidities) and a diagnosis of stage IVb NSCLC. The patient is tested for all common oncogenic biomarkers, including EGFR, ALK, ROS1, MEK, MET, BRAF V600E, and KRAS, but no oncogenic driver is identified. Histological testing reveals SCC.

Dr Socinski: I think that the standard of care is again platinum-based doublet therapy. The choices really re-side between platinum-based therapy plus a taxane, in-cluding paclitaxel, docetaxel, and nab-paclitaxel, and a gemcitabine-containing regimen.57-61 However, I think the evidence suggests that taxane-based therapy is a better approach than gemcitabine therapy.57-61

Gemcitabine has some side-effect advantages that the taxanes do not have. When gemcitabine is used as a single agent, the most common adverse effects are nau-sea and vomiting, anemia, hepatic transaminitis, neutro-penia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema.62

In elderly patients receiving biweekly carboplatin plus gemcitabine as first-line therapy for advanced squa-mous NSCLC, grade 3/4 neutropenia occurred in 12.3% of patients, grade 3/4 thrombocytopenia occurred in 7.1%, and grade 2/3 fatigue occurred in 17.5%.60

For maintenance therapy, we have fewer options.

We do not use bevacizumab or pemetrexed in patients with squamous histology; however, we do have some evidence for maintenance gemcitabine or maintenance taxane therapy.63,64 Nonetheless, there is no clear-cut advantage in that setting, and, in squamous NSCLC, I generally do not use maintenance therapy. I watch pa-tients closely, and then I think about second-line thera-py at the time of disease progression.

We do have data sets in the squamous population that we should discuss. There is a suggestion relative to standard taxane therapy that nab-paclitaxel has higher response rates.65 Response rates are important in the lung-cancer setting as they correlate with symptom re-lief. If you shrink the tumor, the patient feels better.

Dr Pennell: From the stand point of SCC, I think that the choice is clearly one of the taxanes — paclitaxel or nab-paclitaxel — vs gemcitabine. I choose based on which adverse-event profile fits the patient best. Treatment with nab-paclitaxel plus carboplatin is associated with a higher incidence of neutropenia and leukocytopenia compared with gemcitabine plus carboplatin.58 In patients treated with nab-paclitaxel as monotherapy, anemia occurred in 38%, leukopenia in 48%, neutropenia in 38%, thrombocy-topenia in 11%, and febrile neutropenia in 10%.57 Nonhe-matological adverse events include alopecia (67%), fatigue (58%), sensory neuropathy (59%), anorexia (29%), nausea (36%), myalgia (19%), and arthralgia (26%).57 For patients who do not want to lose their hair, typically I would select gemcitabine; for patients who live far away and would rath-er receive treatment every 21 days, I think paclitaxel makes more sense. I am not sure if I buy into nab-paclitaxel be-ing better because of the response rate being somewhat higher.66 However, I am a little more impressed with the data in the elderly population using nab-paclitaxel (Fig).57

Fig A–B. — Kaplan–Meier curve for (A) PFS and (B) OS rates according to cycles of nab-paclitaxel monotherapy in elderly patients with relapsed squamous NSCLC. CI = confidence interval, OS = overall survival, PFS = progression-free survival. Reprinted with permission of Dove Medical Press, from A retrospective analysis of safety and efficacy of weekly nab-paclitaxel as second-line chemotherapy in elderly patients with advanced squamous non-small-cell lung carcinoma, Jin F, Zhu H, Shi F, et al., 2016;11, 2016; permission conveyed through Copyright Clearance Center, Inc.

Cum

ulat

ive

Surv

ival

, %

Cum

ulat

ive

Surv

ival

, %

OS, moPFS, mo

00

20

40

60

80

100

0

20

40

60

80

100

0 2 4 6 8 10 12 5 10 15 20

Median OS11.7 mo (95% CI: 10.33–13.07)8.9 mo (95% CI: 6.94–10.86)

Median PFS7.6 mo (95% CI: 6.60–8.60)4.9 mo (95% CI: 3.92–5.88)

Cycles≥ 3< 3

P = .002

Cycles≥ 3< 3

P = .004

BA


Dr Socinski: Yes, we have to remember that, even though a superior overall response to nab-paclitaxel was demonstrated, this finding did not translate into differences in PFS or OS.57 However, I do consider nab-paclitaxel as the treatment of choice in a patient with heavy-disease burden who is very symptomatic, because, if you have a higher likelihood of shrink-ing the tumor, then that patient is probably experi-ence greater clinical benefit. He or she may live better, though not necessarily longer in that setting.

Dr Pennell: We need to remember that squamous NSCLC patients are often older, and they often have more comorbidities than other NSCLC patients. Co-morbidity is a big factor in these patients. I often use gemcitabine for that reason, but I also use nab-pacli-taxel in some patients because it is associated with less neuropathy and you see patients more often so you can monitor them.57,67 It also has the advantage of not requiring the use of premedication with steroids. Un-fortunately, we do have to think about cost as well.

Dr Socinski: Nab-paclitaxel is FDA approved and has a weekly schedule.68 However, it should not be admin-istered to patients with a baseline neutrophil count of less than 1,500 cells/mm3, and it is recommended that peripheral blood cell counts be monitored frequently in those receiving the agent.68 Some elderly patients like coming weekly because they get more attention, and they can deal with their problems prospectively, while others have geographical issues that make week-ly visits impossible. These needs are why you have to individualize treatments.

The role of necitumumab in squamous NSCLC has to be considered as well. The SQUIRE trial is a large, phase 3 trial of gemcitabine plus cisplatin with or with-out necitumumab as first-line therapy in patients with stage IV squamous cell NSCLC.69 The trial demonstrated an OS advantage, which led to its approval by the FDA and, although no significant difference in response rate was seen, a modest benefit in PFS was observed.69 The primary toxicities of necitumumab include skin rash, gastrointestinal toxicity, and hypomagnesemia.69

Dr Pennell: I have never used necitumumab; however, I do think it is a reasonable choice. It has a statistically significant sur-vival benefit in squamous NSCLC patients when added to the plati-num-based doublet when com-pared with the platinum dou-blet alone (Table 2).69 However, SQUIRE was a huge trial, and it reminds me of the FLEX trial of platinum plus vinorelbine and

cetuximab, which also showed a survival benefit, but there was less than a 2-month difference in median OS between the 2 regimens.70,71

Necitumumab adds toxicity with an epidermal growth factor receptor (EGFR)–type rash and diarrhea, and there was a lack of improvement in response rate.72 Although there is real activity there, until they can do a better job of identifying who benefits and who does not, it is hard to see a clinically meaningful difference with the addition of necitumumab. I have not started using it routinely. I am hopeful that some of the work coming out of the Hirsch Biomarker Analysis Laborato-ry73 will allow us to see something, perhaps with EGFR expression on fluorescence in situ hybridization. For now, it is hard to justify the additional cost and toxicity with marginal benefit.

Dr Socinski: We are in a time where now we are mak-ing judgments about cost and magnitude of benefits. I agree that it has been frustrating that a biomarker has been elusive in this setting. What about the LUX-Lung trial in SCC?

Dr Pennell: LUX-Lung 8 was a trial of afatinib vs er-lotinib in SCC of the lung.74 It was a phase 3 trial that showed longer PFS and OS rates, as well as a slightly higher response rate for afatinib in patients with stage IIIb/IV squamous NSCLC who had progressed after at least 4 cycles of platinum-based chemotherapy.74 How-ever, use of EGFR TKIs has fallen out of favor in EGFR wild-type patients due to marginal activity.7

Dr Socinski: Yes, afatinib is now indicated for meta-static squamous NSCLC that has progressed after plati-num-based chemotherapy.75

Case Study: Second-Line Therapy A 65-year-old man presents with a good ECOG PS (0–1 and no comorbidities) and a diagnosis of stage IVb NSCLC. Second-line therapy is indicated.

A lot has changed in the past year or so and we have a new standard. We have the results of the CheckMate

Table 2. — Survival Outcomes in Stage IV Squamous NSCLC With Necitumumab Plus Gemcitabine/Cisplatin vs Gemcitabine/Cisplatin: IHC Evaluable EGFR-Positive Population

Outcome HR (95% CI)

P Value

Median Survival, mo

Necitumumab + Gemcitabine/Cisplatin

(N = 456)

Gemcitabine/ Cisplatin (N = 468)

Overall 0.79 (0.69–0.92) .002 11.7 10.0

Progression free 0.84 (0.72–0.97) .018 5.7 5.5

CI = confidence interval, HR = hazard ratio, IHC = immunohistochemistry, NSCLC = non–small-cell lung cancer. Data from reference 69.


017 trial of squamous NSCLC comparing nivolumab with docetaxel; it showed a 50% improvement in me-dian survival and a doubling of the response rate.76 This study was an impressive trial that really changed the second-line standard. We also saw that same effect — although to a lesser degree — in the nonsquamous NSCLC CheckMate 057 trial, which led to nivolumab receiving an indication for the treatment of metastat-ic NSCLC in patients who have progressed on or after platinum-based chemotherapy.77,78 KEYNOTE-010 had a similar design to the 2 CheckMate trials, with docetaxel as the control arm compared with pembroli-zumab.79 These trial results have radically transformed our second-line platform.

Dr Pennell: Within a month or two of the approval of nivolumab for squamous cell disease, we were routinely using that in everyone as second-line therapy over che-motherapy. Then we began using nivolumab in adeno-carcinoma and nonsquamous disease almost as rapidly.

Dr Socinski: Nivolumab established itself as the stan-dard not only because it was the first to be approved, but also due to the fact that it was not linked to a bio-marker.80,81 By contrast, pembrolizumab approval was linked to the biomarker PD-L1.80

Dr Pennell: It is important to recognize the different populations involved in the CheckMate and KEYNOTE trials. Pembrolizumab was only approved in patients who were positive for the PD-L1 biomarker, as these individuals were the only patients enrolled in the trial to be randomized to pembrolizumab vs chemothera-py.80 By contrast, in the nivolumab trials, the investi-gators took all comers, and PD-L1 was used to stratify response based on expression.78,81 The overall intent-to-treat population had a big survival benefit without relying on being PD-L1 positive.78 There is a difference in efficacy, especially in nonsquamous patients treated with nivolumab, where higher levels of PD-L1 expres-sion do infer a greater survival benefit and a higher response rate compared with docetaxel.78 However, even patients with no PD-L1 expression have OS and response rates comparable with docetaxel.78

For second-line patients, I would not recommend routine testing of PD-L1 because the only purpose of test-ing would be to select an alternate treatment. There really is no alternate treatment that would be a better choice.

Dr Socinski: I agree, but I think that PD-L1 is going to play a very important role in the first-line setting. What is your take on the different adverse-event profiles of the immunotherapy agents?

Dr Pennell: The majority of patients have very few ad-verse events — maybe some fatigue, aches, and pains.

However, these are often associated with having lung cancer. Nonetheless, up to 10% of patients do have se-rious adverse events, which are usually related to au-toimmune effects secondary to these agents.82 With nivolumab and pembrolizumab, we do not see nearly the level of autoimmune-related adverse events seen with the anti–cytotoxic T-lymphocyte-associated an-tigen 4 agents such as ipilimumab.83,84 Severe to fatal immune-mediated adverse reactions have been report-ed in up to 41% of patients, including 16% who experi-enced enterocolitis, 11% who experienced hepatitis, 4% dermatitis, 2% neuropathy, and 7% hypopituitarism.85 Immune-mediated pneumonitis, meningitis, myocardi-tis, and pericarditis have also been reported.85

However, the adverse events of PD-1 inhibitors can still be serious. With nivolumab, immune-mediat-ed pneumonitis occurred in 3.4% of NSCLC patients, immune-mediated colitis occurred in 2.4%, hepatitis occurred in 0.3%, adrenal insufficiency in 0.3%, hypo-thyroidism in 7.0%, hyperthyroidism in 1.4%, renal dys-function in 0.3%, and immune-mediated rash in 6.0%.81 Other immune-related adverse events associated with nivolumab include encephalitis, pancreatitis, uveitis, iri-tis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain–Barre syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodeni-tis, and sarcoidosis.81 Pembrolizumab therapy has been associated with pneumonitis (3.5%), colitis (0.7%), hy-perthyroidism (1.8%), hypothyroidism (6.9%), hypophy-sitis (0.2%), and type 1 diabetes mellitus (0.1%).80 Other immune-mediated adverse events associated with pem-brolizumab include hepatitis, rash, vasculitis, nephri-tis, hemolytic anemia, serum sickness, and myasthenia gravis.80 Patients need to be monitored for events such as autoimmune colitis, hepatitis, and thyroiditis result-ing in hypothyroidism, but this does not necessarily require altering treatment other than replacing thyroid hormones. However, everyone worries about pneumo-nitis, which occurs in 4% of 5% of patients.86-89 It is com-mon enough that you need to watch for it and be ready to treat it, but it is still relatively uncommon.

Dr Socinski: It really is a small minority of patients — typically less than 5% who experience the more serious immune-related events.90 However, once we start using these agents routinely as first-line therapy — agents that potentially may be used for years in some patients who are receiving benefit — then the awareness of these toxicities will increase. It is going to be important to understand and be able to treat these immune-relat-ed toxicities.

Dr Pennell: As for first-line therapy, KEYNOTE 024 explored pembrolizumab vs platinum-based doublet chemotherapy in treatment-naive patients with very


high-level PD-L1 expression.91 A press release stated that pembrolizumab was superior to chemotherapy for both the primary end point of PFS and the secondary end point of OS.91 Based on these results, an indepen-dent data monitoring committee has recommended that the trial be stopped and patients receiving che-motherapy be offered the opportunity to receive pem-brolizumab.91 Top-line results from CheckMate 026, a phase 3 study of nivolumab vs platinum-based doublet chemotherapy in treatment-naive patients with ad-vanced NSCLC that also expressed PD-L1 but at a lower cutoff level, were also released.92 However, as mono-therapy, nivolumab did not meet its primary end point of improved PFS when compared with platinum-based doublet chemotherapy in this patient population.92 Re-sults from both trials will be presented at the annual congress of the European Society for Medical Oncol-ogy in early October 2016, but, at the time of press, these data were not yet available.

I think most of us expected that immunothera-peutic agents were eventually going to have a role as first-line therapy. We are going to see the need to routinely test for biomarkers to identify patients who would benefit from these drugs as initial therapy. We also have ongoing trials in patients looking at levels of PD-L1 expression, and combination trials of chemo-therapy and immune checkpoint inhibitors as well as immune checkpoint inhibitor maintenance therapy fol-lowing chemotherapy (NCT02758314, NCT02382406, NCT02564380). Testing for the biomarker is going to become part of our standard of care very soon.

Case Study: Treatment of EGFR Mutation-Positive Disease A 65-year-old man presents with a good ECOG PS (0–1 and no comorbidities) and a diagnosis of stage IVb NSCLC. Adenocarcinoma is identified as well as a sensitizing EGFR mutation.

Everyone with NSCLC should be tested first line for EGFR. If you are identifying an activating EGFR muta-tion, then in most cases this will be an exon 19 dele-tion mutation or an exon 21 point mutation. We have excellent randomized phase 3 data from multiple trials suggesting that TKIs (eg, gefitinib, erlotinib, afatinib) are all superior to chemotherapy with probably twice the response rate, twice the PFS, and a more favorable tolerability profile.15,93-96 The phase 2 LUX-Lung 7 tri-al evaluated gefitinib vs afatinib and observed longer PFS with afatinib and a slightly higher response rate.97 There are also data from the LUX-Lung 3 and 6 trials suggesting that patients with an exon 19 deletion po-tentially derived not only a PFS benefit but also an OS benefit with afatinib.98,99

I think that, in a healthy patient in whom there is no concern about skin toxicity or other potential tox-

icities, afatinib is a slightly more effective choice for first-line therapy. However, afatinib does have a higher toxicity rate than the first-generation TKIs.100 Diarrhea occurred in 96% of patients receiving afatinib with 15% of cases being grade 3 in severity, whereas diarrhea oc-curred in 62% of patients receiving erlotinib, with 5% of cases being grade 3/4 in severity (Table 3).75,101,102 In 6.1% of patients receiving afatinib, renal impairment occurred as a result of diarrhea.75

For many of my frail elderly patients, I still use erlotinib as first-line therapy. By contrast, afatinib would probably be my first-line choice for a healthy young person.

Table 3. — Select Adverse Events (All Grades) in Patients Receiving Afatinib, Erlotinib, or Gefitinib

Adverse Event Incidence, %

Afatinib Erlotinib GefitinibDiarrhea 96.0 62.0 34.9

Skin reactions 90.0 85.0 57.9

Stomatitis 71.0 17.0 11.0

Nail disorder 58.0 14.0 7.9

Anorexia/decreased appetite 29.0 52.0 19.7

Pruritus/dry skin 21.0 16.0–21.0 —

Vascular disorder/ hemorrhage 17.0 — 4.3

Cystitis 13.0 — 1.1

Cheilitis 12.0 — —

Pyrexia 12.0 36.0 8.7

Ocular disorder 11.8 17.8 7.0

Hepatic disorder 10.1 — 22.0

Renal failure 6.1 0.5 —

Interstitial lung disease 1.5 1.1 1.3

Bullous/exfoliative skin disorders 0.2 1.2 <0.1

Alopecia — — 4.7

Asthenia — — 17.7

Cerebrovascular accident — 0.6 —

Cough — 48.0 —

Dyspnea — 45.0 —

Gastrointestinal perforation — 0.2 0.2

Hepatic failure — 0.4 —

Hepatitis — — 0.2

Myocardial infarction/ischemia — 0.2 —

Nausea — 33.0 17.8

Pancreatitis — — 0.1

Vomiting — — 13.8

Data from references 75, 101, and 102.


Dr Socinski: What are your expectations when you start a TKI? What do you tell your patients to expect in terms of response and PFS? Then, what do you do when they progress?

Dr Pennell: Well, the good thing about these TKIs and EGFR mutations is that patients start to see improve-ments in symptoms within days to weeks. I usually bring them back 3 to 4 weeks after they start treatment because that is when you can expect to see the skin rash emerge and be ready to jump in with antibiotics (eg, doxycycline, minocycline) or topical agents to help them manage the skin toxicity. For most patients, supportive care for skin toxicity or diarrhea or a dose reduction can allow them to continue treatment. Patients live very ac-tive normal lives on these agents. The average or medi-an time to progression is approximately 1 year.15,93-96

Although I have patients who have been on EGFR TKIs for many years with disease control, inevitably their disease will progress. In the past, I would usually switch these patients to chemotherapy if they had pre-viously received first-line treatment with a TKI. How-ever, these days, we have another choice. For the 50% to 60% of patients who develop acquired resistance and progression on a first-line TKI, if you test them you may identify T790M, which is a gatekeeper muta-tion on exon 20 of EGFR.100 We have an agent that has been approved to treat this — osimertinib — which is very effective in patients with confirmed T790M.103 It requires testing, however, because the agent is only ap-proved if patients are T790M positive.104 In addition, the data suggest that, if this mutation is not present, then osimertinib may not be effective and you may be better off switching to chemotherapy.105

Dr Socinski: Testing upfront is standard. However, should the testing be performed on plasma, urine, or tissue?

Dr Pennell: Tissue is the gold standard; however, ob-taining tissue for progression from all patients is dif-ficult if not impossible. We have good evidence that the commercially available blood-based assays are quite sensitive and reliable.106 If the assay finding is negative for mutations, then you can perform a tissue biopsy. In June 2016, the FDA approved the EGFR mutation test v2, which is a blood-based companion diagnostic tool for erlotinib that includes T790M.107

Dr Socinski: Assuming then that a patient is T790M negative, is standard chemotherapy the option you would recommend?

Dr Pennell: For most patients who have generalized symptomatic progression, I switch them to chemother-apy. In some patients, the progression can be relatively

indolent, and you can watch them without chang-ing treatment for awhile. If they are not symptomatic, then you do not need to rush to change treatment. In one-fifth of these patients, progression can be local-ized to maybe a single site or a few sites. We actually have a clinical trial testing stereotactic radiotherapy to areas where we have very limited focal progression (NCT02450591).

We also have some pretty good biopsy data sug-gesting that not every metastasis develops acquired resistance at the same time, and that patients may sometimes remain on treatment for significantly lon-ger if you ablate the areas that are progressing.108,109 In these cases, patients can remain on their first-line TKI. However, most patients who progress need to switch to something else. For me, stopping the TKI and mov-ing on to chemotherapy is the choice for most patients.

Dr Socinski: I would like to talk about ALK-positive disease, which occurs in up to 5% of patients with NSCLC.110 In the first-line setting, we have randomized data suggesting that crizotinib is better than the best chemotherapy, which is pemetrexed plus a platinum-based agent.110 But, we now have more choices. Crizo-tinib was initially developed as a MET inhibitor, but it has ALK activity. Would you say that crizotinib is still your first-line choice, or are you tempted to use one of the other agents initially?

Dr Pennell: Crizotinib is typically my first-line choice for ALK-positive patients, but I go back and forth about this consideration. A Japanese phase 3 trial of alectinib vs crizotinib demonstrated a significantly prolonged PFS for alectinib.111 Alectinib is approved as second-line therapy in patients with locally advanced or meta-static ALK-positive NSCLC after failure of crizotinib.112 What has not been shown is that alectinib results in improved duration of disease control in patients who start on crizotinib, then switch to alectinib as second-line therapy at the time of progression. This strategy sequence is really what we consider the current stan-dard of care. However, I would like to see a trial that examines the sequencing of the agents to determine which is better. I would not be surprised if alectinib becomes a reasonable standard first-line treatment option. For now, I still use crizotinib.

Dr Socinski: The second-generation TKIs (eg, alec-tinib, ceritinib, investigational agent brigatinib) have demonstrated favorable safety and efficacy profiles but with notable activity in the brain.113

Dr Pennell: The clinical data suggest these second-generation agents penetrate the central nervous sys-tem.113-117 ALK-positive NSCLC patients commonly develop brain metastases.118 Crizotinib is not very ef-


fective in that setting.118 Some have suggested that more than one-half of patients with ALK-positive NSCLC develop brain metastases as the first sign of progression.118 If we can prevent or delay brain metas-tases, then that alone might be a good reason to use a more potent agent as first-line therapy.

Dr Socinski: Because we monitor the brain, frequent-ly we find these lesions when they are relatively small and asymptomatic. TKI therapy can be a more effec-tive alternative for these patients instead of going right to whole-brain or targeted radiotherapy.119 You may be able to delay treating the whole brain with the use of TKIs in this population.

I would also like to point out that the ALK-posi-tive subset of patients seems to be very different than those with a EGFR mutation. Among patients with EGFR mutations, a dominant acquired resistant muta-tion, T790M, affects 50% to 60% of patients.119 The same phenomenon has not been observed in ALK-resistant patients. We have acquired mutations in up to 30% of patients, and 8 different mutations have been de-scribed.120-123 Furthermore, the resistance to ALK-TKIs involves both ALK- and non–ALK-mediated pathways.120

Dr Pennell: It does appear that brigatinib is effective against all of the demonstrated resistance mutations, at least in vitro.124 However, more than 50% of pa-tients do not have an acquired secondary mutation as their mechanism of resistance.123 ALK-positive NSCLC presents a different picture than EGFR mutant-dis-ease does.120-123

ConclusionsDr Socinski: The management of advanced non–small-cell lung cancer has transitioned in the past de-cade or so with our increased understanding of the biology of the different subsets of patients. The emer-gence of immunotherapy — now our second-line standard and soon to become our first-line standard therapy — and the use of biomarkers in this setting are important developments of which clinicians should be aware. There will be a subset of patients who better respond to treatment in the first-line setting with im-munotherapy. However, the complexity of the manage-ment of lung cancer has become exponentially greater than it was 10 or 15 years ago when we thought of the problem as small-cell vs non–small-cell disease. This evolution in how we manage the disease today puts a tremendous amount of pressure on our diagnostic col-leagues to obtain adequate tissue for molecular testing.

We need new ideas for patients. Likewise, we need studies to examine the activity of chemotherapy fol-lowing immunotherapy in patients with non–small-cell lung cancer. The fact that the number of therapeutic options has greatly expanded is a source of optimism;

however, we must be thoughtful about how we ap-proach our patients. We need to do our due diligence in molecular testing and we need to understand when to intervene with immunotherapy and what the ben-efits of that may be.

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A retrospective analysis of safety and efficacy of weekly nab-paclitaxel as second-line chemotherapy in elderly patients with advanced squamous non-small-cell lung carcinoma. Clin Interven Aging. 2016;11:167-173. 58. Loong HH, Chan ACY, Wong ACY. Evolving evidence of the efficacy and safety of nab-paclitaxel in the treatment of cancers with squamous histologies. J Cancer. 2016;7(3):268-275. 59. Villaruz LC, Socinski MA. Is there a role of nab-paclitaxel in the treatment of advanced non-small cell lung cancer? The data suggest yes. Eur J Cancer. 2016;56:162-171. 60. Karampeazis A, Vamvakas L, Kentepozidis N, et al. Biweekly car-boplatin plus gemcitabine as first-line treatment of elderly patients with advanced squamous non-small-cell lung cancer: a multicenter phase I-II trial by the Hellenic Oncology Research Group. Clin Lung Cancer. 2016. Epub ahead of print. 61. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016; 34(25):2969-2979. 62. Gemcitabine [package insert]. Indianapolis, IN; 2014. 63. Kumar G, Woods B, Hess LM, et al. Cost-effectiveness of first-line induction and maintenance treatment sequences in non-squamous non-small cell lung cancer (NSCLC) in the U.S. Lung Cancer. 2015;89(3):294-300. 64. Socinski MA, Govindan R, Spigel D. Clinical roundtable monograph: recent advances in taxanes for the first-line treatment of advanced non-small cell lung cancer. Clin Adv Hematol Oncol. 2012;10(10 suppl 18):1-16. 65. Socinski MA, Bondarenko I, Karaseva K, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus car-boplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30(17):2055-2062. 66. Lipp HP. Clinical value of an innovative taxane-containing formulation [in German]. Med Mnatsschr Pharm. 2013;36(1):14-24. 67. Paclitaxel injection [package insert]. Princeton, NJ; 2011. 68. Paclitaxel [package insert]. Summit, NJ; 2016. 69. Paz-Ares L, Socinski MA, Shahidi J, et al. Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus neci-tumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer. Ann Oncol. 2016;27(8):1573-1579. 70. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13(1):33-42. 71. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemo-therapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525-1531. 72. Gatzemeier U, von Pawel J, Vynnychenko I, et al. First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 trial. Lancet Oncol. 2011;12(1):30-37. 73. University of Colorado. Hirsch Biomarker Analysis Laboratory. http://www.ucdenver.edu/academics/colleges/medicalschool/departments /medicine/MedicalOncology/FredHirsch/Pages/default.aspx. Accessed September 30, 2016. 74. Soria JC, Felio E, Cobo M, et al. Afatinib versus erlotinib as second-


line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897-907. 75. Afatinib [package insert]. Ridgefield, CT; 2016. 76. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. 77. Kazandjian D, Suzman DL, Blumenthal G, et al. FDA approval sum-mary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21(5):634-642. 78. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. 79. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. 80. Pembrolizumab [package insert]. Whitehouse Station, NJ; 2016. 81. Nivolumab [package insert]. Princeton, NJ; 2016. 82. West H. What are the potential side effects? Published December 30, 2014. http://cancergrace.org/cancer-treatments/2014/12/30/what-are -the-potential-side-effects-an-immunotherapy-primer-for-patients-pt-4. Accessed September 26, 2016. 83. Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016. Epub ahead of print. 84. Gonzalez-Rodriguez E, Rodriguez-Abreu D; Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist. 2016;21(7):804-816. 85. Ipilimumab [package insert]. Princeton, NJ; 2015. 86. Abdel-Rahman O, Fouad M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Ther Adv Respir Dis. 2016;10(3):183-193. 87. Seetharamu N, Budman DR, Sullivan KM. Immune check-point inhibitors in lung cancer: past, present and future. Future Oncol. 2016;12(9):1151-1163. 88. Nishino M, Chambers ES, Chong CR, et al. Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res. 2016;4(4):289-293. 89. Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. 2013 ASCO Educational Book. http://meetinglibrary.asco.org/content/181-132. Accessed September 26, 2016. 90. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015;4(5):560-575. 91. BusinessWire [press release]. Pembrolizumab demonstrates superior progression-free and overall survival compared to chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Published June 16, 2016. http://www.businesswire.com/news/home/20160616005393 /en/Merck’s-KEYTRUDA®%C2%A0-pembrolizumab-Demonstrates -Superior-Progression-Free-Survival. Accessed September 26, 2016. 92. Bristol-Myers Squibb. Bristol-Myers Squibb announces top-line re-sults from CheckMate-026, a phase 3 study of nivolumab in treatment-na-ïve patients with advanced non-small cell lung cancer. Published August 5, 2016. http://investor.bms.com/investors/news-and-events/press-releases /press-release-details/2016/Bristol-Myers-Squibb-Announces-Top-Line -Results-from-CheckMate--026-a-Phase-3-Study-of-Opdivo-nivolumab -in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer /default.aspx. Accessed September 26, 2016. 93. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. 94. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gem-citabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213-222. 95. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. 96. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. 97. Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577-589. 98. Deng W, Lei Y, Liu S, et al. Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R. Chin J Cancer Res. 2016;38(3):339-347.

99. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised phase 3 trials. Lancet Oncol. 2015;16(2):141-151. 100. Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res. 2013;2(1):40-49. 101. Erlotinib [package insert]. San Francisco, CA; 2016. 102. Gefitinib [package insert]. Wilmington, DE; 2015. 103. Reichegger H, Jochum W, Forbs D, et al. Rapid intracranial response to osimertinib in a patients with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung. Oncol Res Treat. 2016;39(7-8):461-463. 104. Osimertinib [package insert]. Wilmington, DE; 2016. 105. Wang S, Cang S, Lui D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9:34. 106. Haber DA, Velculescu VS. Blood-based analysis of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014;4(6):650-661. 107. Roche Diagnostics. EGFR mutation test v2. https://molecular.roche.com /assays/cobas-egfr-mutation-test-v2-us-ivd/. Accessed September 22, 2016. 108. Quéré G, Descourt R, Robinet G, et al. Mutational status of syn-chronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer. BMC Cancer. 2016;16:210. 109. Ricciuti B, Chiari R, Chiarini P, et al. Osimertinib (ASD9291) and CNS response in two radiotherapy-naïve patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig. 2016;36(8):683-686. 110. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemo-therapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177. 111. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizo-tinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung can-cer (ALK+ NSCLC): primary results from the J-ALEX study. J Clin Oncol. 2016;34(suppl):abstr 9008. 112. Alectinib [package insert]. South San Francisco, CA; 2015. 113. Facchinetti F, Tiseo M, Di Maio M, et al. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors. Transl Lung Cancer Res. 2016;5(3):301-321. 114. Rosell R, Gettinger SN, Bashenova LA, et al. Brigatinib efficacy and safety in patients (Pts) with anaplastic lymphoma kinase (ALK)-positive (ALK+) non-small cell lung cancer (NSCLC) in a phase 1/2 trial. J Thorac Oncol. 2016;11(4 suppl):S1114. 115. Noonan SA, Camidge DR. PROFILE 1014: lessons for the new era of lung cancer clinical research. Transl Lung Cancer Res. 2015;4(5):642-648. 116. Brower JV, Robins HI. Erlotinib for the treatment of brain metastases in non-small cell lung cancer. Expert Opin Pharmacother. 2016;17(7):1013-1021. 117. Dudnik E, Siegal T, Zach L, et al. Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung can-cer compared with brain radiotherapy. J Clin Neurosci. 2016;26:46-49. 118. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881-1888. 119. Lin NU. Targeted therapies in brain metastases. Curr Treat Options Neurol. 2014;16(1):276. 120. Ulivi P. Non-invasive methods to monitor mechanisms of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer: where do we stand? Int J Mol Sci. 2016;17(7): pii: E1186. 121. Ou S-HI, Bartlett CY, Mino-Kenudson M, et al. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012;17(11):1351-1375. 122. Romanidou O, Landi L, Cappuzzo F, et al. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer. Ther Advan Med Oncol. 2016;8(3):176-187. 123. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014;12(7):429-439. 124. Huang WS, Liu S, Zou D, et al. Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase. J Med Chem. 2016;59(10):4948-4964.


Continuing Medical Education Activity

Statement of NeedIn the United States, an estimated 224,390 new cases of lung cancer will be diagnosed in 2016 and an estimated 158,080 people will die from the disease this year.1 The major subtypes are small-cell lung cancer (13%) and non–small-cell lung cancer (NSCLC; 83%).1 Most persons with lung cancer are diagnosed at a locally advanced or metastatic stage, making systemic therapy the cornerstone of treatment.1 Although 70% to 80% of patients receiving first-line doublet chemotherapy demonstrate clinical benefit, most develop progressive disease within 2 to 3 months of their final cycle.2-7 Use of tumor histology and relevant molecular biomarkers to refine the selection of targeted agents and the advent of novel immunotherapies have improved outcomes for some patients. However, the 5-year survival rate for NSCLC is 21%, indicating a need for continued research on more effective approaches to tumor control.1

References 1. American Cancer Society. Cancer Facts & Figures 2016. http://www.

cancer.org/acs/groups/content/@research/documents/document/ac-spc-047079.pdf. Accessed September 26, 2016.

2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small cell lung cancer: results from a randomised phase III trial. Ann Oncol. 2010;21(9):1804-1809.

3. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind phase 3 study. Lancet. 2009;374(9699):1432-1440.

4. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate com-pared with delayed docetaxel after front-line therapy with gemcitabine plus carbo-platin in advanced non-small cell lung cancer. J Clin Oncol. 2009;27(4):591-598.

5. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best sup-portive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006;52(2):155-163.

6. Leighl NB, Paz-Ares L, Douillard JY, et al. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with pa-clitaxel and carboplatin in advanced non-small cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. J Clin Oncol. 2005;23(12):2831-2839.

7. Williamson SK, Crowley JJ, Lara PN Jr, et al. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005;23(36):9097-9104.

Learning ObjectivesUpon completion of this activity, participants should be able to:• Assess the utility of tumor histology and molecular

biomarker data in treatment planning for advanced NSCLC

• Evaluate emerging and evolving efficacy and safety data on novel therapies for advanced NSCLC

• Create individualized supportive care plans for pa-tients with advanced NSCLC

Target AudienceOncologists and other health care professionals in-volved in the treatment of patients with NSCLC.

Joint ProvidershipThis continuing medical education (CME) activity was developed through a joint providership of Global Education Group and i3 Health.

Release Date: October 15, 2016Expiration Date: October 14, 2017

Accreditation InformationThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint pro-vidership of Global Education Group and i3 Health.

Global Education Group is accredited by the AC-CME to provide continuing medical education for physicians. i3 Health is accredited as a provider of continuing nursing education by the California Board of Registered Nursing (CBRN).

Credit DesignationsACCMEGlobal Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

CBRNi3 Health is approved by the California Board of Regis-tered Nursing, provider no. 13307, for 1 contact hour.

Disclosure of Conflicts of InterestGlobal Education Group requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global Education Group for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recom-mendations.

The faculty, planners, and managers reported the

Instructions for CME/CE Participants


following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

FacultyMark A. Socinski, MD, has received grants/research support from Bristol-Myers Squibb, Clovis, Genentech, Lilly, Pfizer, and Synta, and has served on a speak-ers’ bureau for Bristol-Myers Squibb, Celgene, and Genentech.

Nathan A. Pennell, MD, PhD, serves as a con-sultant/independent contractor for AstraZeneca and Boehringer Ingelheim.

Planning Committee MembersGlobal Education Group, Littleton, Colorado

CME Accreditation: Amanda Glazar, PhD, has no rel-evant financial relationships to disclose.

CME Accreditation: Andrea Funk has no relevant fi-nancial relationships to disclose.

CME Accreditation: Laura Gilsdorf has no relevant financial relationships to disclose.

H. Lee Moffitt Cancer Center & Research Institute, Tampa Florida

Independent Reviewer: Lodovico Balducci, MD, has received honoraria from Amgen, Astellas, Johnson & Johnson, and Teva.

Independent Reviewer: Jhanelle Gray, MD, has re-ceived grants/research support from Array, AstraZen-eca, Merck, and Trovagene, has served on a speakers’ bureau for Genentech, and has served as a consultant for AstraZeneca, Boehringer-Ingelheim, Celgene, Clo-vis, Genentech, and Lilly.

Activity Planner and Independent Reviewer: John M. York, PharmD, Akita Biomedical Consulting, has no relevant financial relationships with commercial in-terests to disclose.

i3 Health, Denville, New Jersey

Activity Planner: Julia Bramwell, MD, has no relevant financial relationships to disclose.

Activity Planner: Michael Bramwell, MPH, has no rel-evant financial relationships to disclose.

Medical Writer: Laurel Ranger, MS, has no relevant financial relationships to disclose.

Discussion of Off-Label/Investigational Uses of Commercial ProductsThis educational activity may contain discussion of published and/or investigational uses of agents not in-dicated by the US Food and Drug Administration and/or other national regulatory agencies in the United States and other countries. Global Education Group and i3 Health do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily rep-resent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of ap-proved indications, contraindications, and warnings. Participants from other countries should consult with their respective regulatory authorities.

SponsorshipFunding for this monograph has been provided by an educational grant from Boehringer Ingelheim, Ge-nentech, and Lilly. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.

DisclaimerEvery effort has been made to ensure that drug us-age and other information are accurately presented; however, the ultimate responsibility rests with the prescribing physician. Global Education Group, i3 Health, Cancer Control, Mark Socinski, MD, and Na-than Pennell, MD, PhD, shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Activity partici-pants are strongly urged to consult any relevant pri-mary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

How to Claim CME/CE Credit1. Read this supplement in its entirety2. To claim CME credit, enter the following URL:

www.i3Health.com/NSCLC3. Complete and submit the post-test and activity evaluation4. Print your Certificate of CreditThis activity is provided free of charge to participants. The estimated time to completion is 60 minutes.

Contact InformationIf you have technical queries about this activity, please contact [email protected]. For information about the accreditation of this activity, please contact Global Education Group by phone at 1-303-395-1782 or e-mail [email protected].

Editorial Board Members

CanCer Control: Journal of the Moffitt CanCer Center (iSSn 1073-2748) is published by h. lee Moffitt Cancer Center & research institute, 12902 Magnolia Drive, tampa, fl 33612. telephone: 813-745-1348. fax: 813-449-8680. e-mail: [email protected]. internet address: cancercontroljournal.org. Cancer Control is included in Index Medicus®/MeDline® and eMBaSe®/excerpta Medica, thomson reuters Science Citation index expanded (SciSearch®) and Journal Citation reports/Science edition. Copyright 2016 by h. lee Moffitt Cancer Center & research institute. all rights reserved. Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the impact of human malignancy. each issue emphasizes a specific theme relating to the detection or management of cancer. the objectives of Cancer Control are to define the current state of cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies.DiSClaiMer: all articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the h. lee Moffitt Cancer Center & research institute, inc, or the institutions with which the authors are affiliated unless clearly specified. the reader is advised to independently verify the effective-ness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).

Most issues and supplements of Cancer Control are available at cancercontroljournal.org

Cancer Control is a member of the Medscape Publishers’ Circle®, an alliance of leading medical publishers whose content is featured on Medscape (www.medscape.com).

Production Team:Veronica Nemeth Editorial Coordinator

Sherri DamloMedical Copy Editor

Diane McEnaney Graphic Design Consultant

Associate Editor of Educational ProjectsJohn M. York, PharmDAkita Biomedical Consulting1111 Bailey Drive Paso Robles, CA 93446Phone: 805-238-2485Fax: 949-203-6115E-mail: [email protected]

For Consumer and General Advertising Information:Veronica NemethEditorial Coordinator Cancer Control: Journal of the Moffitt Cancer Center12902 Magnolia Drive – MBC-JRNLTampa, FL 33612Phone: 813-745-1348Fax: 813-449-8680E-mail: [email protected]

Conor C. Lynch, PhDAssistant MemberTumor Biology

Kristen J. Otto, MDAssociate MemberHead and Neck and Endocrine Oncology

Michael A. Poch, MDAssistant Member Genitourinary Oncology

Jeffery S. Russell, MD, PhDAssistant Member Endocrine Tumor Oncology

Elizabeth M. Sagatys, MDAssistant MemberPathology - Clinical

Saïd M. Sebti, PhDSenior MemberDrug Discovery

Bijal D. Shah, MDAssistant MemberMalignant Hematology

Lubomir Sokol, MD, PhDSenior MemberHematology/Oncology

Hatem H. Soliman, MDAssistant MemberBreast Oncology

Jonathan R. Strosberg, MDAssistant MemberGastrointestinal Oncology

Jennifer Swank, PharmDClinical Pharmacist - Medical Oncology/Internal Medicine

Sarah W. Thirlwell, MSc, MSc(A), RNNurse Director Supportive Care Medicine Program

Eric M. Toloza, MD, PhDAssistant MemberThoracic Oncology

Nam D. Tran, MDAssistant MemberNeuro-Oncology

Jonathan S. Zager, MDSenior MemberCutaneous Oncology

Editor:Lodovico Balducci, MDSenior Member, Senior Adult Oncology ProgramMoffitt Cancer Center

Deputy Editor:Julio M. Pow-Sang, MDSenior MemberChair, Department of Genitourinary OncologyDirector of Moffitt Robotics ProgramMoffitt Cancer Center

Editor Emeritus:John Horton, MB, ChBProfessor Emeritus of Medicine & Oncology

Moffitt Cancer Center Journal Advisory Committee:Daniel A. Anaya, MDAssociate MemberGastrointestinal Oncology

Aliyah Baluch, MDAssistant MemberInfectious Diseases

Dung-Tsa Chen, PhDAssociate MemberBiostatistics

Hey Sook Chon, MDAssistant Member Gynecological Oncology

Jasreman Dhillon, MDAssistant MemberPathology - Anatomic

Jennifer S. Drukteinis, MDAssociate MemberDiagnostic Radiology

Clement K. Gwede, PhDAssociate MemberHealth Outcomes and Behavior

Sarah E. Hoffe, MDAssociate MemberRadiation Oncology

John V. Kiluk, MDAssociate MemberBreast Oncology

Richard D. Kim, MDAssociate MemberGastrointestinal Oncology

Bela Kis, MD, PhDAssistant MemberDiagnostic Radiology

Rami Komrokji, MDAssociate MemberMalignant Hematology

best practices in treatment selection for patients with advanced nsclc · 2018-08-16 · strategies...

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