Advances in the Management of Lung Cancer: Highlights from the 2014 ASCO Annual Meeting

This activity is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

Editors

Julie R. Brahmer, MDAssociate Professor of OncologyThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland

Suresh S. Ramalingam, MD Professor of Hematology and Medical OncologyDirector, Division of Medical OncologyEmory University School of MedicineWinship Cancer InstituteAtlanta, Georgia

Advances in the Management of Lung Cancer: Highlights from the 2014 ASCO Annual Meeting

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An Interactive PDF Newsletter


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

INTRODUCTION .......................................................................................................................................... 1

TARGETING EGFR ........................................................................................................................................ 1

First-Line Therapy .....................................................................................................................................................................1

SQUIRE Trial – Necitumumab With Gemcitabine and Cisplatin in Squamous NSCLC .................................1

Adjuvant EGFR Therapy ...........................................................................................................................................................2

RADIANT Trial – Adjuvant Erlotinib ................................................................................................................................2

SELECT Trial – Adjuvant Erlotinib ...................................................................................................................................4

Pan-HER Inhibitors ....................................................................................................................................................................4

ARCHER 1009 Trial – Comparison of Dacomitinib to Erlotinib as Second-Line Therapy ............................4

Targeting EGFRMUT-Containing Tumors ...............................................................................................................................5

Analysis of the Use of First-Line Afatinib in EGFRMUT-Containing Populations ...............................................5

LUX-Lung 5 – Afatinib and Paclitaxel in Late Stage Disease .................................................................................7

EGFR Inhibitors Targeting Resistant Disease ......................................................................................................................8

AZD9291 .................................................................................................................................................................................8

CO-1686 ................................................................................................................................................................................ 10

HM61713 .............................................................................................................................................................................. 11

TARGETING VEGFR ....................................................................................................................................12

REVEL Trial – Ramucirumab Plus Docetaxel as Second-Line Treatment ........................................................ 12

TARGETING VEGF AND EGFR ....................................................................................................................13

Erlotinib Plus Bevacizumab for First-Line Therapy ................................................................................................ 13

ALK GENE REARRANGEMENT ...................................................................................................................14

PROFILE 1014 – Crizotinib as First-Line Therapy in ALK+ NSCLC ..................................................................... 14

ASCEND-1 Trial – Ceritinib in Advanced Stage ALK+ NSCLC ............................................................................. 15

IMMUNOTHERAPY ....................................................................................................................................17

PD-1 and PD-L1 .................................................................................................................................................................. 17

KEYNOTE 001 – Pembrolizumab in Advanced Malignancies ............................................................................ 17

CA209-012 Study – Nivolumab Alone or in Combination With Erlotinib or Ipilimumab ........................ 18

MEDI4736 – Anti PD-L1 Antibody Therapy in Solid Tumors .............................................................................. 20

SUMMARY .................................................................................................................................................21

POST-TEST AND EVALUATION ..................................................................................................................22

REFERENCES ..............................................................................................................................................22

IIITable of Contents


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

INTRODUCTION .......................................................................................................................................... 1

TARGETING EGFR ........................................................................................................................................ 1

First-Line Therapy .....................................................................................................................................................................1

SQUIRE Trial – Necitumumab With Gemcitabine and Cisplatin in Squamous NSCLC .................................1

Adjuvant EGFR Therapy ...........................................................................................................................................................2

RADIANT Trial – Adjuvant Erlotinib ................................................................................................................................2

SELECT Trial – Adjuvant Erlotinib ...................................................................................................................................4

Pan-HER Inhibitors ....................................................................................................................................................................4

ARCHER 1009 Trial – Comparison of Dacomitinib to Erlotinib as Second-Line Therapy ............................4

Targeting EGFRMUT-Containing Tumors ...............................................................................................................................5

Analysis of the Use of First-Line Afatinib in EGFRMUT-Containing Populations ...............................................5

LUX-Lung 5 – Afatinib and Paclitaxel in Late Stage Disease .................................................................................7

EGFR Inhibitors Targeting Resistant Disease ......................................................................................................................8

AZD9291 .................................................................................................................................................................................8

CO-1686 ................................................................................................................................................................................ 10

HM61713 .............................................................................................................................................................................. 11

TARGETING VEGFR ....................................................................................................................................12

REVEL Trial – Ramucirumab Plus Docetaxel as Second-Line Treatment ........................................................ 12

TARGETING VEGF AND EGFR ....................................................................................................................13

Erlotinib Plus Bevacizumab for First-Line Therapy ................................................................................................ 13

ALK GENE REARRANGEMENT ...................................................................................................................14

PROFILE 1014 – Crizotinib as First-Line Therapy in ALK+ NSCLC ..................................................................... 14

ASCEND-1 Trial – Ceritinib in Advanced Stage ALK+ NSCLC ............................................................................. 15

IMMUNOTHERAPY ....................................................................................................................................17

PD-1 and PD-L1 .................................................................................................................................................................. 17

KEYNOTE 001 – Pembrolizumab in Advanced Malignancies ............................................................................ 17

CA209-012 Study – Nivolumab Alone or in Combination With Erlotinib or Ipilimumab ........................ 18

MEDI4736 – Anti PD-L1 Antibody Therapy in Solid Tumors .............................................................................. 20

SUMMARY .................................................................................................................................................21

POST-TEST AND EVALUATION ..................................................................................................................22

REFERENCES ..............................................................................................................................................22

MEDIA: NEWSLETTEREstimated time to complete activity: 1.0 hourRelease date: Thursday, August 14, 2014 | Expiration date: Thursday, August 13, 2015

INTRODUCTIONThe 2014 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois, provided a comprehensive review of key experimental and clinical data. Included in this newsletter are highlights from the conference covering major plenary sessions, key symposia, and targeted oral and poster presentations on the advances in the management of lung cancer.

EDITORSJulie R. Brahmer, MDAssociate Professor of OncologyThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland

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:

• Describe the most current advances for the diagnosis and staging of patients with lung cancer• Describe the rationale for the development and integration of new therapeutic approaches in lung cancer • Discuss the clinical implications of the results from pivotal clinical trials that have impacted the use of new approaches and strategies for the treatment of NSCLC

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 Thursday, August 14, 2014 through Thursday, August 13, 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 or statement of credit via the website, www.ecgcme.com.

Suresh S. Ramalingam, MD Professor of Hematology and Medical OncologyDirector, Division of Medical OncologyEmory University School of MedicineWinship Cancer InstituteAtlanta, Georgia

http://www.ecgcme.com

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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

Julie R. Brahmer, MD Grants/Research Support Consultant Fees

Bristol-Myers Squibb Company, MedImmune, LLC., Merck & Co., Inc. Merck & Co., Inc.

Suresh S. Ramalingam, MD Consultant Fees Amgen Inc., ARIAD Pharmaceuticals, Inc., AstraZeneca, AVEO Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Celgene Corporation, Genentech, Gilead Sciences, Inc., Lilly USA, LLC, Novartis

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

ACKNOWLEDGEMENTThe editors wish to thank Marie 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 an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

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.



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INTRODUCTIONThe 2014 ASCO Annual Meeting held May 30 through June 2 in Chicago, Illinois provided numerous updates on treatment for non-small-cell lung cancer (NSCLC). Encouraging data were presented for first-line treatment of squamous NSCLC. A number of studies were presented utilizing different therapies for patients harboring EGFR mutations (EGFRMUT) as well as for those with anaplastic lymphoma kinase (ALK) tyrosine kinase gene rearrangements. Data on immunotherapy using antibodies against the programmed cell death protein 1 (PD-1) or its ligand, PD-L1, were also presented. This newsletter provides an overview of the major clinical trial updates presented at the 2014 ASCO Annual Meeting that impact clinical practice.

TARGETING EGFRFirst-Line Therapy SQUIRE Trial – Necitumumab With Gemcitabine and Cisplatin in Squamous NSCLCSquamous NSCLC comprises 25-30% of NSCLC. The phase III randomized SQUIRE trial was directed exclusively at patients with NSCLC and squamous histology and data were presented at the 2014 ASCO Annual Meeting by Thatcher et al.1 The SQUIRE study evaluated the human monoclonal antibody to EGFR, necitumumab, in combination with gemcitabine and cisplatin against gemcitabine/cisplatin alone as first-line treatment.

Patients (N = 1093) were randomized to receive necitumumab/gemcitabine/cisplatin every 3 weeks (n = 545) or gemcitabine/cisplatin every 3 weeks (n = 545). If patients in the necitumumab/gemcitabine/cisplatin arm were able to complete 6 rounds of treatment with no disease progression, then they moved on to necitumumab monotherapy for maintenance therapy. The primary endpoint of the study was overall survival (OS) with secondary endpoints of progression-free survival (PFS) and overall response rate (ORR). Data for an exploratory endpoint of the role of EGFR expression in the archived tumor tissue based on H-score was also presented.

Patients were required to have stage IV disease with squamous histology. Knowledge of EGFR expression status was not necessary for inclusion. Patients were stratified by geographic region and performance status. Overall the population was over 90% smokers and a heavy metastatic population and over 90% of patients in each arm had 2 or more metastases. The patient population was well matched between the 2 arms of the study.

Median OS was superior with the addition of necitumumab to chemotherapy; 11.5 months vs 9.9 months with a HR = 0.84 (95% CI 0.74-9.96) and P = 0.012. (Figure 1A).

Progression-free survival was also improved by a modest extent with necitumumab (HR = 0.85, 95% CI 0.74-0.98 P = 0.020). (Figure 1B) Overall response rate (31.2% vs 28.8%) was not significantly different with a P = 0.400; however, the disease control rate (DCR) was increased from 77.0% to 81.8% in the necitumumab arm (P = 0.043).

Overall the post-study therapy between the 2 arms was balanced with 47.3% of patients in the experimental arm and 44.7% of patients in the chemotherapy arm receiving further therapy. However, there was some imbalance in the docetaxel and erlotinib groups. A higher percentage of necitumumab patients received docetaxel treatment while a higher percentage of chemotherapy patients received erlotinib.

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EGFR expression was analyzed by H-score. With a cutoff of 200 there was no significant predictive value of H-score for either OS or PFS (Figure 2).

There was an increase in grade 3 or greater adverse events (AEs) in the necitumumab arm (72.1% vs 61.6%). Increased grade 3 or higher events occurring in the necitumumab arm were hypomagnesemia (9.3% vs 1.1%), skin rash (7.1% vs 0.4%), and venous thromboembolic events (5% vs 2.6%). The necitumumab arm also experienced more serious AEs (47.8% vs 37.5%) and more AEs leading to discontinuation of treatment (31.2% vs 24.6%). There was no significant difference in neutropenia, febrile neutropenia, anemia, or thrombocytopenia.

The addition of necitumumab to gemcitabine/cisplatin therapy provides a modest but significant increase in PFS, OS, and DCR in a squamous NSCLC population, which has not seen recent significant advances in treatment.

Adjuvant EGFR Therapy RADIANT Trial – Adjuvant ErlotinibErlotinib is approved as a second- or third-line treatment2 for advanced NSCLC. It has also been demonstrated to be effective as first-line therapy in patients with EGFR activating mutations3 and as maintenance therapy.4 Kelly and colleagues tested erlotinib in an adjuvant setting in the RADIANT phase III randomized, double-blind trial.5,6

Figure 1. Overall survival (OS) and progression-free survival (PFS) in the ITT population after treatment with gemcitabine/cisplatin (Gem-Cis) with or without necitumumab (Neci).

A. Overall Survival B. Progression-Free Survival

N = 1093

N = 1093

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8 104 620 12 22 2418 201614 26 36 3832 343028 40

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Time Since Randomization (months)Follow-up time (median): Gem-Cis + Neci: 25.2 months; Gem-Cis: 24.8 months

Median OS (95% CI), months:Gem-Cis + Neci: 11.5 (10.4, 12.6) Gem-Cis: 9.9 (8.9, 11.1)

HR (95% CI): 0.84 (0.74, 0.96); P = 0.012

Patients/Events:Gem-Cis + Neci: 545/418Gem-Cis: 548/442

1yr OS

2yr OS

47.7%

42.8%19.9%

16.5%

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840 12 242016 3228

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Median PFS (95% CI), months:Gem-Cis + Neci: 5.7 (5.6, 6.0) Gem-Cis: 5.5 (4.8, 5.6)

HR (95% CI): 0.85 (0.74, 0.98); P = 0.020*

*Log Rank Test (stratified)

Figure 2. Overall survival (OS) and progression-free survival (PFS) analyzed by EGFR H-Score with a cutoff point of 200.

ITT population (N = 1093) 0.84(0.74, 0.96)

OS HR(95% CI)

0.75(0.60, 0.94)

0.90(0.75, 1.07)

H-Score ≥ 200 (n = 374)

H-Score < 200 (n = 608)

0.5 1.0 1.5

Favors Gem-Cis + Neci Favors Gem-Cis

Interaction P value: 0.235

0.85(0.74, 0.98)

PFS HR(95% CI)

0.88(0.70, 1.11)

0.83(0.69, 0.99)

0.5 1.0 1.5

Favors Gem-Cis + Neci Favors Gem-Cis

Interaction P value: 0.675

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The study randomized 973 patients 2:1 for treatment with 150 mg erlotinib per day, (n = 623) or placebo (n = 350). Enrollment criteria were completely resected patients with stage IB-IIIA disease and increased EGFR expression determined by either IHC or FISH. Prior adjuvant chemotherapy was allowed. The primary endpoint of the study was disease-free survival (DFS) with a secondary endpoint of OS. Additional secondary endpoints were OS and DFS within the subset of the population that contained EGFR activating mutations del19 or L858R.

The DFS was 50.5 months with erlotinib versus 48.2 months in the placebo group and the difference was not statistically significant (HR = 0.90, P = 0.3235) (Figure 3A). The study failed to meet its primary endpoint of increasing DFS with adjuvant erlotinib. The median OS was not reached for either group with a median follow-up of 47 months.

A subgroup analysis of patients with del19 and L858R EGFRMUT was also reported. A total of 161 patients were positive for EGFRMUT with n = 102 treated with erlotinib and n = 59 in the placebo group. The EGFRMUT group overall had a higher proportion of females, Asian, and never smokers compared to the total study population. Additionally the 2 treatment arms in this subgroup were unbalanced with respect to stage of disease, tumor size, and previous adjuvant chemotherapy with the erlotinib group containing more stage IB patients, patients with larger tumors, and patients with less prior chemotherapy.

Subgroup analysis indicated that erlotinib was favored in patients with EGFRMUT tumors but was not statistically significant due to hierarchical testing. There is a trend towards longer DFS in the EGFRMUT subgroups treated with erlotinib (46.4 months vs 28.5 months, P = 0.0391) (Figure 3B) but the data set is too small and imbalanced to draw firm conclusions. Further study of the EGFRMUT positive population is planned.

Patients randomized to erlotinib experienced more total AEs (98.0% vs 89.5%) and more grade 3 or greater AEs (45.7% vs 28%) compared to placebo. Predominant grade 3 AEs included rash (22.3% vs 0.3%) and

Figure 3. Disease-free survival (DFS) after adjuvant erlotinib compared to placebo. A) DFS in the total study population; B) DFS in the EGFRMUT subgroup.

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Erlotinib PlaceboA.

Placebo (156 events)Median: 48.2 m

Erlotinib (254 events)Median: 50.5 m

Log rank test: P = 0.3235

HR: 0.90 (95% CI: 0.741, 1.104)

Number at Risk

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PlaceboErlotinib 76 2268 1094 0

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Erlotinib PlaceboB.

Placebo (32 events)Median: 28.5 m

Erlotinib (39 events)Median: 46.4 m

Log rank test: P = 0.0391 (nor statistically significant due to hierachical testing)

HR: 0.61 (95% CI: 0.384, 0.981)

Number at Risk

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diarrhea (6.2% vs 0.3%). Within the erlotinib arm 26.7% of patients discontinued treatment due to drug related AEs while only 2.3% of the placebo population discontinued. There were no differences in AEs between the EGFRMUT subgroup and the total study population.

Although the RADIANT trial failed to meet its primary endpoint of increased DFS, the data suggests that adjuvant erlotinib might benefit a subset of patients whose tumors contain EGFRMUT.

SELECT Trial – Adjuvant ErlotinibThe phase II SELECT trial was a non-randomized study examining the efficacy of adjuvant erlotinib presented by Pennell et al.7 Patients were selected to receive 150 mg erlotinib daily for 2 years. Criteria for selection were resected stage IA-IIIA NSCLC with an EGFRMUT and prior adjuvant chemotherapy or radiation therapy. The patient population (N = 100) consisted of primarily females (77%), never smokers (59%), and non-Asians (83%). The primary endpoint was DFS.

The 2-year DFS survival rate is 89% with a median follow-up of 3.4 years and the median DFS has not yet been reached. Compared to historical control data the DFS results in the SELECT study demonstrate a favorable effect with erlotinib (P = 0.0047). Compliance with treatment was good with 69% of patients receiving at least 22 months of therapy although 40% required a dose reduction. Patients who experienced disease recurrence did so predominantly at a single site (41%) and after cessation of erlotinib with a median time to recurrence of 8.5 months. Biopsies of recurrent samples (n = 18, 68%) were genotyped and only 1 had acquired a T790M mutation. Erlotinib treatment of patients with recurrence was effective.

No grade 4 events were reported. Grade 3 events included rash (13%), diarrhea (3%), and fatigue (2%).

The SELECT trial concluded that extended treatment with erlotinib is feasible and provides an increase in DFS compared to historical controls. Taken together with the RADIANT data, further evaluation of erlotinib in patients with EGFRMUT is warranted. A randomized phase III study will soon be initiated by the Alliance cooperative group.

Pan-HER InhibitorsARCHER 1009 Trial – Comparison of Dacomitinib to Erlotinib as Second-Line TherapyDacomitinib is an oral, irreversible inhibitor of EGFR, HER-2, and HER-3. Dacomitinib therapy had previously demonstrated an increase in PFS in a phase II trial. Ramalingam and colleagues presented data from the phase III ARCHER 1009 trial at the 2014 ASCO Annual Meeting.8

The ARCHER 1009 trial was a randomized double-blind comparison of dacomitinib to erlotinib for patients with advanced/metastatic NSCLC as a second- or third-line therapy. The primary endpoint of the ARCHER 1009 trial was PFS with secondary endpoints of OS, best ORR, duration of response (DOR), and safety. The trial was also designed to examine a subpopulation of patients with wild-type KRAS.

Patients (N = 878) were randomized to receive either 45 mg of dacomitinib once daily (n = 439) or 150 mg erlotinib once daily (n = 439). Patients who had progressed on a prior therapy (maximum of 2) were eligible to enroll. Stratification factors were histology, race (Asian vs non-Asian), ECOG status of 0-1 vs 2, and smoking status. The 2 study arms were well matched. Within the dacomitinib arm 256 patients (58.3%) were KRAS wild-type while there were 263 patients (59.9%) in the erlotinib arm who were KRAS wild-type.

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Progression-free survival did not differ among the 2 arms of the study with HR = 0.941 and 2-sided P = 0.46. Similarly, OS was also the same for treatment with either dacomitinib or erlotinib, HR = 1.08, P = 0.82 (Table 1). There was a slightly higher improvement in ORR from 8.2% to 11.4% (P = 0.083) after treatment with dacomitinib compared to treatment with erlotinib.

Among KRAS wild-type patients, PFS (HR = 1.022, P = 0.83), OS (HR = 1.10, P = 0.80), and ORR (13.3% in the dacomitinib arm vs 11.0% for erlotinib, P = 0.261) did not differ between the dacomitinib and erlotinib arms.

In comparison to erlotinib, grade 3/4 diarrhea (72.8% vs 47.5%) and stomatitis (37.2% vs 20.2%) were more common in the dacomitinib arm. Dose discontinuation rates were higher with dacomitinib (7.3% vs 4.6%) than for erlotinib. Treatment-related discontinuations occurred for diarrhea (n = 4 dacomitinib; n = 1 erlotinib) and dehydration/renal injury (n = 3) all in the dacomitinib arm. Very few grade 4 AEs and no grade 5 AEs were seen.

Overall, dacomitinib did not prolong OS or PFS as salvage therapy in a population with an advanced disease state. Ongoing studies include a phase III comparison of dacomitinib to gefitinib in patients with an EGFR activating mutation. (ARCHER 1050, NCT01774721).

Targeting EGFRMUT-Containing Tumors The 2 most common EGFR activating mutations are: exon 19 deletions (del19) and L858R. These activating mutations occur more commonly in Asian populations than in non-Asian populations.9

Analysis of the Use of First-Line Afatinib in EGFRMUT-Containing PopulationsAfatinib is an oral, irreversible inhibitor of EGFR that is FDA approved for first-line treatment of metastatic NSCLC in patients with del19 or L858R mutations. The LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) were phase III trials comparing the use of afatinib to standard chemotherapy in patients with stage IIIB/IV adenocarcinoma.

In both trials patients were randomized 2:1 to receive afatinib, 40 mg/day (oral) or chemotherapy. In the LL3 trial, the chemotherapeutic regimen was cisplatin/pemetrexed for up to 6 cycles while in the LL6 trial the chemotherapy was gemcitabine/cisplatin for up to 6 cycles. Thus the study arms were:

LL3• Afatinib, n = 230• Cisplatin/pemetrexed, n = 115

LL6• Afatinib, n = 242• Gemcitabine/cisplatin, n = 122

Enrollment criterion included the presence of an EGFRMUT and no prior treatment with either chemotherapy for advanced disease or treatment with an EGFR tyrosine kinase inhibitor (TKI). Patients were also required to have an ECOG status of 0-1. The LL3 trial enrolled 345 patients from a global

Table 1. Overall survival (OS) and overall response rate (ORR) of dacomitinib vs erlotinib.

Dacomitinib Erlotinib P Value

n = 439 n = 439

OS (months) 7.9 8.4 0.82

ORR 11.4% 8.2% 0.083

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population and the LL6 trial enrolled 364 patients from an Asian population. The primary endpoint of each study was PFS with ORR, DCR, and OS as secondary endpoints. The populations between the 2 studies were similar except for geographic location.

Earlier analysis of both LL3 and LL6 indicated an increased PFS with afatinib within the subpopulation of patients with activating EGFRMUT (del19 and L858R).10,11 However, OS was not significantly different than chemotherapy. Subgroup analysis demonstrated that afatinib was favored in patients harboring del19 mutations. This led to the combined analysis of LL3 and LL6 EGFRMUT populations that was presented at the 2014 ASCO Annual Meeting.

Yang et al presented a pooled analysis of patients with EGFRMUT from the LL3 and LL6 trials.12 Between the 2 trials, 631 patients with either del19 or L858R mutations were studied. Of these, 419 patients received afatinib and 212 received chemotherapy. Median follow-up was 36.5 months. Overall survival in the combined group was slightly increased with an OS of 27.3 months with afatinib vs 24.3 months with chemotherapy (Table 2). However, OS was increased by 11 months in the patient treatment group with del19 mutations while OS was statistically unchanged in the L858R mutation group (Table 3, Figure 4). These data suggest afatinib is an effective option with improvement in survival for patients with del19 mutations.

In summary, although OS was not significantly increased for the patient population with EGFR activating mutations in either of these studies alone, when the data was combined there was a small, but significant, increase in OS for these patients. Furthermore, the subset of patients with del19 activating mutations saw an increase of 11 months in OS indicating that afatinib could be very effective in treating this portion of the NSCLC population. The relative efficacy of afatinib compared to first generation EGFR TKI is being studied in a randomized study for patients with an activating mutation.

Figure 4. Overall survival analysis of EGFR mutation positive patients from the combined LL3 and LL6 data set.

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192173223236 217 160202230 38 22117145 90 6 1 05013172 63103119 95 5587113 9 13851 27 1 0 01443

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Median,monthsHR (95% CI),P value

39 423024 33 45 48 513627

128 111167183 154 91141181 20 116480 51 3 0 02770

69 618293 78 557586 14 93250 25 4 1 02040

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LUX-Lung 5 – Afatinib and Paclitaxel in Late Stage DiseaseThe LUX-Lung 5 open label phase III trial studied afatinib treatment alone in a non-randomized study of patients with progressive disease (Part A) followed by a comparison of afatinib plus paclitaxel to single-agent chemotherapy in Part B. Schuler et al presented an update of the Part B study (N = 202) results.13 The goal of this study was to determine whether continuation of an EGFR TKI beyond disease progression in combination with subsequent therapies is beneficial.

Patients with stage IIIB/IV disease, who had received at least 1 prior chemotherapy and failed erlotinib or gefitinib after 12 weeks or more of benefit were eligible for the non-randomized Part A portion of the study (N = 1154). Eligibility for Part B, reported here, was a successful benefit for greater than or equal to 12 weeks of afatinib treatment in Part A followed by disease progression (n = 202).

Patients in Part B were randomized 2:1 into 2 arms. The larger arm (n = 134) received afatinib (40 mg/day) plus paclitaxel (80 mg/m2/week). The second arm (n = 68) received single agent chemotherapy of the investigators choosing, although paclitaxel was preferred. The goal of the study was to determine if continuous EGFR inhibition was beneficial. Progression-free survival doubled from 2.8 months to 5.6 months in the afatinib plus paclitaxel arm over that in the chemotherapy arm (Table 4). This is the first demonstration that continuous EGFR inhibition provides a benefit in delaying disease progression; however, OS was not significantly changed. Subgroup analysis favored afatinib plus paclitaxel in all groups.

Table 2. Overall survival in patients with activating EGFR mutations after afatinib or chemotherapy.

LL3N = 307

LL6N = 324

CombinedN = 631

Afatinibn = 203

Chemotherapyn = 104

Afatinibn = 216

Chemotherapyn = 108

Afatinibn = 419

Chemotherapyn = 212

OS, months 31.6 28.2 23.6 23.5 27.3 24.3

HR (95% CI) 0.78 (0.58-1.06) 0.83 (0.62-1.09) 0.81 (0.66-0.99)

P value P = 0.1090 P = 0.1756 P = 0.0374

OS, overall survival; HR, hazard ratio; CI, confidence interval; LL3, LUX-Lung 3 trial; LL6, LUX-Lung 6 trial.

Table 3. Overall survival in patients with del19 EGFR mutations after afatinib or chemotherapy.

LL3N = 169

LL6N = 186

CombinedN = 355

Afatinibn = 112

Chemotherapy n = 57

Afatinibn = 124

Chemotherapy n = 62

Afatinibn = 236

Chemotherapy n = 119

OS months 33.3 21.1 31.4 18.4 31.7 20.7

HR (95% CI) 0.54 (0.36-0.79) 0.54 (0.44-0.94) 0.59 (0.45-0.77)

P value P = 0.0015 P = 0.0229 P = 0.0001

OS, overall survival; HR, hazard ratio; CI, confidence interval; LL3, LUX-Lung 3 trial; LL6, LUX-Lung 6 trial.

8 Table of Contents


There was a significant increase in ORR in the afatinib plus paclitaxel arm vs the chemotherapy arm (32.1% vs 13.2%, P = 0.0049). There was also a significant increase in DCR with afatinib plus paclitaxel (74.6% vs 45.6%, P < 0.0001).

Adverse effects experienced by greater than 20% of the patient population in the afatinib plus paclitaxel arm were diarrhea (53.8%), alopecia (32.6%), asthenia (27.3%), decreased appetite (22.0%), fatigue (20.5%), and rash (20.5%). Overall AEs were manageable and as expected. Peripheral neuropathy was similar for both groups. Afatinib plus paclitaxel patients had a higher discontinuation rate of 18.9% vs 6.7% for chemotherapy.

Overall, the study met the primary endpoint. Afatinib plus paclitaxel significantly prolonged PFS over chemotherapy alone in a patient population that had progressed with a previous EGFR TKI indicating that continuation of afatinib beyond progression might extend the efficacy of chemotherapy.

EGFR Inhibitors Targeting Resistant DiseasePatients treated with EGFR TKIs invariably develop resistance to treatment and subsequently experience disease progression. Acquired mutation in EGFR at T790M is a common cause of resistance.

Data for several third generation EGFR TKIs were presented at the 2014 ASCO Annual Meeting. These are all oral, irreversible inhibitors that specifically bind to both the activating mutant and resistant mutant forms (T790M) of EGFR while sparing the wild-type EGFR. This also minimizes the rash that frequently accompanies inhibition of wild-type EGFR. These are the first inhibitors reported to specifically address the population with acquired resistance where there are no approved treatments available.

AZD9291AZD9291 is a third generation, oral, irreversible, EGFR TKI and targets proteins resulting from both activating mutations in EGFR (del19 and L858R) as well as the resistance conferring mutation T790M while showing little effect on wild-type EGFR. Data for the phase I portion of the AURA trial were reported by Janne et al.14 Patients demonstrating acquired resistance to EGFR TKIs with measurable disease were enrolled in either dose escalation or dose expansion arms. Eligibility included radiological documentation of disease progression with previous EGFR TKI therapy. Additionally, the dose expansion arm required T790M testing from a current biopsy sample. Primary endpoints of the study were safety and tolerability, while secondary endpoints were pharmacokinetics (PK), maximum tolerated dose (MTD), and preliminary efficacy.

Table 4. Progression-free survival (PFS) and overall survival (OS) after treatment with afatinib + paclitaxel compared to chemotherapy alone.

Afatinib +Paclitaxel

Investigator Chemotherapy HR (95% CI) P Value

n = 134 n = 68

PFS, months 5.6 2.8 0.60 (0.43-0.85) 0.0031

OS, months 12.2 12.2 1.00 (0.70-1.43) 0.9936

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At the time of reporting, 232 patients were enrolled. Thirty-one of these were in the escalation arm while 201 were in the expansion arm. Median number of prior therapies for both arms was 3 and the median number of prior EGFR TKI therapies was 1. Asian patients comprised 71% and 63% of the escalation and expansion arms, respectively.

Patients received 20, 40, 80, 160, or 240 mg of AZD9291 orally once a day. The distribution of T790M mutations within the expansion cohort (n = 201) was 120 positive (T790M+), 56 negative (T790M-), and 25 were unknown due to sampling or test error.

While the ORR for the total patient population was 53% (n = 205), T790M+ patients had a higher ORR (64%) (n = 107) than total population while T790M- mutations exhibited a much lower ORR (22%) (n = 50) (Table 5). The overall DCR within the T790M+ population was 94% (n = 107). The longest response rate (RR) to date is > 9 months and ongoing and there was 1 complete response. Responses were detectable in most patients at the first imaging study performed after 6 weeks of therapy. There was no effect of immediate prior TKI therapy on the RR within the T790M+ population; however, there was a decrease in RR among T790M- patients with immediate prior TKI treatment. This indicates that the responses noted in the T790M- might be related to re-treatment with an EGFR inhibitor following an EGFR TKI-free interval. Analysis of PFS (Figure 5) is preliminary but clearly demonstrates a robust effect in T790M+ patient population.

In patients treated with the recommended dose of 80 mg/day (n = 74), 22% experienced AEs greater than grade 3, and there was a 4% discontinuation of treatment and no dose reductions. One case of grade 3 diarrhea was reported.

Breakthrough designation has been granted by the FDA for AZD9291 in metastatic T790M+ NSCLC demonstrating disease progression on previous EGFR TKI therapy. Phase II and III trials (AURA) with AZD9291 are ongoing.

Figure 5. Progression-free survival by T790M EGFR mutation status after AZD9291 treatment.

1.0

0.8

0.6

0.4

0.2

0.0

0.9

0.7

0.5

0.3

0.1

30 36120 18 42246

Prob

abilit

y of

Pro

gres

sion

-Fre

e Su

rviv

al T790M+ (95% CI)T790M- (95% CI)

Study Week

Table 5. Overall response rate (ORR) and overall disease control rate (ODCR) after AZD9291 treatment stratified by T790M mutation status.

Total Patient PopulationN = 205

T790M+n = 107

T790M-n = 50

ORR 53% 64% 22%

ODCR 83% 94% 56%

T790M+ contains the EGFR resistance mutation; T790M- does not harbor the EGFR resistance mutation.

10 Table of Contents


CO-1686CO-1686 is an oral, irreversible EGFR TKI that targets both activating and resistant mutant forms of EGFR with little to no effect on wild-type EGFR. The results of a phase I/II study of CO-1686 were presented at the 2014 ASCO Annual Meeting by Sequist et al.15

The phase I study enrolled patients with advanced NSCLC known to have an activating mutation and prior EGFR TKI therapy. Primary endpoints of the phase I study were safety and PK. The phase II study, TIGER X, is an expansion study and additionally required a T790M+ biopsy for enrollment. Primary endpoints for the phase II study are ORR and DOR per RECIST v1.1.

Between all arms of the study 120 patients were enrolled. The initial study used a free base form of the drug with doses up to 900 mg but transitioned to a hydrogen bromide (HBr) salt formulation later with 10 patients transitioning from the free base form. All current and planned studies use the HBr formulation, which has a favorable bioavailability profile. The number of patients treated with an efficacious dose (900 mg BID free base or ≥ 500 mg BID HBr formulation) was 72.

The 72 patients were stratified into 2 arms by the number of previous EGFR TKI therapies. The median number of previous therapies was 3 and the median number of prior TKIs was 2. One arm contained those patients with 1 prior EGFR TKI treatment and the other arm those patients with 2 or greater EGFR TKI. Within each arm patients received 500, 625, or 750 mg of CO-1686 (HBr) BID.

Within the T790M+ population (n = 40), the estimated ORR was 58%. The median PFS has not been reached; however, Kaplan-Meier estimates exceed 12 months (Figure 6). Some patients exhibited a CNS response to treatment though this was not universal and further study is needed. To date over 75% of the patients remain on the study.

The toxicity profile was characterized by nausea (35%) and impaired glucose tolerance/hyperglycemia in 53% of patients. Issues with glucose metabolism were controlled by dose reduction or oral medication, predominantly metformin. Although a high proportion of patients experienced glucose metabolism effects, no patients discontinued the

study due to this AE. Adverse effects indicating targeting of wild-type EGFR, such as rash, occurred in only 4% of the population and were grade 1 events. The other major AE was diarrhea in 24% of the population.

Figure 6. Kaplan-Meier estimate of progression-free survival after CO-1686 therapy in patients with T790M EGFR mutation.

1.0

0.8

0.6

0.4

0.2

0.0

0.9

0.7

0.5

0.3

0.1

150 270180 300600 90 210120 24030 330 360 390 420

15 (6) 5 (7)8 (7) 4 (7)30 (5)40 (0) 26 (6) 6 (7)18 (6) 6 (7)39 (1) 2 (7) 1 (7) 1 (7) 0 (7)

Surv

ival

Pro

babi

lity

PFS (days)

Censored

At Risk (events)

Median PFS not reached;current estimate > 12 monthsN = 40

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Further studies are enrolling or planned. TIGER X continues its expansion and TIGER 1 and TIGER 2 are phase II studies comparing CO-1686 with erlotinib as a first-line treatment or as second-line treatment after prior TKI, respectively. The planned phase III TIGER 3 trial will compare CO-1686 to chemotherapy as a second-line treatment. CO-1686 has also been given the FDA breakthrough designation.

HM61713A phase I study with another novel third generation inhibitor was reported by Kim et al.16 Similar to AZD9291 and CO-1686, HM61713 is an oral agent that targets mutant EGFR proteins. Enrollment in the study required patients to have been previously treated with an EGFR TKI and the primary endpoints were safety and tolerability with secondary endpoints of PK and efficacy.

Patients eligible for the dose escalation trial (N = 35) must have progressed on at least 2 prior treatments, one of which was an EGFR TKI and were given doses of HM61713 ranging from 50 mg to 800 mg. The expansion trial (N = 83) was stratified into 2 arms based on timing of most recent TKI therapy. Arm A patients were within 4 weeks of progression on a previous EGFR TKI (n = 42) while Arm B patients experienced progression ≥ 4 weeks prior to entering this study (n = 41). The median number of prior therapies was 2. Both arms received a dose of 300 mg per day although the MTD has not been determined yet and an 800 mg dose escalation cohort is currently ongoing. Within the expansion portion of the trial 57.8% of patients were T790M+ with 64.3% in arm A and 51.2% in arm B.

Overall, the DCR was 61.9% for Arm A and 73.2% for Arm B. As seen in Table 6 the majority of the responses were in individuals who are T790M+ with a RR of 29.2% vs 11.8% in those that are T790M-. Despite the MTD not being reached there were 2 cases of drug limiting toxicity (DLT) in escalation dose cohort.

Adverse effects reported for greater than 10% of the patients were nausea (32.2%), skin exfoliation (26.3%), rash (23.7%), diarrhea (21.2%), and decreased appetite (21.2%). The majority of AEs were grade 1 or 2 and 2 patients discontinued due to AEs.

Table 6. Response rate and disease control rate after treatment with HM61713.

Expansion Cohort T790M+ T790M-

Arm A< 4 wk Since

EGFR TKI

Arm B≥ 4 wk Since

EGFR TKI

Total Arm A< 4 wk Since

EGFR TKI

Arm B≥ 4 wk Since

EGFR TKI

Total

N = 83 n = 27 n = 21 n = 48 n = 15 n = 19 n = 34

Partial Response 18 8 6 14 2 2 4

Confirmed 15 7 5 12 1 2 3

Unconfirmed 3 1 1 2 1 1

Stable Disease 38 10 12 22 6 9 15

Progressive Disease 27 9 3 12 7 8 15

Response Rate 21.7% 29.6% 28.6% 29.2% 13.3% 10.5% 11.8%

Disease Control Rate 67.5% 66.7% 85.7% 75.0% 53.3% 57.9% 55.9%

T790M+ contains the EGFR resistance mutation; T790M- does not harbor the EGFR resistance mutation.



In summary, HM61713 provided an increase in DCR and RR in patients with T790M mutations and some benefit for those patients resistant to EGFR TKI therapy without T790M mutations.

TARGETING VEGFRThe vascular epithelial growth factor (VEGF) and its receptors (VEGFR) are involved in angiogenesis. Bevacizumab is an antibody to VEGF which was FDA approved for the treatment of NSCLC in 2006 and remains the only approved anti-angiogenesis treatment in NSCLC. Encouraging data for a phase III trial of an anti-VEGFR-2 antibody, ramucirumab, were presented at the 2014 ASCO Annual Meeting.

REVEL Trial – Ramucirumab Plus Docetaxel as Second-Line TreatmentThe REVEL trial assessed the combination of an antibody targeting VEGFR-2 with chemotherapy. Perol reported on behalf of the study group the results of this large phase III, randomized, double-blinded trial of docetaxel with ramucirumab (RAM + DOC) versus docetaxel plus placebo (PL + DOC).17 Ramucirumab is a human monoclonal antibody that binds to the extracellular portion of VEGFR-2. It was recently FDA approved for use as second-line treatment in advanced gastric cancer.

The primary endpoint of the REVEL trial was OS with secondary endpoints of PFS and ORR. The study was designed to show a 1.7-month improvement in OS.

The study enrolled 1253 patients with stage IV NSCLC encompassing both squamous and non-squamous types. Patients were allowed to have had previous treatment with bevacizumab but not with prior docetaxel or monotherapy EGFR TKI. Patients were randomized into the 2 arms with stratification for ECOG status PS 0 vs 1; gender; prior maintenance therapy; and East-Asia vs the rest of the world. Patients received 75 mg/m2 docetaxel once every 3 weeks (n = 628) alone or in combination with 10 mg/kg ramucirumab (n = 625). Although the majority of the patients had non-squamous histology, 25% of the ramucirumab arm and 27.4% of the placebo arm had squamous histology.

For patients on the RAM + DOC arm both the PFS (4.5 months vs 3.0 months, P < 0.0001) and the OS were superior (10.5 months vs 9.1 months, HR 0.857, P = 0.0235) (Figure 7). The tumor RR was also improved with the combination regimen (22.9% vs 13.6%) (Table 7). There were 3 complete responses in the RAM + DOC population and 2 in the PL + DOC population.

Figure 7. Progression-free survival (A) and overall survival (B) in response to treatment with docetaxel (DOC) with and without ramucirumab (RAM).

100

60

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0

40

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12 156 930 18 33 3627 302421

59 38204 120383628 11 0 03 03737 17172 95301625 9 0 02 034

Prog

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Free

Sur

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l (%

)

Survival Time (months)

RAM + DOCPL + DOCCensored

Number at RiskRAM + DOCPL + DOC

RAM + DOCPL + DOCRAM + DOC vs PL + DOCStratified HR (95% CI) = 0.762 (0.677-0.859)Stratified log rank P < 0.0001

4.5 (4.2-5.4)3.0 (2.8-3.9)

11.1%6.7%

Median (95% CI) Censoring RateA. 100

60

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80

12 156 930 18 33 3627 302421

231 156415 329527628 103 2 023 114570197 129386 306501625 86 0 023 93656

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(%)

Survival Time (months)

RAM + DOCPL + DOCCensored

Number at RiskRAM + DOCPL + DOC

RAM + DOCPL + DOCRAM + DOC vs PL + DOCStratified HR (95% CI) = 0.857 (0.751-0.979)Stratified log rank P = 0.0235

10.5 (9.5-11.2)9.1 (8.4-10.0)

31.8%27.0%

Median (95% CI) Censoring RateB.

13Table of Contents


Overall grade 3 or greater AEs were similar in the 2 arms (78.9% vs 71.8%). Grade 3 or greater AEs in the ramucirumab arm included neutropenia (48.8% vs 39.8%) and febrile neutropenia (15.9% vs 10.0%). Thrombocytopenia grade 1/2 was also increased with ramucirumab (10.5% vs 4.5%). Grade 5 events were similar between the 2 arms (5.4% vs 5.8%).

The gains in PFS, OS, ORR, and DCR were statistically significant demonstrating that the addition of ramucirumab to docetaxel provides a patient benefit. This is the first study to demonstrate improved survival with a combination regimen in the salvage therapy setting. It is also the first study to demonstrate improved survival with the use of a VEGFR inhibitor added to chemotherapy in patients with squamous histology.

TARGETING VEGF AND EGFR Erlotinib Plus Bevacizumab for First-Line TherapyEGFR TKI monotherapy (erlotinib, gefitinib) provides a PFS of 9.2 to 13.7 months in EGFRMUT population.18,19 The JO25567 study, presented by Kato et al, compared erlotinib in combination with bevacizumab to erlotinib alone in chemotherapy-naïve patients as a first-line therapy.20

Patients with chemotherapy-naïve stage IIIB or IV EGFRMUT positive NSCLC were eligible for this phase II open label randomized study. Patients with squamous NSCLC, brain metastases, or EGFR T790M mutations were excluded. The primary endpoint of the study was PFS with secondary endpoints of OS, ORR, safety, and quality of life assessments.

A total of 154 patients were enrolled and randomized into 2 well matched treatment arms (n = 77 each). Two patients withdrew early from the erlotinib/bevacizumab arm and were not included in the analysis. Progression-free survival was significantly improved in the erlotinib/bevacizumab arm (P = 0.0015) (Figure 8). Both patients with del19 or L858R mutations benefit from the combined treatment (Table 8).

Table 7. Objective response rate (ORR) and disease control rate (DCR) after treatment with docetaxel with or without ramucirumab.

RAM + DOCn = 628

PL + DOCn = 625

P Value

Complete Response, n (%) 3 (0.5) 2 (0.3)

ORR %, (95% CI) 22.9 (19.7-26.4) 13.6 (11.0-16.5) < 0.001

DCR %, (95% CI) 64.0 (60.1-67.8) 52.6 (48.6-56.6) < 0.001

RAM, ramucirumab; DOC, docetaxel; PL, placebo.

Table 8. Median PFS in months categorized by EGFR mutation.

EGFR Mutation del19 L858R

TreatmentErlotinib/

Bevacizumab n = 40

Erlotinibn = 40

Erlotinib/Bevacizumab

n = 35

Erlotinibn = 37

Median PFS,months

18.0 10.3 13.9 7.1

HR (95% CI) 0.41 (0.24-0.72) 0.67 (0.38-1.18)

PFS, progression-free survival.



Overall response rate was not significantly different between the 2 arms (69.3% vs 63.6%, P = 0.4951); however, the DCR was significantly higher in the erlotinib/bevacizumab group (99% vs 88% P = 0.0177). The median DOR of erlotinib/bevacizumab was 13.3 months vs 9.3 months and there were 3 complete responses in the erlotinib/bevacizumab arm and 1 in the erlotinib alone arm.

The safety profile of the combination treatment raised no new concerns; however, there were several types of AEs that were more common with combination treatment. The majority

of all patients experienced rash (99% in both arms); however, greater than or equal to grade 3 rash was more common in the erlotinib/bevacizumab patients (25% vs 20%). In addition to rash, hypertension and proteinuria were higher in this population with more incidences of greater than grade 3 hypertension with erlotinib/bevacizumab (60% vs 10%). Hypertension was managed with medication and there were no discontinuations due to this AE. The leading causes of discontinuation of therapy due to AEs were proteinuria (15%) and hemorrhagic events (12%) with a discontinuation of bevacizumab in 41% and an overall discontinuation rate of 16% vs 18% (erlotinib/bevacizumab vs erlotinib).

The addition of bevacizumab to erlotinib as a first-line response increases PFS in a patient population containing activating EGFRMUT. The OS data is immature and will be reported at a later time. These promising data are being verified by another ongoing study in the United States.

ALK GENE REARRANGEMENTChromosomal rearrangements of the ALK gene and the echinoderm microtubule-associated protein-like 4 (EML4) gene are found in 3-7% of NSCLC cases.21 These rearrangements confer on this subset of NSCLC, known as ALK positive (ALK+) NSCLC, the sensitivity to ALK inhibitors. Currently 2 treatments targeting ALK+ cancers are approved by the FDA, crizotinib and very recently, ceritinib. Crizotinib is approved for patients with metastatic NSCLC who are ALK+ while ceritinib is approved for ALK+, metastatic, NSCLC in patients who have progressed on or are intolerant of crizotinib. Patients treated with crizotinib frequently acquire resistance to the drug.22 Ceritinib is effective in tumors that have acquired resistance to crizotinib as well as a first-line agent.23

PROFILE 1014 – Crizotinib as First-Line Therapy in ALK+ NSCLCMok et al presented data from the phase III PROFILE 1014 study that compared the ALK inhibitor crizotinib with chemotherapy as first-line treatment.24 Patients (N = 343) were randomized to receive either 250 mg crizotinib twice daily (n = 172) or chemotherapy (n = 171) consisting of pemetrexed 500 mg/m2 with either cisplatin (75 mg/m2) or carboplatin AUC 5-6 every 3 weeks for up to 6 cycles.

Figure 8. Progression-free survival determined by independent review after treatment with first-line erlotinib (E) plus bevacizumab (B) or erlotinib alone.

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0.010 1812 2040 6 148 162 22 24 26 28

53 2049 136975 64 3860 3072 8 4 4 029 1224 105777 44 2139 1866 5 2 1 0

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abilit

y

Time (months)

EBE

Number at Risk

9.7 16.0

EB E16.0 9.7

0.54 (95% CI: 0.36-0.79)0.0015

Median (months)HR

P value**Log rank test, two-sided.

15Table of Contents


Eligibility criteria included advanced, recurrent, or metastatic NSCLC (non-squamous) and ALK+ with measurable disease. Patients could have no prior systemic treatment for advanced disease, and must have ECOG PS 0-2 scores. The arms of the study were well matched.

Overall there was a significant increase in PFS in the crizotinib arm (Figure 9). Objective response rate determined by independent radiologic review was also significantly increased from 45% to 74% in the crizotinib arm (Table 9). The median DOR was 49.0 weeks with crizotinib vs 22.9 weeks for chemotherapy.

There was a higher incidence of elevated transaminases and in particular grade 3/4 events in the crizotinib arm (14% vs 2%). In the chemotherapy arm higher levels of grade 3/4 neutropenia were observed (15% in chemotherapy vs 11% in crizotinib). Overall there were higher levels of vision disorders, diarrhea, edema, vomiting and constipation in the crizotinib arm although these were predominantly grade 1 or 2 events. Only 1 grade 5 AE was reported to be related to treatment in a patient that had crossed over to the crizotinib arm. Discontinuation of therapy related to AEs was 5% in the crizotinib arm and 8% in the chemotherapy arm.

In summary, the PROFILE 1014 trial met its primary endpoint of prolonging PFS with first-line crizotinib versus chemotherapy. Crizotinib therapy also provided an increased RR over chemotherapy.

ASCEND-1 Trial – Ceritinib in Advanced Stage ALK+ NSCLCThe initial goal of the ASCEND-1 phase I trial was to determine the MTD followed by an expansion of enrollment. The primary endpoints of this expansion were anti-tumor efficacy and safety. The trial was open to patients with advanced stage ALK+ cancers and 255 were enrolled. Of those, 246 had NSCLC and are the focus of this report by Kim et al.25

All patients were treated with 750 mg of ceritinib daily. Median follow-up was 7.0 months and 52% are still on therapy. Within the NSCLC population, n = 83 were naïve to previous ALK inhibitor treatment while n = 163 had previously received crizotinib. In patients previously treated with an ALK inhibitor, 91% developed progressive disease and 77% of these had an ALK inhibitor as their last prior treatment. The study population was heavily pre-treated with 42.7% of patients receiving more than 3 prior treatments.

Figure 9. Progression-free survival comparing crizotinib treatment to chemotherapy in advanced stage patients.

100

60

20

0

40

80

20 2510 1550 30 35

19 765 38120172 1 02 136 12105171 0 0

PFS

Prob

abilit

y (%

)

Time (months)Number at RiskCrizotinib

Chemotherapy

Events, n (%)Median, monthsHR (95% CI)P

Crizotinib(n = 172)

Chemotherapy(n = 172)

100 (58) 137 (80)10.9

0.45 (0.35-0.60)< 0.0001

7.0

Table 9. Objective response rate and duration of response in advanced stage patients after treatment with crizotinib or chemotherapy.

Crizotinib Chemotherapy P Value Treatment Difference

95% CI

n = 172 n = 171

ORR 74% 45% < 0.0001 29% 20-39

DOR, weeks 49.0 22.9

ORR, objective response rate; DOR, duration of response.



Figure 10. Ceritinib therapy progression-free survival (PFS) in patients with ALK rearrangements based on prior treatment with ALK inhibitors (ALKi).

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15 1860 9 123

2 058163 29 101035 03883 22 11637 096246 51 21166

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Median: non-estimable(95% CI 8.31, non-estimable)PFS rate at 12 months: 61.3%

Number of Patients Still at RiskNSCLC with prior ALKi

NSCLC ALKi naïveAll NSCLC

ALK inhibitor treated (n = 163)ALK inhibitor naïve (n = 83)All (N = 246)

Median: 8.21 months(95% CI 6.70, 10.12)PFS rate at 12 months: 39.1%Median: 6.90 months(95% CI 5.39, 8.41)PFS rate at 12 months: 28.4%

Patients who had been previously treated with ALK inhibitor therapy had lower DOR (7.39 months) than the total study population (9.69 months) (Table 10). Patients who were ALK inhibitor-naïve had a better DOR rate of 65.2% compared to either the entire study population (33.0%) or the ALK inhibitor-treated population (17.9%).

ALK inhibitor-naïve patients also had a higher ORR than ALK inhibitor-treated patients (Table 11). The PFS rate for the total study population was 61.3% with a median PFS of 8.21 months (Table 11 and Figure 10).

Patients were screened for brain metastases at baseline with 124 patients screening positive. Objective response rate, DOR, and PFS for the 125 patients with brain metastases were similar to those in the total study population. Within this subpopulation 10 patients pre-treated with an ALK inhibitor and 4 patients who were ALK inhibitor-naïve had measureable (by RECIST 1.0) brain metastases. Overall intracranial response rate (OIRR) was 50% in these 14 patients with an OIRR of 40% in ALK inhibitor-pre-treated patients and 75% in ALK inhibitor-naïve patients, including 1 complete response.

Major AEs reported were diarrhea (86%), nausea (80%), vomiting (60%), fatigue (52%), most of which were grade 1 or 2. Additionally 80% experienced an increase in alanine aminotransferase (ALT) level, of which 27% were grade 3/4 and 75% demonstrated an increase in aspartate aminotransferase (AST) with 13% grade 3/4. Dose reductions were required in 59%

of the patients due to AEs and 9.4% discontinued treatment due to AEs. Ten patients (3.9%) developed interstitial lung disease/pneumonitis and 1 of these patients died. Two other patients discontinued treatment and the remaining patients were given dose reductions or dose interruptions.

Table 10. Duration of response (DOR) in ALK+ patients treated with ceritinib.

ALK Inhibitor-Treated ALK Inhibitor-Naïve Total

n = 89 n = 55 N = 144

DOR, months 7.39 NE 9.69

DOR rate at 12 months 17.9% 65.2% 33.0%

NE, not estimable.

Table 11. Overall response rate (ORR) and progression-free survival (PFS) in an ALK+ patient population treated with ceritinib.

ALK Inhibitor-Treated ALK Inhibitor-Naïve Total

n = 163 n = 83 N = 246

ORR 89 (54.6%) 55 (66.3%) 155 (58.5%)

PFS, months 6.90 NE 8.21

PFS rate at 12 months 28.4% 39.1% 61.3%

PFS, progression-free survival; NE, not estimable.

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Ongoing studies of ceritinib include phase III trials of ceritinib vs chemotherapy in patients previously treated with crizotinib and chemotherapy (NCT01828112) or in chemotherapy and crizotinib-naïve patients (NCT01828099). Phase II trials are also progressing.

IMMUNOTHERAPYPD-1 and PD-L1The programmed cell death 1 protein (PD-1) is an immune checkpoint receptor, which is expressed by activated T-cells.26 PD-1 interacts with the ligands PD-L1 and PD-L2 and then down-regulates T-cell activation. Some tumors including NSCLC, express PD-L1, which then binds to the PD-1 receptor and suppresses T-cell function thus preventing T-cells from attacking the tumor.27,28 Several different antibody-based therapies targeting either PD-1 or PD-L1 in NSCLC were presented at the 2014 ASCO Annual Meeting and are described in the next section.

KEYNOTE 001 – Pembrolizumab in Advanced MalignanciesKEYNOTE 001 was designed as a phase I 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 non-cytotoxic. The primary endpoint of the NSCLC portion of the study is RR as determined by both RECIST v1.1 and by investigator assessment (irRC).

The data reported by Rizvi et al was for a patient population with stage IV disease and treatment naïve.29 Further criteria for enrollment were EGFR and ALK mutation negative (although the first 11 patients enrolled were allowed to have such mutations) and tumors positively expressing PD-L1. A portion of the study was devoted to validating a prototype assay for PD-L1 expression using an antibody compared to a clinical trial assay using the same antibody. Expression was scored as a percentage of PD-L1 expressing tumor cells and a score of greater than or equal to 1% as assessed by the prototype assay was required for entry into the study. Imaging was every 9 weeks.

Eighty-four treatment-naïve patients were enrolled and of these 73 had evaluable tumor samples for PD-L1 screening. After screening, 57 patients were deemed to have PD-L1 expression (78%), and, of these, 45 were eligible for the study by imaging. Patients were randomized 1:1 to receive 10 mg/kg pembrolizumab every 2 weeks vs every 3 weeks. The first 11 patients enrolled in the study were randomized to receive 2 mg/kg or 10 mg/kg every 3 weeks.

The patient population was predominantly former smokers (69%), had a median age of 70, and included a higher proportion of males (56% vs 44%). Of those screened, 1 patient had an EGFR mutation (1/41) and 1 had ALK rearrangement (1/38). The majority of the population had non-squamous NSCLC (76% vs 22%) with 2% (n = 1) having unknown histology. At the time of data cutoff 25 patients were still on treatment.

The ORR determined by RECIST v1.1 was 26% and 47% as determined by irRC (Table 12). The DCR was 64% by central review and 78% by irRC and the median DOR has not yet been reached. At the time of data analysis, the median PFS was 27.0 weeks by RECIST criteria and 37.0 weeks by investigator review. The majority of responders remain on treatment (64% by RECIST and 85% by irRC).



Treatment-related AEs that resulted in discontinuation included 1 case of grade 3 pneumonitis and 1 grade 2 case of acute kidney injury. Overall discontinuation was 18% including disease progression and either patient or physician choice. Grade 1/2 AEs were experienced by 80% of the treatment population with fatigue (22%) and pruritus (13%) being most common.

Upcoming trials of pembrolizumab include the KEYNOTE-024 phase III study comparing pembrolizumab monotherapy with platinum based doublet therapy in treatment-naïve, PD-L1 expressing, metastatic patients.

CA209-012 Study – Nivolumab Alone or in Combination With Erlotinib or IpilimumabThe CA209-012 study was designed to evaluate the safety, tolerability, and clinical activity of nivolumab either alone or in combination with other agents. Nivolumab is a fully humanized monoclonal IgG4 antibody directed against the PD-1 receptor. By blocking the receptor the antibody blocks the activation of PD-1 by PD-L1 or PD-L2 and thus blocks PD-1 mediated suppression of T-cells. Three cohorts were presented: the use of nivolumab as monotherapy in a first-line treatment setting; nivolumab in combination with ipilimumab in never treated patients; and nivolumab with erlotinib. These separate cohorts were part of a multiple arm phase I trial. Endpoints of a 24-week PFS rate and ORR are reported.

Patients enrolled in CA209-012 had stage IIIB or IV NSCLC and were chemotherapy-naïve. Additionally patients had an ECOG status of 0-1. All patients were treated until progressive disease or unacceptable toxicity occurred. The efficacy of treatment was evaluated by RECIST v1.1. Additional exploratory assessments of PD-L1 expression were evaluated by IHC with a cut off of 5% expressing cells.

Data for nivolumab monotherapy were presented by Gettinger et al.30 Patients received nivolumab at 3 mg/kg every 2 weeks. Twenty patients were enrolled in this portion of the study. The patient population was divided between squamous (45%) and non-squamous (50%) histology.

Table 12. Overall response rate (ORR) and disease control rate (DCR) after treatment with pembrolizumab as measured by RECIST and investigator review.

RECIST v1.1 Central Review irRC, Investigator Review

ORR DCR ORR DCR

Pembrolizumab dose n n (%)(95% CI)

n (%)(95% CI)

n n (%)(95% CI)

n (%)(95% CI)

2 mg/kg Q3W 6 2 (33%)(4%-78%)

3 (50%)(12%-88%)

6 4 (67%)(22%-96%)

5 (83%)(35%-100%)

10 mg/kg Q3W 20 4 (20%)(6%-44%)

14 (70%)(46%-88%)

22 10 (46%)(24%-68%)

18 (82%)(60%-95%)

10 mg/kg Q2W 16 5 (31%)(11%-59%)

10 (63%)(35%-85%)

17 7 (41%)(18%-67%)

12 (71%)(44%-90%)

Total 42 11 (26%)(14%-42%)

27 (64%)(48%-78%)

45 21 (47%)(32%-62%)

35 (78%)(63%-89%)

Q3W, every 3 weeks; Q2W, every 2 weeks.

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The study showed a 30% (n = 6/20) ORR with 2 patients having a complete response, 1 each with squamous and non-squamous histology, and 1 additional patient with an unconfirmed complete response (Table 13). PD-L1 expression in tumor samples appears to correlate with response with an ORR of 50% in patients whose tumors express PD-L1. The ORR was higher for patients with non-squamous histology (80% versus 20%).

The PFS rate was 60% at 24 weeks with a median PFS of 36.1 weeks. The 1-year OS rate was 75% and median OS was not yet reached.

Treatment-related AEs were experienced by 85% of the patients and four patients experienced grade 3/4 treatment-related AEs. These included increased AST, ALT, hyperglycemia, rash, and cardiac failure. Two patients discontinued treatment. No pneumonitis was observed.

Nivolumab Plus Erlotinib Rivzi et al presented data from the nivolumab plus erlotinib cohort (N = 21).31 This population was 62% female, 95% had stage IV disease, and 95% had previously been treated with erlotinib. All participants had EGFR mutations comprised of del19 (57%), L858R (43%), T790M (33%), and S768I (5%). The dosing regimen was 3 mg/kg nivolumab (IV) every 2 weeks and 150 mg/day of erlotinib (oral).

The ORR was 19% (Table 13) with 43% exhibiting stable disease and a median follow-up time of 71.9 weeks. Within the patients resistant to erlotinib therapy, 15% achieved a partial response. The single patient not previously treated with erlotinib achieved a near complete response at the time of data cut-off with duration of 72.3 weeks and ongoing. The median PFS was 29.4 weeks.

All patients experienced treatment-related AEs but grade 3 AEs were low (24%). Grade 3 events were diarrhea (n = 2), increased AST (n = 2), increased ALT (n = 1), and weight loss (n = 1). No pneumonitis or grade 4 or 5 AEs were reported. Discontinuation as a result of treatment-related AEs was 19%.

Nivolumab Plus Ipilimumab Antonia et al presented data from the nivolumab plus ipilimumab portion of the trial (N = 49).32 Patients were separated by histology (squamous, n = 18 and non-squamous, n = 31). The majority of the patients had stage IV disease (range 88-100%). The majority of the patients tested were EGFRMUT negative.

Table 13. Objective response rate and median PFS reported with nivolumab treatment alone and in combination with either erlotinib or ipilimumab.

Nivolumab Nivolumab + Erlotinib

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg

Squamous Non-Squamous Squamous Non-Squamous

N = 20 N = 21 n = 9 n = 15 n = 9 n = 16

ORR 30% 19% 11% 13% 33% 13%

PFS, weeks 36.1 29.4 8.9 32.9 20.6 9.9



Patients of each histological type were randomized into 2 treatment arms. Treatment consisted of an induction phase of 21-day cycles dosing every 3 weeks with nivolumab and ipilimumab. Patients were then moved to monotherapy nivolumab at 3 mg/kg every 2 weeks after 4 cycles. The treatment cohorts were:

• Squamous: 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (n = 9)• Non-squamous: 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (n = 15)• Squamous: 3 mg/kg nivolumab plus 1 mg/kg ipilimumab (n = 9)• Non-squamous: 3 mg/kg nivolumab plus 1 mg/kg ipilimumab (n = 16)

The median follow-up time was 38.1 months and the ORR ranges from 11-33% (Table 13). The median PFS ranged from 8.9 to 32.9 weeks with an average for the 1 mg/kg nivolumab plus 3 mg/kg ipilimumab arm of 16.1 weeks versus 14.4 weeks for the 3 mg/kg nivolumab plus 1 mg/kg ipilimumab arm. A median OS of 44.3 weeks was reached in the squamous, 1 mg/kg nivolumab plus 3 mg/kg ipilimumab arm. No other arms reached a median OS. There are ongoing responses in 75% of patients.

The investigators tested 38 patient tumor samples for PD-L1 expression and determined that 16 of the samples were PD-L1+ and 22 were PD-L1-. The positive patients were found in both squamous (n = 7) and non-squamous samples (n = 9). Median PFS was similar for PD-L1+ samples (14.4 weeks) and PD-L1- samples (13.6 weeks).

Treatment-related AEs of grade 3/4 were observed in 49% of the study population. The most commonly reported grade 3/4 AEs were pneumonitis (6%), diarrhea (10%), colitis (8%), and increased ALT (8%) and AST (8%). Grade 3/4 events were more common in the induction phase of the study than in the monotherapy maintenance phase. Over the course of the study, 35% of patients discontinued therapy due to treatment-related AEs.

An additional treatment arm (n = 31) receiving 1 mg/kg nivolumab plus 1 mg/kg ipilimumab has been added to the study.

Overall results from these studies indicate that nivolumab may be a feasible treatment option both as monotherapy and as combined therapy with either erlotinib or ipilimumab. PD-L1 expression may be required for maximum efficacy as a monotherapy, but the data suggests that it may not be required in combination with ipilimumab. Additionally, the study indicates that in combination with erlotinib, nivolumab can be safe and effective in patients with acquired erlotinib resistance. Phase II and III trials are ongoing.

MEDI4736 – Anti PD-L1 Antibody Therapy in Solid TumorsPD-L1 is one of the ligands for PD-1. MEDI4736 is an engineered human antibody against PD-L1 that is designed to minimize cytotoxicity. Brahmer et al reported on a phase I dose escalation and expansion cohort of patients with NSCLC as part of a larger trial focusing on maximum tolerable dose, safety, and efficacy of MEDI4736 in solid tumors.33

Key eligibility criteria were advanced disease and ECOG performance status of 0-1. Prior anti –CTLA-4 therapy was permitted but prior anti PD-1 or anti PD-L1 therapy was not. A total of 155 patients with NSCLC have been treated with MEDI4736. The majority of patients had non-squamous histology (58%), were former or current smokers (82%), and had been treated with at least 1 prior therapy (99%).

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In the expansion cohort patients (n = 143) were treated with 10 mg/kg of MEDI4736 (IV) every 2 weeks for 1 year. Doses within the escalation arm (n = 12) of the study were 0.1, 0.3 1.0, 30, and 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks.

Median follow-up was 6 weeks in non-squamous and 6.1 weeks in the squamous NSCLC patient population. The majority of the patients had not reached the 12-week tumor assessment. PD-L1 activity was measured and correlated with response using RECIST criteria (Table 14). Of the patients reaching the 12-week point the ORR was 16% (9/58) and the DCR was 35% (20/58).

Among the total population 25% of the patients experienced grade 3/4 AEs and 23% experienced serious AEs regardless of relation to the experimental treatment. Based upon investigator evaluation, 3% of the grade 3/4 AEs and 1% of the serious AEs were treatment related. Grade 3/4 events included fatigue (7%), nausea (5%), vomiting (5%), arthralgia (4%), and rash (4%).

SUMMARYThe 2014 ASCO Annual Meeting provided a number of insights into treatment of NSCLC. Overall, there are promising new therapies for the treatment of NSCLC. In the particularly difficult to treat squamous NSCLC population, first-line treatment with necitumumab provided a small but significant increase in OS and PFS.

For the NSCLC population as a whole, the anti-angiogenesis antibody, ramucirumab, in conjunction with docetaxel, provided a positive benefit as a second-line therapy. The use of erlotinib as an adjuvant therapy in NSCLC was discouraged by the phase III RADIANT trial although there are indications from this trial and the SELECT trial that adjuvant erlotinib may be beneficial in the subpopulation of patients with EGFRMUT. Dacomitinib proved to be non-superior to erlotinib as a salvage therapy.

For patients with EGFRMUT NSCLC and in particular those patients with resistant disease, several third generation EGFR TKI (AZD9291, CO-1686, HM61713), show promising results and 2 of these have received FDA breakthrough status. The combined data from the LL3 and LL6 trials indicate favorable efficacy for afatinib as a first-line treatment in EGFRMUT NSCLC. Targeting both EGFR and VEGF with erlotinib plus bevacizumab increased the PFS of EGFRMUT patients.

The use of crizotinib as a first-line therapy is indicated in ALK+ NSCLC and the addition of ceritinib to the armamentarium for ALK+ NSCLC provides further options for those patients. In particular the ability of ceritinib to potentially target brain metastases was promising.

Finally, preliminary data for several immunotherapies was very encouraging. The CA209-012 study of nivolumab alone and in combination provided evidence of improved PFS in several different patient populations. Two other immunotherapies also appear promising: MEDI4736 (anti-PD-L1) and pembrolizumab. This continues to be an area of intense investigation.

Table 14. Week 12 objective response rate by RECIST after MEDI4736 treatment.

MEDI4736

10 mg/kg Q2W All doses

Response evaluable 13% (6/47) 16% (9/58)

PD-L1+ 39% (5/13) 25% (5/20)

PD-L1- 5% (1/19) 3% (1/29)

Q2W, every 2 weeks.



REFERENCES1. Thatcher N, Hirsch FR, Szczesna A, et al. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC)

chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8008.

2. Shepherd FA, Pereira JR. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-132.3. Mok TSK, Wu Y-L, Yu C-J, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as

first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(30):5080-5087. 4. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a

multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11(6):521-529. 5. 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): RADIANT results [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 7501.

6. 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 (suppl 15). Abstract 7513.

7. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 7514.

8. Ramalingam SS, Janne PA, Mok T, et al. Randomized, double-blinded study of dacomitinib, an irreversible pan-human epidermal growth factor receptor (HER) inhibitor, versus erlotinib for second-line/third-line therapy of locally advanced/metastatic non-small cell lung cancer (ARCHER 1009) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8018.

9. Shi Y, Au JS-K, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non–small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154-162.

10. Sequist LV, Yang JC-H, 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.

11. Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine 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.

12. Yang JC-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8004.

13. Schuler MH, Yang C-H, Park K, et al. Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatanib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatanib – LUX-Lung 5 (LL5) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8019.

14. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8009.

15. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8010.

16. Kim D-W, Lee DH, Kang JH, et al. Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8011.

17. Perol M, Ciuleanu T-E, Arrieta O, et al. REVEL: a randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy [abstract]. J Clin Oncol. 2014;32(suppl 18). Abstract LBA8006.

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18. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121-128.

19. Zhou C, Wu Y-L, 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.

20. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer (NSCLC): an open-label randomized trial [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8005.

21. 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.

22. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17.

23. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-1197. 24. Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts)

with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8002.

25. Kim D-W, Mehra R, Tan DS-W, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8003.

26. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 27. Chen Y, 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. 28. 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. 29. Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced

non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8007.30. Gettinger SN, Shepherd FA, Antonia SJ, et al. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in

advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8024.

31. Rizvi NA, Chow LQM, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8022.

32. Antonia SJ, Gettinger SN, Chow LQM, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8023.

33. Brahmer JR, Rizvi NA, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC [abstract]. J Clin Oncol. 2014;32(suppl 15). Abstract 8021.

Advances in the Management of Lung Cancer: Highlights from the 2014 ASCO Annual Meeting

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