lung cancer highlights from the 39th european society for medical oncology (esmo) congress

This activity is supported by independent educational grants from Genentech and Lilly USA, LLC.

EditorsAlex Adjei, MD, PhD, FACPSenior Vice President, Clinical ResearchProfessor and Chairman, Department of MedicineKatherine Anne Gioia Chair in Cancer MedicineRoswell Park Cancer InstituteBuffalo, New York

Ramaswamy Govindan MDCo-Director, Section of Medical OncologyProfessor of MedicineDivision of OncologyWashington University School of MedicineSt. Louis, Missouri

Translating Today’s Science into Tomorrow’s Practice: Lung Cancer Highlights from the 39th European Society for Medical Oncology (ESMO) Congress

This activity is provided by

An Interactive PDF Newsletter


TABLE OF CONTENTS (CLICK THE SECTION YOU WISH TO VIEW)

Introduction .............................................................................................................................................. 1

Immunotherapy ........................................................................................................................................ 1

Vaccine Adjuvant Therapy: The MAGRIT Trial .................................................................................................................1

KEYNOTE-001: Pembrolizumab in Advanced NSCLC ...................................................................................................1

EGFR Targeted Therapies ......................................................................................................................... 3

IMPRESS Trial of Maintenance Gefitinib Plus Chemotherapy ...................................................................................3

RADIANT Trial of Adjuvant Erlotinib ...................................................................................................................................4

LUX-Lung 8 Trial in Squamous Cell Carcinoma ..............................................................................................................6

ALK-Rearranged NSCLC ............................................................................................................................ 8

Alectinib as Second-Line Therapy in ALK-Rearranged NSCLC ..................................................................................8

Other Targets: BRAF, HER2 ....................................................................................................................... 9

Dabrafenib for BRAF V600E Mutations in NSCLC ..........................................................................................................9

Neratinib in HER2 Mutant NSCLC (PUMA-NER-4201) ..................................................................................................9

TARGET Trial: Vintafolide as a Second-Line Treatment ............................................................................................. 11

Molecular Analysis/Biomarkers ............................................................................................................. 12

Evolution of the Genomic Landscape in NSCLC ......................................................................................................... 12

Genomic Changes in Tumors From Multiple Relapses ............................................................................................. 13

Conclusion ............................................................................................................................................... 13

Post-Test and Evaluation ........................................................................................................................ 13

References ............................................................................................................................................... 14

IIITable of Contents


MEDIA: NEWSLETTEREstimated time to complete activity: 1.0 hourRelease date: Friday, November 21, 2014 | Expiration date: Friday, November 20, 2015

INTRODUCTIONThe 2014 ESMO Congress Annual Meeting provided an in-depth focus of the current environment and how it may affect lung cancer care. Included in this newsletter are highlights from major plenary sessions, oral sessions, and select poster presentations resulting in a detailed summary of current and developing therapy options in lung cancer.

EDITORSAlex Adjei, MD, PhD, FACPSenior Vice President, Clinical ResearchProfessor and Chairman, Department of MedicineKatherine Anne Gioia Chair in Cancer MedicineRoswell Park Cancer InstituteBuffalo, New York

TARGET AUDIENCE The target audience for this activity is medical oncologists, hematologist/oncologists, surgeons, radiation oncologists, pathologists, oncology pharmacists, and other allied healthcare professionals caring for patients with lung cancer.

EDUCATIONAL OBJECTIVESAt the conclusion of this activity, participants should be able to:

• Discuss clinical trial data to improve outcomes for patients with early stage lung cancer • Describe the strengths and weaknesses of significant clinical trials designed to improve outcomes for patients with metastatic lung cancer• Explain the implications of genetic analysis and biomarkers on treatment selection and response as they currently relate to patients with lung cancer

DESIGNATION OF CREDITPHYSICIAN CONTINUING EDUCATION Accreditation Statement Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

METHOD OF PARTICIPATIONThere are no fees for participating and receiving CME credit for this activity. During the period Friday, November 21, 2014 through Friday, November 20, 2015, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test and evaluation.

CME CREDITPhysicians who complete the post-test with a score of 80% or better may view and print their credit letter via the website, www.ecgcme.com.

Ramaswamy Govindan MDCo-Director, Section of Medical OncologyProfessor of MedicineDivision of OncologyWashington University School of MedicineSt. Louis, Missouri

IV Table of Contents


POLICY ON DISCLOSUREIt is the policy of ECG that the faculty, authors, planners, and other persons who may influence content of this CME activity disclose all relevant financial relationships with commercial interests in order to allow ECG to identify and resolve any potential conflicts of interest.

The Following Faculty Members Have Declared Relevant Financial Relationships

Alex Adjei, MD, PhD, FACP No financial relationships to disclose

Ramaswamy Govindan, MD Consultant Fees Bayer HealthCare Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Covidien, Genentech, GlaxoSmithKline, Mallinckrodt, Merck & Co., Inc, Pfizer Inc

STAFF DISCLOSUREPlanners and managers at ECG have no relevant financial relationships to disclose.

ACKNOWLEDGEMENTThe editors wish to thank Marie N. Becker, PhD for assistance in writing this document.

DISCLOSURE OF OFF-LABEL USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. ECG does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity do not necessarily represent the views of ECG. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Please refer to the official prescribing information for each product or consult the Physicians’ Desk Reference for discussion of approved indications, contraindications, and warnings.

ACKNOWLEDGEMENT OF COMMERCIAL SUPPORTThis activity is supported by independent educational grants from Genentech and Lilly USA, LLC.

CME INQUIRIESFor further information, please contact:Educational Concepts Group, LLC 1300 Parkwood Circle SE, Suite 325Atlanta, Georgia 30339Phone: 1.866.933.1681 | Fax: 1.866.933.1692www.ecgcme.com

None of the contents may be reproduced in any form without prior written permission from the publisher. This activity may be accessed at www.ecgcme.com.

http://www.ecgcme.com

http://www.ecgcme.com

1Table of Contents


INTRODUCTIONThe 39th European Society for Medical Oncology (ESMO) Congress held September 26-30, 2014 in Madrid, Spain provided updates from a number of clinical trials for the treatment of non-small-cell lung cancer (NSCLC). This newsletter provides an overview of the major clinical trial updates presented at this Congress that impact clinical practice.

IMMUNOTHERAPYVaccine Adjuvant Therapy: The MAGRIT TrialMelanoma specific antigen A3 (MAGE-A3) is a tumor specific antigen. The MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 CI) vaccine consists of a recombinant protein and immunostimulants directed at the MAGE-A3 antigen. The MAGRIT trial was intended to test the efficacy of MAGE-A3 CI in an adjuvant setting for NSCLC. The results from this phase III, double-blind, randomized, placebo-controlled trial were presented by Vansteenkiste et al.1 The primary endpoint of the trial was disease-free survival (DFS) with a secondary endpoint of overall survival (OS).

MAGRIT was a global trial with an enrollment of N = 2312. Patients with stage I, II, or IIIA resected NSCLC were eligible. In addition, confirmation of expression of MAGE-A3 was determined by RT-PCR. The population was stratified based on whether patients had received prior chemotherapy. The patients were randomized 2:1 to receive MAGE-A3 CI or placebo. Administration of MAGE-A3 CI was 13 injections over 27 months and 2272 patients were treated. There was no significant difference between the demographics of the study arms.

The majority of patients experienced an adverse event (AE) with more AEs in the treatment arm (90% vs 73%); however, the percentage of grade 3 AEs was equivalent in both arms (16%) as was the percentage of serious AEs (22%). Reported grade 3 or greater events were pyrexia (< 1%), pain (< 1%), and myalgia (< 1%) in the treatment arm and fatigue (< 1%) in both arms. Over 50% of the patients in both arms received the planned 13 doses.

Neither the primary endpoint of improved DFS nor the secondary endpoint of OS was reached. The median DFS was 60.5 months in the MAGE-A3 CI arm and 57.9 months in the placebo arm, P = 0.7379 and the hazard ratio (HR) was 1.02 with a 95% confidence interval (CI) of 0.89-1.18 (Figure 1). No significant differences were seen in any subgroups. The median OS has not yet been reached but OS curves overlap as seen in Figure 1. No differences in DFS were observed in the chemotherapy-naïve population with median DFS of 58.0 months vs 56.9 months, P = 0.7572.

The predictive gene signature discovered in metastatic melanoma was not predictive in NSCLC.2 This large trial demonstrated that the MAGE-A3 CI vaccine is not effective in NSCLC.

KEYNOTE-001: Pembrolizumab in Advanced NSCLCTherapies that target the programmed cell death 1 protein (PD-1) or its ligand PD-L1 are some of the most promising ongoing studies in several types of cancer. PD-1 is an immune checkpoint receptor, which is expressed by activated T-cells.3 After interaction with 1 of 2 ligands, PD-L1 or PD-L2, PD-1 downregulates T-cell activation thus preventing T-cells from attacking the tumor.4,5 Many NSCLC tumors express the PD-L1 ligand.

2 Table of Contents


KEYNOTE-001 was designed as a phase Ib trial of the anti-PD-1 antibody, pembrolizumab (MK-3475, lambrolizumab) in patients with advanced carcinoma, melanoma, or NSCLC. Pembrolizumab is a humanized IgG4 PD-1 blocking antibody that has been modified to be devoid of antibody mediated cytotoxicity and has been approved by the FDA for metastatic melanoma after progression on ipilimumab. The primary endpoint of KEYNOTE-001 was overall response rate (ORR) as determined by both RECIST v1.1 and by investigator assessment (irRC). Data was presented by Garon et al for a pooled analysis of NSCLC patients from the expansion phase of KEYNOTE-001.6

For patients to be eligible for the trial, they must have progressed on prior treatment and have measurable disease, although 1 expansion arm, n = 45, was treatment-naïve patients. PD-L1 expression was determined by immunohistochemistry (IHC) with the 22C3 antibody and positive expression was defined as greater than or equal to 1% of tumor cells expressing the protein. Strong expression was defined as ≥ 50% of tumor cells exhibiting membranous staining while weak expression was 1-49% of cells staining. Patients with EGFR mutations and anaplastic lymphoma kinase (ALK) gene rearrangements were allowed if previously treated with appropriate therapy. Patients with active brain metastases were excluded. The expansion cohorts (N = 307) are seen in Figure 2. There were 3 dosing regimens across the cohorts: 10 mg/kg q3w; 10 mg/kg q2w or 2 mg/kg q3w. Pooled data (n = 262) for all the cohorts except the nonrandomized 2 mg/kg q3w (n = 45) cohort were presented.

Fewer than 10% of patients experienced grade 3 or greater AEs with 1 death initially thought to be related to drug toxicity, but later determined to not be due to treatment. Fatigue, arthralgia, or nausea of grade 3 or greater occurred in < 1% of the population

Figure 1. Disease-free survival and overall survival results from the MAGRIT trial of MAGE-A3 CI immunotherapy.

DFS OS1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Dis

ease

-Fre

e S

urvi

val

MAGE-A3 CI (597 events)Median: 60.5 (95% CI: 57.2, -)

Placebo (298 events)Median: 57.9 (95% CI: 55.7, -)

P* = 0.7379HR: 1.02 (95% CI: 0.89, 1.18)

Median FU 38.8 months

0 6 12 18 24 30 36 42 48 54 60 66 72

1515 1257 1115 1013 887 656 476 339 220 127 19 2757 639 562 514 448 328 253 180 114 62 6 0

Time Since Randomization (Months)Number at RiskMAGE-A3 CIPlacebo

*Likelihood ratio test from cox regression model stratified by CT and adjusted for baseline variables used as minimization factors.

MAGE-A3 CI Placebo

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ove

rall

Sur

viva

l

MAGE-A3 CI (343 events)Median: not reached

Placebo (174 events)Median: not reached

P* = 0.6994HR: 1.04 (95% CI: 0.86, 1.24)

0 6 12 18 24 30 36 42 48 54 60 66 72

1515 1459 1370 1273 1101 827 607 421 275 159 31 6757 731 693 654 570 427 330 235 145 78 14 5

Time Since Randomization (Months)Number at RiskMAGE-A3 CIPlacebo

*Likelihood ratio test from cox regression model stratified by CT and adjusted for baseline variables used as minimization factors.

MAGE-A3 CI Placebo

DFS, disease-free survival; OS, overall survival; FU, follow-up

Figure 2. Trial design for the KEYNOTE-001 trial of pembrolizumab.

Pembro, pembrolizumab; q2q, every 2 weeks; q3q; every 3 weeks.

• PD-L1 + tumors• ≥ 2 previous therapies

• PD-L1 - tumors• ≥ 2 previous therapies


Nonrandomized(N = 33)


Randomized(N = 144)

• PD-L1 + tumors• Treatment naive

Randomized(N = 45)



R(1:1)

Rc

(1:1)R

(3:2)

Pembro10 mg/kg

q3w

Pembro10 mg/kg

q3w

Pembro10 mg/kg

q3w

Pembro10 mg/kg

q2w

Pembro10 mg/kg

q2w

Pembro2 mg/kg

q3w

Pembro2 mg/kg

q3w

Pembro10 mg/kg

q2w

3Table of Contents


with fatigue being the most commonly reported AE at 20%. Pneumonitis occurred in 4% of patients and 2% of those cases were grade 3 or greater.

The majority of patients (58%) exhibited tumor shrinkage. The ORR by RECIST v1.1 for the study population (n = 236) was 21% (95% CI 16-27) with an ORR of 26% (95% CI 14-42, n = 42) for treatment-naïve patients and 20% (95% CI 15-26, n = 194) for those previously treated (Table 1). Similar response rates were seen for nonsquamous and squamous histology (23% and 18%, respectively). The ORR was 27% among current and former smokers and 9% among never smokers. Response rates for all doses and schedules were similar. Overall response rate determined by irRC was higher in the treatment-naïve group (Table 1). The responses seen are durable with 100% of the treatment-naïve population demonstrating ongoing response and 77% of those previously treated continuing to respond.

Median progression-free survival (PFS) was higher by 17 weeks for treatment-naïve individuals than those previously treated and the median OS was not reached in the treatment-naïve population.

Overall response rate correlated with PD-L1 expression levels, with a 37% ORR in those patients whose tumors strongly expressed PD-L1 (41/129) compared to a 17% ORR in patients with weak expression (46/129) and 10% in patients who did not express PD-L1 (42/129). Individuals with higher PD-L1 expression demonstrated longer PFS and OS.

Additional KEYNOTE trials are ongoing in patients who have progressed after platinum therapy and as a first-line therapy based on PD-L1 expression compared to platinum-based chemotherapy.

EGFR TARGETED THERAPIESIMPRESS Trial of Maintenance Gefitinib Plus Chemotherapy Patients with EGFR mutations who are treated with EGFR tyrosine kinase inhibitors (TKI) almost always acquire resistance to those inhibitors. Mok et al designed the IMPRESS phase III trial to examine whether continued EGFR inhibition with chemotherapy beyond disease progression was beneficial compared to chemotherapy alone.7 The primary endpoint of the study was PFS and secondary endpoints were OS, ORR, and disease control rate (DCR).

Table 1. Overall response rate (ORR), median PFS, and OS for patients treated with pembrolizumab.

Total Treatment-Naïve Previously Treated

n = 236 n = 42 n = 194

ORRRECIST v1.1

21%(95% CI 16-27)

26%(95% CI 14-42)

20%(95% CI 15-26)

n = 262 n = 45 n = 217

ORR, irRC 23%(95% CI 18-29)

47%(95% CI 32-62)

18%(95% CI 13-24)

Median PFS, RECIST v1.1

13 wk(95% CI 9.4-17.6)

27 wk(95% CI 14-45)

10 wk(95% C 9.1-15.3)

OS 8.2 mo(95% CI 7.3-NR)

NR 8.2 mo(95% CI 7.3-NR)

ORR, overall response rate; PFS, progression-free survival; OS, overall survival; mo, months; wk, weeks; NR, not reached.

4 Table of Contents


Eligibility for the study required patients with EGFR mutant, locally advanced or metastatic NSCLC who were progressing on first-line gefitinib therapy. Patients (N = 265) were randomized 1:1 to receive gefitinib (250 mg/day) plus cisplatin (75 mg/m2)/pemetrexed (500 mg/m2) or cisplatin/pemetrexed plus placebo. The gefitinib arm contained 133 patients and the placebo arm contained 132. The patient demographics were somewhat unbalanced with respect to age and brain metastases, with more patients greater than or equal to 65 years in the gefitinib arm and more patients with brain metastases at baseline in the chemotherapy arm.

The number of grade 3 AEs was similar in both arms (44.7% with gefitinib vs 41.7% in placebo). The most common AEs were nausea (64% vs 61%) and decreased appetite (49% vs 34%). Adverse events leading to death were found in both arms. There were 5 deaths in the gefitinib arm and 8 deaths in the placebo arm. Of those deaths, 2 in the gefitinib arm and 1 in the placebo arm were considered to be related to treatment. There is also a difference in post-therapy treatment with those in the placebo arm more likely to receive subsequent platinum-doublet therapy or another EGFR TKI.

The primary endpoint of increased PFS was not met with a median PFS of 5.4 months in both arms (Figure 3). The HR was 0.86 with a CI of 0.65-1.13 and a P value of 0.273. The OS data is immature; however, it favors the placebo arm with a 17.2-month survival vs 14.8 months in the gefitinib arm (HR = 1.62, P = 0.029) (Figure 3). The other secondary endpoints of ORR and DCR were not significant (P values of 0.76 and 0.038, respectively). The median follow-up time was 11.2 months.

The authors conclude that there is no benefit to continued gefitinib therapy in patients who have progressed while being treated with gefitinib.

RADIANT Trial of Adjuvant ErlotinibThe RADIANT trial was a large randomized phase III trial of adjuvant erlotinib vs placebo in NSCLC. Erlotinib is currently FDA approved for treatment of EGFR mutated, advanced NSCLC. The study enrolled 973 patients with demonstrated EGFR expression via IHC or fluorescence in situ hybridization (FISH) and they were randomized 2:1 into the erlotinib (n = 623) or placebo arms (n = 350). The study failed to meet its primary endpoint of improved DFS; however, subgroup analysis indicated that a subset of the population

Figure 3. PFS and OS results from the IMPRESS trial of gefitinib post progression.

PFS OS1.00.90.80.70.60.50.40.30.20.10.0

Prob

abilit

y of

PFS

Gefitinib (n = 133)Placebo (n = 132)

0 2 4 6 8 10 12 14Time of Randomization (Months)

Median PFS, monthsNumber of events, n (%)

5.498 (73.7)

5.4107 (81.1)

Gefitinib(n = 133)

Placebo(n = 132)

HR (95% CI) = 0.86 (0.65, 1.13); P = 0.273

1.00.90.80.70.60.50.40.30.20.10.0

Prob

abilit

y of

OS

Gefitinib (n = 133)Placebo (n = 132)

0 2 4 6 8 10 12 14 16 18 20 22 24 26Time of Randomization (Months)

Median PFS, monthsNumber of events, n (%)

14.850 (37.6)

17.237 (28.0)

Gefitinib(n = 133)

Placebo(n = 132)

HR (95% CI) = 1.62 (1.05, 2.52); P = 0.029

PFS, progression-free survival; OS, overall survival

5Table of Contents


that contains EGFR mutations did show an increase in DFS with erlotinib.8,9 At the 2014 ESMO Congress, Eberhardt et al presented an exploratory analysis of common and rare EGFR mutations found in the RADIANT trial study population while Altorki et al presented data on the prognostic role of EGFR mutations and results of an analysis of DFS by stage.10,11

Eberhardt et al analyzed the RADIANT study population for EGFR mutations other than the common del19 and L858R mutations and their effect on DFS.10 The mutation status of EGFR exons 18-21 of 921 patients was analyzed. EGFR mutations in exons 18-21 were found in 21.5% (n = 198) of the population. Within the population of patients (n = 198) with tumors containing EGFR mutations, 161 (81%) were common mutations defined as del19 or L858R, while rare mutations were found in only 37 (19%) of patients. Within the common mutation subset, 12 patients had additional non-common mutations.

Table 2 shows the DFS for all mutation subgroups. The median DFS was greater for patients with del19 mutations treated with erlotinib and the median DFS was not reached by the L858R and rare mutations subgroups treated with erlotinib. It is important to keep in mind that the RADIANT study was not designed to assess the efficacy of erlotinib in patients with EGFR mutations. The use of erlotinib in patients with completely resected EGFR mutant NSCLC should only be considered in the context of a clinical trial.

Table 2. Disease-free survival by EGFR mutation type.

EGFR mutations DFS

Subgroup (n) Arm n Events Median (mo) HR, 95% CI

Common (161)

Del19/L858R E 102 39 46.4 0.61 (0.38-0.98)

P 59 32 28.5

Del19 E 56 23 46.4 0.68 (0.36-1.28)

P 33 17 26.4

L858R E 46 16 NR 0.55 (0.27-1.12)

P 26 15 29.3

Rare Only (37)

All E 19 7 NR 1.30 (0.47-3.60)

P 18 8 NR

Exon 20 E 11 4 NR 1.09 (0.29-4.09)

P 10 5 35.0

NR, not reached.

The presentation by Altorki et al focused on the prognostic value of the common EGFR mutations, del19 and L858R. Within the total patient population, 17.5% (161/921) were found to have common EGFR mutations. The EGFR mutation population differed from the study population in containing a higher percentage of women, never smokers, Asians, and adenocarcinoma histology. This population also exhibited smaller tumors but more stage IIIA tumors (22.4% vs 13.7%).

6 Table of Contents


The comparison of DFS between the EGFR mutation-positive and EGFR wild-type populations within the placebo group indicated a non-significant, but lower DFS for the EGFR mutation group of 28.5 months vs 55.1 months (P = 0.2258) even after adjusting for baseline variables. Similar analysis of the del19 and L858R populations of the placebo arm, also demonstrated a lower DFS for the patients harboring EGFR mutations. Despite trends towards a lower DFS, the authors conclude that there is no significant prognostic value of EGFR mutations with a HR of 1.20 (95% CI 0.724-1.994).

Figure 4 shows an analysis of DFS by stage for the EGFR mutation-positive population. A non-significant increase in DFS was observed in the EGFR mutation-positive patients with erlotinib treatment for stages IB and II disease but not stage III disease.

In both analyses, the sample size was small and the additional variables in the study population may have affected the results. The trend towards an increased DFS in the EGFR mutation-positive population with erlotinib treatment suggests further studies of adjuvant erlotinib are needed.

LUX-Lung 8 Trial in Squamous Cell CarcinomaThere are very few effective treatments for squamous NSCLC (SCC), which comprises approximately 30% of NSCLC cases. The LUX-Lung 8 (LL8), phase III trial was designed to compare afatinib to erlotinib as second-line treatment in these patients and data was

reported at the 2014 ESMO Congress by Goss et al.12 Afatinib is an irreversible inhibitor of HER2, HER4, and EGFR and is approved in the US for treating EGFR mutation-positive NSCLC.13 The primary endpoint of LL8 was PFS by RECIST v1.1 criteria with a key secondary endpoint of OS and other secondary endpoints of ORR, DCR, tumor shrinkage, quality of life, and safety. In addition to squamous cell histology, patients must have progressed after prior first-line treatment with platinum-based chemotherapy (≥ 4 cycles) and have an ECOG status of 0-1. The population was stratified by

Figure 4. Disease-free survival (DFS) by stage after erlotinib treatment in an EGFR mutation positive population.

1.00.90.80.70.60.50.40.30.20.10.0

DFS

Pro

babi

lity

0 6 12 18 24 30 36 42 48 54 60 66DFS (months)

Erlotinib Placebo

Stage IB

Erlotinib: n = 52 (11 events)Median: Not reachedPlacebo: n = 23 (9 events)Median: Not reachedWald test: P = 0.1425HR, 0.517 (95% CI, 0.214-1.248)

1.00.90.80.70.60.50.40.30.20.10.0

DFS

Pro

babi

lity

0 6 12 18 24 30 36 42 48 54 60 66DFS (months)

Erlotinib Placebo

Stage II

Erlotinib: n = 30 (14 events)Median: 44.75 moPlacebo: n = 17 (11 events)Median: 16.62 moWald test: P = 0.0940HR, 0.507 (95% CI, 0.229-1.123)

1.00.90.80.70.60.50.40.30.20.10.0

DFS

Pro

babi

lity

0 6 12 18 24 30 36 42 48 54 60 66DFS (months)

Erlotinib Placebo

Stage IIIA

Erlotinib: n = 18 (13 events)Median: 34.69 moPlacebo: n = 18 (11 events)Median: 27.73 moWald test: P = 0.7769HR, 1.124 (95% CI, 0.500-2.525)

7Table of Contents


Asia vs the rest of the world. The eligible patient population (N = 669) was randomized into 2 arms with 1 arm (n = 335) receiving 40 mg of afatinib qd and the other arm (n = 334) receiving 150 mg of erlotinib qd.

The 2 arms were well-balanced demographically and 95% of the patients were smokers. Disease progression was monitored by radiographic progression at 0, 8, 12, 16 weeks and every 8 weeks thereafter. At the time of data cut-off, 70 patients remained on treatment with afatinib and 69 with erlotinib.

The percentage of patients experiencing any AE was similar for the 2 arms (98% vs 96%); however, there were more AEs leading to dose reductions in the afatinib arm (24% vs 12%). The percentage of grade 3 or greater AEs, serious AEs, and fatal AEs were similar between the 2 arms. The most common AEs were rash, diarrhea, and stomatitis. There were more grade 3 or greater cases of diarrhea and stomatitis with afatinib and more incidences of grade 3 rash with erlotinib.

Progression-free survival as assessed by independent review was 2.4 months with afatinib vs 1.9 months in the erlotinib arm with a HR = 0.822 and P = 0.0427 (Figure 5). Investigator assessed PFS was 2.7 vs 1.9 months with a HR = 0.78, P = 0.0053 (Figure 5). Subgroup analysis for patient-reported outcomes favored afatinib. Independent review of DCR and ORR demonstrated an increase in both DCR and ORR with odds ratios of 1.44 and 1.63 and P values of 0.0203 and 0.2332, respectively (Table 3). Tumor shrinkage was also greater with afatinib compared to erlotinib.

Although the increase in PFS by 0.5 months was small in terms of time it was statistically significant compared to erlotinib. Overall, tumor shrinkage was greater, RR was higher, and DCR was significantly higher with afatinib. Afatinib provides a greater PFS for SCC patients compared to erlotinib.

Figure 5. LUX-Lung 8 PFS by independent and investigator review.

PFS, independent review PFS, investigator review1.0

0.8

0.6

0.4

0.2

0.0

Estim

ated

PFS

Pro

babi

lity

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

335 266 127 96 54 45 28 25 16 15 8 8 4 2 2 1334 256 112 72 43 34 15 12 6 5 0 0 0 0 0 0

Time (months)

Total randomized, n (%)Patients progressed/diedMedian PFS, months

335 (100)202 (60)

2.4

334 (100)212 (64)

1.9

Afatinib Erlotinib

No. of patientsAfatinibErlotinib

HR 0.82295% CI (0.676-0.998)

Log-rank P value 0.0427

1.0

0.8

0.6

0.4

0.2

0.0

Estim

ated

PFS

Pro

babi

lity

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

335 260 137 110 66 56 30 28 19 17 12 9 5 1 1 0334 252 119 78 49 40 18 15 9 8 2 1 0 0 0 0

Time (months)

Total randomized, n (%)Patients progressed/diedMedian PFS, months

335 (100)228 (68)

2.7

334 (100)242 (72)

1.9

Afatinib Erlotinib

No. of patientsAfatinibErlotinib

HR 0.7895% CI (0.65-0.93)

Log-rank P value 0.0053

CI, confidence interval; HR, hazard ratio

Table 3. Comparison of PFS, DCR, and ORR between patients treated with afatinib or erlotinib.

Afatinib Erlotinib HR1 or odds ratio2 P Value

n = 335 n = 334

PFS, months 2.4 1.9 0.821 0.0427

DCR 45.7% 36.8% 1.442 0.0203

ORR 4.8% 3% 1.632 0.2332

Progression-free survival (PFS) by RECIST v1.1; DCR, disease control rate; ORR, overall response rate.

8 Table of Contents


ALK-REARRANGED NSCLCAlectinib as Second-Line Therapy in ALK-Rearranged NSCLCChromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene are found in 3-7% of NSCLC cases.14 The most common rearrangement is between the ALK gene and the echinoderm microtubule-associated protein-like 4 (EML4) gene. Tumors containing ALK rearrangements are sensitive to the ALK inhibitor crizotinib, used as first-line treatment. Resistance to crizotinib frequently arises and ceritinib was recently approved by the FDA for treatment after crizotinib. Alectinib is another selective ALK inhibitor that is capable of crossing the blood/brain barrier.15

The primary objectives of the JP28927 study were the dosing regimen of alectinib (multiple daily low doses versus fewer larger doses) and food effect on the higher capsule dose.16 Data for food effects, safety, and bioequivalency were presented at the 2014 ASCO Annual Meeting.17 Secondary outcomes were to evaluate the efficacy of alectinib in patients previously treated with crizotinib and the effect on brain metastases. The study design is shown in Figure 6.

Eligibility for the study included patients with stage IIIB/IV or recurrent NSCLC who were determined to be ALK+ by FISH or RT-PCR. Thirty-five patients were enrolled in the study.

The most frequently reported AE was constipation. One grade 3 case of pulmonary thrombosis was reported and 1 case of grade 1 interstitial lung disease.

Seto et al reported an ORR of 58.3% (95% CI 36.6-77.9) for patients previously treated with crizotinib, some of whom had not experienced disease progression (n = 24) (Figure 7).16 For those patients who suffered disease progression on crizotinib (crizotinib failure, n = 20), the ORR was 50.0% (CI 95% 27.2-72.8). At 10.2 months follow-up the median PFS has not yet been reached.

Figure 6. Study design of JP28927 trial of alectinib.

20/40 mg capsules8 capsules bid

150 mg capsules2 capsules bid

150 mg capsules2 capsules bid

20/40 mg capsules8 capsules bid

R

Primary endpoint is to evaluate bioequivalence among drug formulations, safety and food effect with 150 mg capsules.

Eligibility criteriaStage IIIB/IV or

recurrenceALK+ by FISH or

RT-PCR PS 0-1

Asymptomatic brain mets or those not

requiring treatment were allowed

Figure 7. Tumor shrinkage after treatment with alectinib in patients previously treated with crizotinib.

Pts discontinued crizotinib due to reason other than PD

Pts experienced PD on crizotinib

Pts with history of 2 ALK inhibitor treatments

*including crizotinib failure

CrizotinibPre-treatment*

CrizotinibFailure

n = 24 n = 20

58.3%(36.6-77.9)

ORR (CR + PR)(95% CI)

50%(27.2-72.8)

100%

50%

-100%

-50%

0%

-30%

PD, progressive disease; ORR, overall response rate; CR, complete response; PR, partial response.

9Table of Contents


OTHER TARGETS: BRAF, HER2Dabrafenib for BRAF V600E Mutations in NSCLCBRAF mutations occur in approximately 2% of the patients diagnosed with NSCLC in Europe and the US.18,19 Although BRAF mutations in NSCLC are relatively rare, patients harboring BRAF mutations have a poorer prognosis. Planchard presented results from a phase II, single-arm trial of stage IV patients with BRAF V600E mutations treated with dabrafenib.20 The primary endpoint of the trial was investigator assessed ORR by RECIST v1.1 criteria. Secondary endpoints were PFS, DOR, OS, and safety.

This trial was conducted in 11 countries and at the time of data cutoff N = 84 patients were enrolled with n = 78 in the second-line or greater treatment group. Inclusion criteria included stage IV NSCLC, BRAF V600E mutation based on local testing, ECOG PS 0-2, measurable disease by RECIST v1.1, and prior progression on chemotherapy. The median age of the study population was 66 years with equal numbers of males and females. Never smokers comprised 37% of the population and 22% of the population was Asian. Median time to progression on previous treatment was 1.2 months and the percentage of patients with only 1 prior treatment was 51% and those with more than 2 was 32%. All patients received 150 mg of dabrafenib twice daily.

Almost half of the population (45%) experienced grade 3 or greater AEs and 1 grade 5 intracranial hemorrhage was reported. AEs leading to discontinuation were 6%. Serious AEs related to treatment comprised 29% (24/84). The most common serious AEs were cutaneous SCC 12% (10/84), pyrexia 6% (5/84), basal cell carcinoma 5% (4/84), decreased ejection fraction 2% (2/84), and pneumonia 2% (2/84).

For those patients receiving dabrafenib after ≥ 2 prior treatments, 25 of those patients exhibited partial responses (PR), 19 had stable disease (SD), and 23 had progressive disease (Table 4). Within the first-line treatment population (n = 6), there were 3 PD and 3 SD. The median DOR was 11.8 months (5.4 – not reached) with 13/25 (52%) still on therapy. A median PFS of 5.5 months (95% CI 2.8-7.3) was reported. The ORR was 32% and DCR was 56% by independent review. One case study with responses in brain metastasis was reported.

The study authors conclude that dabrafenib provides a meaningful clinical benefit for patients with BRAF V600E tumors.

Neratinib in HER2 Mutant NSCLC (PUMA-NER-4201)HER2 mutations occur in approximately 2% of NSCLC.21,22 The majority of those mutations are insertions in exon 20, which is the tyrosine kinase domain. Neratinib is a pan ErbB (HER) inhibitor that strongly inhibits EGFR, HER2, and HER4. Downstream of the ErbB pathway, is the PI3 kinase (PI3K) pathway, which in this study, is targeted by inhibiting mTOR with temsirolimus, resulting in a dual blockade of the ErbB pathway.

Table 4. Response to dabrafenib in patients with BRAF V600E mutated tumors.

Best Response Independent Review Investigator Review

N = 64 N = 78

PR 18 (28) 25 (32)

SD 15 (23) 19 (24)

PD 23 (36) 23 (29)

Not evaluable 3 (13) 11 (14)

ORR* 28% (95% CI 17.6-40.8) 32% (95% CI 21.9-43.6)

DCR† 51% (95% CI 38.7-64.3) 56% (95% CI 44.7-67.6)

PR, partial response; SD, stable disease; PD, progressive disease. *ORR confirmed CR and PR;†DCR = CR + PR + SD.

10 Table of Contents


Results from a planned interim analysis of stage I of a phase II randomized trial of neratinib with or without temsirolimus were presented by Besse et al.23 The primary endpoint of the study is ORR with secondary endpoints of DOR, PFS, OS, clinical benefit rate, and safety.

Eligible patients were those with stage IIIB/IV NSCLC or later with HER2 mutations. Stage I of the study enrolled N = 27 patients, who were randomized 1:1 into 2 arms:

• Neratinib, 240 mg/day orally• Neratinib, 240 mg/day orally + temsirolimus, 8 mg/wk, IV; with escalating temsirolimus to

15 mg/wk after cycle 1 if tolerable

Crossover to the combination arm was allowed after disease progression on neratinib alone and 5 patients did crossover. All patients were given mandatory prophylaxis for diarrhea with loperamide. The arms of the study were well matched. One patient in the neratinib arm also exhibited a KRAS mutation. No patients had EGFR mutations or ALK arrangements.

The most common AE was diarrhea with 77% of patients in the neratinib arm and 100% of patients in the combination arm experiencing mainly grade 1 or 2 even with prophylaxis. Three patients exhibited grade 3 diarrhea but 2 were not compliant with prophylaxis. There were no grade 4 or 5 treatment-related events. In the neratinib arm, there were 2 dose reductions and 4 in the combination arm both due to neratinib toxicity.

The majority of the HER2 mutations (89%) were within exon 20. All the patients in the combination arm had exon 20 mutations, and 77% of those in the neratinib alone arm had exon 20 mutations.

The ORR in the combination arm was 21% with 3 partial responses, 2 of which were confirmed (Table 5). The rate of SD was higher in the combination arm, 79% vs 54% in the neratinib alone arm. The median PFS was 1.1 month higher in the combination arm.

Dual blockade of the ErbB pathway with neratinib and temsirolimus resulted in a better ORR and PFS than inhibition with neratinib alone. A second stage expansion study with 39 patients was initiated after the cutoff of ≥ 2 responses at the 12-week timepoint in stage I was met and is ongoing.

Table 5. Best overall response to neratinib or neratinib plus temsirolimus.

Neratinib Neratinib + Temsirolimus

Efficacy, n (%) n = 13 95% CI n = 14 95% CI

ORR* 0 (0) 0-21 3† (21) 6-47

PR 0 (0) 3† (21)

SD 7 (54) 11 (79)

PD 6 (46) 0 (0)

Median PFS, months 2.9 1.4-NE 4.0 2.9-9.8

*RECIST v1.1; †2 out of 3 responses confirmed. CI, confidence interval; NE, not estimable; PFS, progression-free survival.

11Table of Contents


TARGET Trial: Vintafolide as a Second-Line TreatmentMany cancers, including NSCLC, express the folate receptor. Vintafolide (V) is a folate-vinca alkaloid conjugate that targets the folate receptor. Hanna et al presented data from the TARGET trial, a randomized phase II trial comparing V vs V plus docetaxel (DTX) vs DTX alone as second-line therapy.24 The primary endpoint of the study was PFS with secondary endpoints of ORR, DCR, and OS.

Eligibility criteria were stage IIIB or IV NSCLC of any histology and 1 prior chemotherapy. Patients were scanned with a folate targeting imaging molecule for folate receptor expression. The study was stratified by 4 criteria:

• Time since last chemotherapy (< 3 vs ≥ 3 mo)• Best response to prior chemotherapy• Stage IIIB vs IV• Prior EGFR tyrosine kinase inhibitor

Patients (N = 199) were randomized 1:1:1 to receive V alone, V + DTX, or DTX alone. Dosing for V was 2.5 mg given IV on days 1, 4, 8, 11 q3wk and for DTX 75 mg/m2 IV on day 1 q3w. The arms of the trial were well balanced with the majority of patients having adenocarcinoma histology (65% in V, 63% in V + DTX, 72% in DTX); stage IV disease and 13-16% had been previously treated with an EGFR inhibitor.

No new AEs were reported. Grade 3 or higher neutropenia was detected in the combination arm > 70% vs 2% in the V alone arm and > 50% in the DTX arm. Grade 3 peripheral neuropathy was also higher in the combination arm (9% in V + DTX vs 2% in V and 0% in DTX). High levels of V dose reductions (81%) were required in the V + DTX arm and 85% of those were due to hematologic toxicity. Within the V arm, the level of dose reductions was 22%. No dose reductions of DTX were required in the DTX alone arm but 15% were required in the combination arm.

The primary endpoint of improved PFS was negative as V + DTX failed to show a 50% improvement in PFS compared to DTX alone (Figure 8). Table 6 shows the unstratified data analysis for all patients. There was also no significant difference in OS compared to DTX alone. After stratification, the PFS and OS

Table 6. ORR, PFS, OS, and DCR for patients treated with vintafolide, vintafolide plus docetaxel, or docetaxel alone.

V V + DTX DTX

All patients, unstratified n = 63 n = 68 n = 68

ORR 6% 22% 13%

Median PFS, months 1.6 4.2 3.3

PFS HR (vs DTX; 95% Cl) 1.35 (0.92-1.96) 0.75 (0.52-1.09) -

P value* 0.9421 0.0696 -

Median OS, months 8.4 11.5 8.8

OS HR (vs DTX; 95% Cl) 1.05 (0.68-1.61) 0.88 (0.58-1.36) -

P value* 0.5818 0.2874 -

DCR (PR and SD) all patients 41.2% 70.6% 60.3%

*1-sided P values; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; DCR, disease control rate; V, vintafolide; DTX, docetaxel; PR, partial response; SD, stable disease.



Figure 8. Progression-free survival for patients treated with vintafolide, vintafolide plus docetaxel, or docetaxel alone.

All patients

% P

atie

nts

Prog

ress

ion

Free

Months

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15

63 21 5 2 1 068 38 17 7 1 068 35 13 3 0 0

V onlyV + DTXDTX only

V, vintafolide; DTX, docetaxel

Adenocarcinoma

% P

atie

nts

Prog

ress

ion

Free

Months

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15

41 16 2 0 0 043 23 11 5 1 049 24 9 2 0 0

V onlyV + DTXDTX only

V onlyV+ DTXDTX only

414349

333342

TreatmentPatients Events

V onlyV+ DTXDTX only

636868

525459

TreatmentPatients Events

Number at riskNumber at risk

differences between V + DTX and DTX were still not statistically significant (P values of 0.1175 and 0.1066, respectively). Within the adenocarcinoma subgroup; however, the HR for OS in adenocarcinoma patients was 0.51 (95% CI 0.28-0.94) with a P value of 0.0147.

One case of a response to V + DTX in brain metastases was presented. Subgroup analysis favored the combination arm.

In comparison to docetaxel alone, the combination therapy resulted in clinically significant improvement in all endpoints within the study population and an increase in OS of 5.9 months in the adenocarcinoma group.

MOLECULAR ANALYSIS/BIOMARKERSEvolution of the Genomic Landscape in NSCLCNSCLC has one of the highest mutation rates of cancers examined to date.21,25 As the era of personalized medicine continues to evolve, knowledge of the genomic landscape of NSCLC will become increasingly important for guiding therapeutic decisions. Two studies reported at the 2014 ESMO Congress address the genetics underlying NSCLC.

Jamal-Hanjani et al presented results from a study examining genomic mutations in NSCLC.26 The goal of the study was to examine the clonal pattern of mutations in a number of tumors via sampling different areas of the tumor. The hope was to better identify the intra-tumor mutational heterogeneity of NSCLC tumors.

The study comprised 13 patients with stage IA through IIIB NSCLC who were eligible for curative resection. Of these patients, 3 had squamous cell histology, 8 had adenocarcinoma histology, 1 was a mix of squamous and adenocarcinoma, and the remaining patient had an undifferentiated histology. Samples were taken from different regions of the primary tumor; snap frozen and later DNA was isolated for whole exome sequencing. Tumor DNA sequences were compared to DNA isolated from blood. Sequencing was validated via Ion Torrent at over 1000X. Mutations consisted of single nucleotide variations, insertions, deletions, and chromosome rearrangements.

13Table of Contents


The authors found that intra-tumor heterogeneity ranged from 5-61% with a median of 30%. Putative driver mutations were determined using pan-cancer and lung cancer data sets. For some tumors these mutations were found in the “trunk” of the evolutionary tree, ie, present in all samples from that tumor whereas in other tumors driver mutations were found in the “branches” representing later evolution.

The study raises several issues and questions. First, it is clear that clinically, physicians are limited by practical concerns such as time, money, and surgical constraints that result in sampling bias. Second, it is not clear the relevance of tumor heterogeneity for therapeutic outcome. For instance, is treating a potential driver mutation even if it arises later in the evolutionary life of a tumor, still effective? It is also not known what impact tumor heterogeneity has on the outcome of clinical trials. Finally there is the issue of drug resistance arising in part due to clonal selection for resistant cells after treatment.

Some of these questions are being addressed by the TRACERx study. This is a large (N = 850) study taking place in the United Kingdom to collect primary tumors and analyze multiple regions from those tumors. Patients will be followed for 5 years. Circulating tumor cells and circulating DNA will also be analyzed. The goal is to establish the impact of heterogeneity, to identify actionable mutations, and to determine if clonal heterogeneity is important for therapeutic response.

Genomic Changes in Tumors From Multiple RelapsesAnother genomic study was presented by Calles et al.27 This study examined the tumors from patients with early stage NSCLC who underwent multiple resections. A total of 15 patients were identified and tumors from 6 of these patients were evaluated. From these 6 patients a total of 20 samples were available for a median number of samples per patient of 3. DNA was extracted from formalin-fixed paraffin embedded samples and compared to germline DNA. Sequencing was carried out for 504 genes at a mean depth of 186X.

The study concluded that in 4/6 patients the tumors exhibited a distinct mutational profile indicating genetically distinct tumors were present at different times. In the remaining 2 individuals, the genetic analysis indicated that the tumors resected later shared a common genetic profile with the primary tumor indicating that they were relapses of the primary tumor, although tumors resected later contained additional mutations. The authors suggest that massively parallel sequencing may be useful to determine if subsequent tumors represent a recurrence or novel disease.

CONCLUSIONThe molecular and therapeutic landscape of NSCLC continues to change at a rapid pace. Information reported at the 2014 ESMO Congress provided new insights into the treatment of NSCLC that will help guide future practice.

Click here to take the Post-Test and Evaluation

http://www.ecgcme.com/online-education/translating-todays-science-tomorrows-practice-lung-cancer-highlights-39th-european

http://www.ecgcme.com/online-education/translating-todays-science-tomorrows-practice-lung-cancer-highlights-39th-european



REFERENCES1. Vansteenkiste JF, Cho B, Vanakesa T, et al. MAGRIT, a double-blind, randomized, placebo-controlled

phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). ESMO Congress. 2014. Abstract 1173O.

2. Ulloa-Montoya F, Louahed J, Dizier B, et al. Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol. 2013;31(19):2388-2395.

3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.

4. Chen Y-B, Mu C-Y, Huang J-A. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98(6):751-755.

5. Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014;94(1):107-116.

6. Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC). ESMO Congress. 2014. Abstract LBA43.

7. Mok TS, Wu Y, Nakagawa K, et al. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the phase III, randomised IMPRESS study. ESMO Congress. 2014. Abstract LB2A_PR.

8. Kelly K, Altorki NK, Eberhardt WEE, et al. A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(15 suppl). Abstract 7501.

9. Shepherd FA, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial [abstract]. J Clin Oncol. 2014;32(15 suppl). Abstract 7513.

10. Eberhardt W, Shepherd F, Altorki N, et al. Common and rare EGFR mutations (EGFR M+) in the RADIANT trial. ESMO Congress. 2014. Abstract 1178PD.

11. Altorki N, Kelly K, O’Brien M, et al. L858R activating mutation (M+) subgroup in RADIANT: baseline characteristics, prognostic role, and disease-free survival (DFS) by stage. ESMO Congress. 2014. Abstract 1177OPD.

12. Goss G, Felip E, Cobo M, et al. A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8). ESMO Congress. 2014. Abstract 1222O.

13. Dungo RT, Keating GM. Afatinib: first global approval. Drugs. 2013;73(13):1503-1515.14. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung

cancer. N Engl J Med. 2010;363(18):1693-1703.15. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced

non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013;14(7):590-598.

15Table of Contents


16. Seto T, Hida T, Nakagawa K, et al. Anti-tumor activity of alectinib in crizotinib pre-treated ALK-rearranged NSCLC in JP28927 study. ESMO Congress. 2014. Abstract 1224O.

17. Nakagawa K, Hida T, Seto T, et al. Antitumor activity of alectinib (CH5424802/RO5424802) for ALK-rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study. ASCO Meeting Abstracts. 2014;32(15 suppl). Abstract 8103.

18. Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers (BM) France: results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). ASCO Meeting Abstracts. 2013;31(15 suppl). Abstract 8000.

19. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574-3579.

20. Planchard D, Kim T, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): a multicenter, open-label, phase II trial (BRF113928). ESMO Congress. 2014. Abstract LBA38_PR.

21. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550.

22. Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31(16):1997-2003.

23. Besse B, Soria J, Yao B, et al. Neratinib (N) with or without temsirolimus (TEM) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study. ESMO Congress. 2014. Abstract LBA39_PR.

24. Hanna N, Juhász E, Cainap C, et al. A randomized, phase II trial comparing vintafolide versus vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC) patients. ESMO Congress. 2014. Abstract LBA40_PR.

25. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-525.

26. Jamal-Hanjani M, Wilson G, Bruin ED, et al. Evolution of the genomic landscape in non-small cell lung cancer. ESMO Congress. 2014. Abstract LBA36.

27. Calles A, Thorner AR, Sholl LM, et al. Genomic changes in lung cancer patients with multiple lung relapses. ESMO Congress. 2014. Abstract 1180PD.

lung cancer highlights from the 39th european society for medical oncology (esmo) congress

Documents

advanced nsclc

lung cancer highlights

magrit trial

target trial

alkrearranged nsclc

her2 mutant nsclc pumaner

tomorrows practice

european society