Novel Therapies for the Treatment of Non-small Cell Lung Cancer

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1 Novel Therapies for the Treatment of Non-small Cell Lung Cancer Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Clinical Associate Director, Lung SPORE Co-Director, UPMC Lung Cancer Center of Excellence Co-Leader, Lung Cancer Program University of Pittsburgh Piittsburgh, Pennsylvania

2 Lung Cancer Facts & Figures Most common cause of cancer-related mortality in US Accounts for more deaths than breast, prostate, and colorectal cancers combined Histologically and molecularly a very heterogeneous disease Unfavorable stage distribution at the time of diagnosis (screening not routinely practiced) 25,000-30,000 never-smoking Americans will develop lung cancer this year (more common than esophageal, gastric, ovarian, testis, Hodgkin s, myeloma, CML. ACS Facts & Figures 2010) Historically shrouded by therapeutic nihilism

3 Evolution of NSCLC Subtyping from Histologic to Molecular-Based NSCLC as one disease AKT1 PIK3CA BRAF HER2 Adenocarcinoma MAP2K1 NRAS ROS1 RET ALK EGFR Unknown KRAS Squamous Cell Cancer FGFR1 Amp EGFRvIII Li T, et al. J Clin Oncol. 2013;31(8): Unknown PI3KCA EGFR DDR2

4 Changes in the Therapeutic Landscape of Stage IV Lung Cancer Adeno LCC-NOS SqCC SCLC

5 Changes in the Therapeutic Landscape of Stage IV Lung Cancer HER2 EGFR mutants ALK ROS/RET/BRAF/Others KRAS KRAS Adeno LCC-NOS SqCC SCLC

6 Changes in the Therapeutic Landscape of Stage IV Lung Cancer HER2 PD-L1+ EGFR mutants ALK ROS/RET/BRAF/Others KRAS KRAS Adeno LCC-NOS SqCC SCLC

7 Paradigm Shift in Pathology... Tissue sent to pathology Morphologic analysis Tumor genotyping IHC, special stains Tumor biomarkers

8 NSCLC Biopsy: Key Factors Adequate tissue for molecular analysis is critical to best select first-line NSCLC therapy Determination of EGFR mutation and ALK translocation status is indicated Should other genes be evaluated? ROS1, KRAS, BRAF, HER2, others Rebiopsy at time of progression helpful in determining resistance mechanisms Bone biopsy less ideal due to decalcification and degradation of DNA Liquid biopsies in development

9 Why Does Testing Matter? Survival By Use of Targeted Therapy Genotype/Therapy Median OS 95% CI Oncologic driver + targeted therapy Oncologic driver + no targeted therapy 3.49 months months No targeted therapy 2.08 months Kris MG, et al. JAMA. 2014;311(19):

10 Actionable Molecular Alterations in Advanced NSCLC EGFR ALK ROS1 BRAF met ret

11 EGFR Mutation: Distribution and Incidence Y Y Y Y Y 18 P-loop αc helix A-loop 19 Kinase domain 20 Exon Insertion L858R Others G719 Deletion Incidence (N = 569) 3.2% 48.2% * 3.7% ** 42.7% * 2.2% * Activating mutations with increased EGFR-TKI sensitivity. ** Resistance mutations Mitsudomi T et al. Cancer Sci. 2007;98(12):

12 EGFR Mutation: Distribution and Incidence Y Y Y Y Y 18 P-loop αc helix A-loop 19 Kinase domain 20 Exon Insertion L858R Others G719 Deletion Incidence (N = 569) 3.2% 48.2% * 3.7% ** 42.7% * 2.2% * Activating mutations with increased EGFR-TKI sensitivity. ** Resistance mutations Mitsudomi T et al. Cancer Sci. 2007;98: Common Mutations 12

13 IPASS Study Design Patients Chemonaïve Age 18 years Gefitinib (250 mg / day) Endpoints Primary Progression-free survival (noninferiority) Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease n = 609 1:1 randomization Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # n = 608 Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Mok TS, et al. N Engl J Med. 2009;361(10):

14 IPASS Study Design Homogeneous Population Endpoints Primary Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB / IV disease Gefitinib (250 mg / day) n = % Asian 1:1 randomization 100% Adenocarinoma Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # n = % Female 94% Never Smokers Progression-free survival (noninferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Mok TS, et al. N Engl J Med. 2009;361(10):

15 Progression-Free Survival in EGFR Mutation Positive and Negative Patients (n = 437) EGFR Mutation Positive EGFR Mutation Negative Probability of Progression-Free Survival At risk: Gefitinib (n = 132) Carboplatin / paclitaxel (n = 129) HR (95% CI) = 0.48 (0.36, 0.64) P<.0001 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Months Gefitinib C/P Treatment by subgroup interaction test, P<.0001 EGFR mutation rate 60% Mok TS, et al. N Engl J Med. 2009;361(10): Probability of Progression-Free Survival At risk: Gefitinib (n = 91) Carboplatin / paclitaxel (n = 85) HR (95% CI) = 2.85 (2.05, 3.98) P<.0001 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Months Gefitinib C/P

16 Objective Response Rate in EGFR Mutation Positive and Negative Patients Overall Response Rate (%) 71.2% 47.3% Gefitinib Carboplatin / paclitaxel EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p= EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p= (n = 132) (n = 129) (n = 91) (n = 85) Mutation positive 1.1% 23.5% Mutation negative Odds ratio >1 implies greater chance of response on gefitinib Mok TS, et al. N Engl J Med. 2009;361(10):

17 First-Line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients Study Treatment N Median PFS, Mos ORR, % Median OS, Mos Maemondo [1] Mitsudomi [2,3] OPTIMAL [4,5] EURTAC [6] LUX-Lung 3 [7] LUX-Lung 6 (8) Gefitinib vs carboplatin/ paclitaxel Gefitinib vs cisplatin/ docetaxel Erlotinib vs carboplatin/ gemcitabine Erlotinib vs platinum-based chemotherapy Afatinib vs CDDP/ pemetrexed Afatinib vs CDDP/ gemcitabine vs 5.4 (P<.001) 9.2 vs 6.3 (P<.0001) 13.1 vs 4.6 (P<.0001) 9.7 vs 5.2 (P<.0001) 11.1 vs 6.9 (P =.001) 11.0 vs 5.6 (P<.0001) 73.7 vs (P<.001) 62.1 vs (P<.0001) 83.0 vs (P<.0001) 64.0 vs (P value not reported) 69.0 vs (P<.001) 67.0 vs (P<.001) 30.5 vs (P =.31) 36 vs 39 (HR: 1.19) HR: (P =.65) 19.3 vs 19.5 (P =.87) Not reported Not reported 1. Maemondo M, et al. N Engl J Med. 2010;362: Mitsudomi T, et al. Lancet Oncol. 2010;11: Mitsudomi T, et al. J Clin Oncol. 2012; 30(suppl): Abstract Zhou C, et al. Lancet Oncol. 2011;12: Zhang C, et al. J Clin Oncol. 2012; 30 (suppl): Abstract Rosell R, et al. Lancet Oncol. 2012;13: Sequist LV et al. J Clin Oncol. Jul 2013; [Epub ahead of print]. 8. Wu YL et al. J Clin Oncol 2013:31(suppl): Abstract 8016.

18 Approved EGFR TKIs Gefitinib Erlotinib Afatinib Price $6000 $6000 $6000 Rash 2% 14% 16% Nail Disorder 0.1% 0% 11% Stomatitis 0.3% 1% 9% Diarrhea 3% 5% 15% ILD 1.3% 1.1% 1.5% T790M activity No No No PFS over Chemo OS over Chemo Yes Yes Yes No No No

19 OS in Patients With Common EGFR Mutations LUX-Lung 3 LUX-Lung 6 Combined HR 0.81 P =.037 Yang JC, et al. Lancet Oncol. 2015;16(2):

20 OS in Del 19 Subgroup LUX-Lung 3 LUX-Lung Afatinib n = 112 Pem/Cis n = 57 Median, months HR (95%CI), 0.54 ( ), P = Afatinib n = 124 Gem/Cis n = 62 Median, months HR (95%CI), 0.64 ( ), P =.0229 Estimated OS probability Afatinib Cis/Pem Estimated OS probability Afatinib Cis/Gem Time (months) No of patients Afatinib Pem/Cis Time (months) No of patients Afatinib Gem/Cis Yang JC et al. J Clin Oncol. 2014;32(Suppl): Abstract Yang JC, et al. Lancet Oncol. 2015;16(2):

21 OS in L858R Subgroup L858R/LUX-Lung 3 L858R/LUX-Lung Afatinib (n = 91) Cis/Pem (n = 47) 1.0 Afatinib (n = 92) Cis/Gem (n = 46) Median, months Median, months HR (95% CI) 1.30 ( ) P = HR (95% CI) 1.22 ( ) P =.3432 Estimated OS probability Afatinib Cis/Pem Estimated OS probability Afatinib Cis/Gem No. of patients: Time (months) Afatinib Cis/Pem Time (months) No. of patients: Afatinib Cis/Gem Yang JC, et al. Lancet Oncol. 2015;16(2):

22 EGFR Mutation Positive Patients in LUX-Lung Trials LUX-Lung 2 Phase II (N = 129) LUX-Lung 3 Phase III (N = 345) LUX-Lung 6 Phase III (N = 364) Del19 n = 408 n = 52 n = 170 n = 186 L858R n = 330 n = 54 n = 138 n = 138 Uncommon n = 100 n = 23 n = 37 n = 40 Patients with uncommon mutations treated with afatinib Uncommon n = 75 n = 23 n = 26 n = 26 Yang JC, et al. Presented at: World Conference on Lung Cancer; October 2013; Sydney, Australia. Abstract O Yang et al. Lancet Oncol. 2015;16(2):

23 Subgroups of Patients With Uncommon Mutations Group 1 Other (Exon 18, 19, 20, 21) (n = 38) Mutations (n) L861Q alone (12) G719X alone (8) G719X + S768I (5) G719X + L861Q (3) E709G or V + L858R (2) S768I + L858R (2) S768I alone (1) L861P alone (1) P848L alone (1) R776H + L858R (1) L861Q + Del19 (1) K739_1744dup6 (1) Group 2 De Novo T790M (n = 14) T790M alone (3) T790M + Del19 (3) T790M + L858R (6) T790M + G719X (1) T790M + L858R+G719X (1) Group 3 Exon 20 Insertions (n = 23) All Exon 20 Yang JC, et al. Presented at: World Conference on Lung Cancer; October 2013; Sydney, Australia. Abstract O Yang et al. Lancet Oncol. 2015;16(2):

24 Tumor Shrinkage in Patients With Uncommon Mutations, by Independent Review (n = 67 a ) * Maximum change from baseline (%) * * De novo T790M (n=14) T790M alone(*), T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X Exon 20 insertions (n=20) Other (n=33) L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R, S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6 a Yang JC, et al. Presented at: World Conference on Lung Cancer; October 2013; Sydney, Australia. Abstract O Yang et al. Lancet Oncol. 2015;16(2):

25 Progression-Free Survival and Overall Survival by Independent Review Group 1 Group 2 Group 3 Other De Novo Exon 20 (Exon 18, 19, 20, 21) T790M Insertions (n = 38) (n = 14) (n=23) Median PFS, mo (range) 10.7 (0.0 a a ) 2.9 ( ) 2.7 ( ) Median OS, mo (range) 18.6 (0.0 a a ) 14.9 ( ) 9.4 ( a ) a Patient data censored. NE, not estimable; PFS, progression-free survival; OS, overall survival. Yang JC, et al. Presented at: WCLC; October 2013; Sydney, Australia. Abstract O Yang JC, et al. Lancet Oncol. 2015;16:

26 EGFR TKIs Vs Platinum Doublets in EGFR Mutant NSCLC Eight of 8 trials have shown in predominantly exon 19/21 EGFR mutations: - Improved PFS - Improved ORR - Better toxicity profile - Better QoL Uncommon mutations some may be sensitive, but not all 26 Zero of 8 trials have shown a survival benefit - Crossover effect (but 100% of patients do not crossover) - Development of resistance - Combined analysis of LUX-Lung 3 & 6 showed an OS benefit

27 Fig. The Frequency of Observed Drug Resistance Mechanisms Sequist LV, et al. Sci Transl Med. 2011;3(75):75ra26.

28 TIGER-X: Phase I/II Trial of Rociletinib in EGFR TKI-Pretreated EGFR Mutation Positive NSCLC Study Design Key Eligibility Criteria Advanced or recurrent NSCLC with a documented activating EGFR mutation Prior treatment with EGFR-directed therapy Recent biopsy available or willing to undergo a new on-study biopsy; plasma samples collected Phase II only: Disease progression while on treatment with EGFR-directed therapy T790M+ biopsy at the time of study entry Treated stable CNS metastases allowed Phase I (Dose Escalation) Rociletinib treatment (free base rociletinib followed by 500, 625, 750, and 1000 mg bid HBr 21-day cycles; escalate to MTD HBr, hydrobromide Solomon B, et al. Ann Oncol. 2015; 26(suppl 1): Abstract TIGER-X interim results Phase II Expansion Cohorts (Required Central Tissue T790M Testing) Second-line patients PD upon 1 immediate prior TKI >Second-line patients PD upon 2 TKIs or chemotherapy 500 mg bid 625 mg bid 750 mg bid Updated results in centrally confirmed tissue T790M patients are presented Data cutoff, Aug 11, 2015 n = 43 for safety; n = 37 for evaluable efficacy

29 100 Best Response to Rociletinib (All Doses) in 243 Centrally Confirmed Tissue T790M+ Patients SLD Change from Baseline (%) mg 625 mg 750 mg 1000 mg Total N ORR (%) DCR (%) ORR, objective response rate; DCR, disease control rate 500mg BID HBr 625mg BID HBr 750mg BID HBr 1000mg BID HBr + Ongoing 100 SLD, sum of longest diameters

30 Maturing PFS in 270 Centrally Confirmed T790M+ Patients at 500mg or 625mg BID Probability of PFS All patients No baseline CNS disease At Risk (Events) 270 (0) 163 (0) 187 (39) 104 (71) 57 (80) 118 (16) 68 (32) 37 (38) 29 (89) 20 (44) 9 (90) 8 (45) 8 (92) 7 (47) 5 (94) 5 (48) + Censored (35% maturity) All Patients No Baseline CNS Disease Median PFS Months All Patients 8.0 No Baseline CNS Disease Time (months) 2 (94) 2 (48) 2 (94) 2 (48) 2 (94) 2 (48) 1 (94) 1 (48) 0 (94) 0 (48) *Data analyzed 27 Apr PFS, progression-free survival.

31 Tiger-X: Common Treatment-Related AEs Treatment-Related AEs Occurring in >10% of Patients Any Grade 500 mg bid n = 119 Rocelitinib Dose, n (%) 625 bid 750 mg bid n = 236 n = mg bid n = 6 Hyperglycemia 42 (35) 107 (45) 56 (59) 4 (67) Diarrhea 39 (33) 94 (40) 28 (30) 4 (67) Nausea 23 (19) 79 (34) 35 (37) 3 (50) Fatigue 23 (19) 67 (28) 28 (30) 2 (33) QTc prolongation 16 (13) 53 (23) 25 (26) 3 (50) Decrease appetite 18 (15) 38 (16) 24 (25) 2 (33) Muscle spasms 17 (14) 30 (13) 20 (21) 1 (17) Vomiting 10 (8) 38 (16) 13 (14) 0 (0) Weight loss 12 (10) 21 (9) 16 (17) 1 (17) Grade > 3 Hyperglycemia 20 (17) 56 (24) 34 (36) 2 (33) The most common AEs across all doses included hyperglycemia, diarrhea, nausea, fatigue, QTc prolongation, and decreased appetite No interstitial lung disease was observed in the 500 mg bid dose group No paronychia was observed; minimal rash and stomatitis were observed The incidence of grade 3 QTc prolongation at 500 mg bid was 2.5% Gadgeel S, et al. Ann Oncol. 2015; 26 (suppl 1): Abstract 3088.

32 AURA-2: Phase II, Open-Label Trial of Osimertinib in Pretreated T790M+ Advanced NSCLC Patients with confirmed EGFR mutant locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI Age 18 years ( 20 years in Japan) Confirmation of tumor EGFR mutation associated with EGFR TKI At least one lesion suitable for accurate repeated measurements WHO PS 0 or 1 Acceptable organ function Stable brain metastases allowed Central T790M testing* of biopsy sample collected following confirmed disease progression T790M+ (n=210) T790M Osimertinib 80 mg once daily Not eligible for enrollment Primary objective: To investigate the efficacy of Osimertinib by assessment of ORR (RECIST v1.1 blinded independent central review) *The EGFR T790M mutation status of the patient s tumor was prospectively determined by the designated central laboratory using the cobas EGFR Mutation Test (Roche) by biopsy taken after confirmation of disease progression on the most recent treatment regimen. Mitsudomi T, et al. Presented at: WCLC; October 2015; Denver, Colorado. Abstract 1406.

33 AURA-2: Efficacy Data in EGFR Mutation- Positive Patients That Progressed on Prior EGFR TKI Endpoint Data cutoff, May 1, 2015.*Population: evaluable for response set (n=199). Investigator-assessed ORR was also 71% (95% CI, 64%-77%). Response required confirmation after 4 weeks. Stable disease 6 weeks included the RECIST visit window (±7 days). Population: evaluable for response analysis set. Population: full analysis set (n=210). Median PFS by investigator assessment was NC (95% CI, 9.3 months-nc). Maturity: 37%. NC=not calculable. Total ORR* (95% CI), % 71 (64-77) Complete response, n (%) 2 (1) Partial response, n (%) 139 (70) Stable disease 6 weeks, n (%) 41 (21) Progressive disease, n (%) 15 (8) DCR (95% CI), % 92 (87-95) Median DOR (95% CI), months 7.8 (7.1-NC); Maturity: 27% Remaining in response (95% CI), % 6 months 9 months 75 (65-82) NC (NC-NC) Range of DOR, months Median PFS (95% CI), months 8.6 ( ); Maturity: 38% Remaining alive and progression free (95% CI), % 6 months 9 months 70 (63-76) 48 (36-58) Follow-up for PFS, months 6.7 Mitsudomi T, et al. Presented at: WCLC; October 2015; Denver, Colorado. Abstract 1406.

34 AURA-2: Adverse Events (All Causality) AEs by Preferred Term, Occurring in 15% of Patients Overall* Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Total n (%) Any AE 66 (31) 76 (36) 61 (29) 203 (97) Rash (grouped terms) 82 (39) 5 (2) 1 (1) 88 (42) Diarrhea 71 (34) 8 (4) 2 (1) 81 (39) Dry skin 48 (23) 4 (2) 0 52 (25) Nausea 31 (15) 3 (1) 0 34 (16) Paronychia 24 (11) 8 (4) 0 32 (15) Constipation 30 (14) 2 (1) 0 32 (15) Pruritus 29 (14) 3 (1) 0 32 (15) Fatigue 22 (11) 10 (5) 0 32 (15) Select AEs of interest ILD (group terms) 2 (1) 0 2 (1) 4 (2) Hyperglycemia 2 (1) 1 (1) 0 3 (1) QT prolongation 4 (2) 2 (1) 5 (2) 11 (5) Population: Full analysis set (n = 210). Data cut-off: May 1, Note: ILD grouped term AEs were reported in 4 (1.9%) patients, all patients were in the 3rd-line cohort. As of June 1, 2015, of more than 1200 patients across all studies dosed with osimertinib, ILD grouped term events were reported in approximately 2.9% of patients (35 events): 9 Grade 1, 6 Grade 2, 18 Grade 3, 2 currently ungraded. Of these, a total of 4 patients are reported to have died due to ILD (Grade 5). *Each patient has only been represented with the maximum reported CTCAE grade for each system organ class/preferred term. No AEs Grade 4 were recorded in 10% of patients overall. One (1%) Grade 4 and 4 (2%) Grade 5 AE were reported in the full analysis set. CTCAE, Common Toxicity Criteria for Adverse Events; ILD, interstitial lung disease. Mitsudomi T, et al. Presented at: World Conference on Lung Cancer; October 2015; Denver, Colorado. Abstract 1406.

35 ASCO November 13, 10:32 AM On November 13, 2015, the U. S. Food and Drug Administration granted accelerated approval to osimertinib once daily tablets for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDAapproved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

36 Management of EGFR Mutation + Patients Test all non-squames and squames (for the latter depending on smoking history) Standard of care = EGFR TKI (erlotinib/afatinib/gefitinib) Re-test at progression look for T790M (rocelitinib & osimertinib are coming soon) Tissue and blood-based testing are complementary Think locoregional therapies if PD limited Tolerate slow PD Optimal therapy for PD should be guided by repeat molecular testing

37 ALK Rearrangement in Cancer ALK-positive cancers: Inversion Or Translocation NSCLC: EML4-ALK, KIF5B-ALK, TFG-ALK (3%-5%) 1 - First described in 2007 Anaplastic large cell lymphoma: NPM-ALK 1 Inflammatory myofibroblastic tumor: TPM3-ALK, TPM4-ALK 2 Other solid tumors 2 1. Mossé YP, et al. Clin Cancer Res. 2009;15(18): Chiane R, et al. Nat Rev Cancer. 2008;8:11-24.

38 Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC Maximum Change in Tumor Size (%) % Progressive disease Stable disease Confirmed partial response Confirmed complete response *Partial response patients with 100% change have nontarget disease present. Kwak EL, et al. N Engl J Med. 2010;363(18):

39 PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum* in Advanced NSCLC Phase III trial (N = 344) ALK-positive patients with nonsquamous NSCLC and no prior systemic treatment for advanced disease PFS (%) Progression-Free Survival Crizotinib (n = 172) Chemotherapy (n = 172) Events, n (%) 100 (58) 137 (80) Median, mo HR (95% CI) 0.45 ( ) P <.0001 PFS benefit seen across all subgroups Eg, age, sex, smoker, time since Dx ORR: 74% with crizotinib vs 45% with chemo (P<.0001) *Carboplatin or cisplatin Mok T, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8002.

40 Ceritinib in ALK+ NSCLC: Best % Change From Baseline in Target Lesions Other second-generation ALK inhibitors in development: CH (alectinib) AP26113 X-396 ASP3026 GSK CEP Best Change From Baseline (%) Prior crizotinib treatment No prior crizotinib treatment ORR (CR + PR): 58% Prior crizotinib: 56% Crizotinib naive: 62% Disease progression or death -100 Shaw AT, et al. N Engl J Med. 2014;370(13): Pts

41 Marked Activity of Alectinib in Patients With Crizotinib-Resistant ALK+ NSCLC Systemic BOR: PD (n=22) SD (n=35) PR (n=61) Sum of longest diameter, maximum decrease from baseline (%) * * * * * * * * * * *** ** * * * * ** * * 100 * * *Chemotherapy-naïve patients Updated analysis cut-off 8 Jan 2015 Ou S-H, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8008.

42 NP28673 and NP28761: Efficacy Data NP (N = 138) NP (N = 87) Alectinib 600 mg bid IRC RE Population (n = 122) Prior Chemotherapy (n = 96) Chemotherapy Naïve (n = 26) IRC RE Population (n = 67) ORR (95% CI), % 50.8 ( ) 44.8 ( ) 73.1 ( ) 52.2 ( ) DCR (95% CI), % 78.7 ( ) 77.1 ( ) 84.6 ( ) 79.1 ( ) Median DOR (95% CI), months 14.1 (10.9-NE) 13.2 ( ) NE 13.5 (6.7-NE) Median PFS, months 8.9 NR NR month OS event-free rate (95% CI), % NR NR NR 71.0 ( ) NP28761 (North American) & NP28673 (Global): Ph II trials of alectinib in crizotinib-failed ALK+ pts NE, not evaluable; NR, not reported; RE, response-evaluable. 1. Barlesi F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract Shaw AT, et al. Presented at: World Conference on Lung Cancer; October 2015; Denver, Colorado. Abstract 1261.

43 Conclusions ALK+ NSCLC Test all non-squames and squames (the latter depending on smoking history) Standard of care TKI (crizotinib ceritinib) Other TKIs coming soon Mechanisms of acquired resistance - Secondary mutations - ALK amplification - Bypass pathway activation Role of rebiopsy/retest remains uncertain Brain mets particularly common

44 ROS 1 First report of new driver mutation: ROS1 in 2012 ROS1: 18/1073 (1.7%) tumors Younger patients Never-smokers Adenocarcinoma Crizotinib activity Bergethon K et al. J Clin Oncol. 2012;30(8): Jänne PA, et al. J Clin Oncol. 2012;30(8):

45 Clinical Response to Crizotinib in Patient with ROS1 Bergethon K et al. J Clin Oncol. 2012;30(8):

46 Crizotinib in ROS1 NSCLC Med PFS mos ORR - 72% Med DOR mos Shaw AT, et al. N Engl J Med. 2014;371(21):

47 LCMC: Clinicopathologic Features and Outcomes in BRAF-Mutant Adenocarcinoma BRAF found in 2.2% of adenocarcinomas 81% were V600E 50:50 male:female; median age 65 (42-80) More likely to occur in smokers versus other subsets of oncogenic drivers (EGFR, ALK, etc) Double mutation rate was higher in BRAF patients versus other subsets (16% vs 5%, P =.45) No survival differences were seen Villaruz LC, et al. Cancer. 2014;121(3):

48 Dabrafenib Inhibits BRAF V600 Kinase and Trametinib Inhibits Downstream MEK Signaling Dabrafenib mode of action Reversible, small molecule BRAF inhibitor ATP competitive BRAF V600E: IC nm Trametinib mode of action Reversible, small molecule MEK1 and MEK2 allosteric inhibitor MEK1 and MEK2: IC and 0.9 nm Dabrafenib RTKs P P BRAF V600 SOS Grb2 P P SHC P P BRAF RAS MEK ERK1/2 CRAF PI3K/AKT/mTOR pathway Trametinib Davies H, et al. Nature. 2002;417(6892): ; Platz A, et al. Mol Oncol. 2008;1(4): ; Karasarides M, et al. Oncogene. 2004;23(37): ; Long GV, et al. N Engl J Med. 2014;371(20): ; Gilmartin AG, et al Clin Cancer Res. 2011;17(5): p90rsk MSK1 Proliferation, Growth, Survival

49 Maximum Percent Reduction from Baseline Measurement Maximum Reduction of Sum of Lesion Diameters By Best Confirmed Response in 2 nd -Line (N = 78) BRAF V600E Treated With Dabrafenib Best Confirmed Response PR SD PD NE ORR - 32% Planchard D, et al. Ann Oncol 2014;25(suppl 4): Abstract LBA38_PR.

50 Maximum Reduction of Sum of Lesion Diameters By Best Confirmed Response in 2 nd -Line (N = 24 a ) V600E Treated With Dabrafenib + Tremetinib Maximum Percent Reduction at Time of Best Disease Assessment Best Confirmed Response ORR - 63% PR SD PD -100 a 1 patient discontinued at day 23 and did not have any post-baseline scans for efficacy. The median duration of response was not reached

51 Summary - BRAF D + T demonstrated clinically meaningful antitumor activity with a higher ORR when compared indirectly with dabrafenib monotherapy in BRAF V600E mutated NSCLC ORR = 63% and DCR = 88% for dabrafenib plus trametinib ORR = 32% and DCR = 56% for dabrafenib as monotherapy 1 Safety profile is manageable and similar to previous studies in melanoma Cohort B has completed recruitment with 59 subjects A third cohort investigating D + T in previously untreated V600E mutant Stage IV NSCLC is actively recruiting 1 Planchard D, et al. Ann Oncol. 2014;25(suppl 4): Abstract LBA38_PR.

52 Hepatocyte Growth Factor (HGF)/MET Signaling Pathway Transduces Invasive Growth Signals from Mesenchymal to Epithelial Cells Appleman LJ. J Clin Oncol. 2011;29(36):

53 MET Is Amplified in a Subset of Lung Cancers MET amplification level categories: Expected frequencies MET/CEP7 Ratio Number of specimens MET amplification classification % of total < Negative 92.6% >1.8 - < Low 3.6% >2.2 - < Intermediate 3.0% >5.0 6 High 0.8% Total % 800 consecutive NSCLC samples tested at Colorado Molecular Correlates Lab from 2009 to Detailed demographic data not available. Samples were unselected with respect to other biomarker status, but may have been enriched for adenocarcinoma, never smokers, young age, and female, based on time period of testing. Garcia L, University of Colorado, personal communication

54 Tumor Shrinkage Seen With Crizotinib in Intermediate and High MET Cohorts Best percent change from baseline in target tumor lesions a by patient % Change From Baseline Low MET n = Intermediate MET n = 6 c c High MET n = 6 Disease progression Stable disease Partial response b Complete response b Threshold for partial response a Confirmed objective responses. b Based on investigator assessment. c Two patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment. Camidge DR, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8001.

55 Summary: MET Exon 14 Splice Mutation Frequency ~4% (TCGA Nature 2014) Predominant histologic type Clinical features Method of clinical detection First-line targeted therapy Mechanism(s) of acquired resistance Adenocarcinoma, also in pulmonary sarcomatoid carcinoma Appears slightly more common in never smokers NGS based diagnostics, can also be detected by traditional Sanger sequencing MET TKIs, such as crizotinib MET MAbs, not yet assessed in this context Unknown at present Future directions - Prospective clinical trial of MET inhibitors in patients whose tumors harbor MET exon 14 splice mutations - Rational combination therapies to prolong response/delay resistance - Ascertain mechanisms of acquired resistance to MET TKIs in this context

56 Results- Treatment Response

57 RET-Rearranged Lung Cancers 1%-2% of unselected non-small cell lung cancers Clinical features young, never or former light cigarette smokers Pathology lung adenocarcinoma: most common histology solid subtype and signet ring cells Diagnosis break apart fluorescence in situ hybridization (FISH) next-generation sequencing (NGS) Ju YS, et al, Genome Res. 2012;22(3): Wang R, et al. J Clin Oncol. 2012;30(35): Lee SE, et al. Mod Pathol. 2015;28(4): Images courtesy of Lu Wang, Charles Leduc, and Natasha Rekhtman, Department of Pathology, Memorial Sloan Kettering Cancer Center

58 30% Response to Cabozantinib in Patients with RET-Rearranged Lung Adenocarcinomas 0% -30% Best Response % (n) PR 44% (7/16) confirmed unconfirmed 38% (6/16) 6% (1/16) -60% -90% SD 56% (9/16) ORR 38% (95% CI 15%-65%) ORR 12wks 36% (95% CI 13%-65%) (5 PRs of 14 evaluable at 12 wks) imaging performed at baseline, 4 weeks, and every 8 weeks thereafter response evaluable patients received 1 cycle of therapy confirmed PR SD PR - partial response, SD - stable disease ORR overall response rate, CI - confidence interval

59 A Roadmap of Immunotherapy-Tumor Interactions 4 Trafficking of T cells to tumors Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists 2 6 Recognition of cancer cells by T cells CARs Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 1 7 Killing of cancer cells Anti PD-L1 Anti PD-1 IDO inhibitors Chen DS, et al. Immunity. 2013;39(1):1-10.

60 Anti-PD-1 Antibodies: Mechanism of Action PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function 10 Nivolumab/pembrolizumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-L2 to restore T-cell antitumor function IFNγ Tumor cell IFNγR T-cell receptor MHC PD-L1 PD-1 PD-L2 PD-1 PI3K NFκB Other Shp-2 T cell Shp-2 T-cell receptor CD28 PD-1 PD-1 MHC B7 PD-L1 PD-L2 Dendritic cell Nivolumab/Pembrolizumab: PD-1 Receptor Blocking Ab

61 Immunotherapy in NSCLC Year in Review March 2015 Nivolumab approved in squamous cancers following platinum-based therapy - CheckMate 017 October 2015 Pembrolizumab approved in PD-L1 positive NSCLC following platinum-based therapy (companion diagnostic) KEYNOTE-001 October 2015 Indication expanded to nonsquamous NSCLC for nivolumab (complementary diagnostic) CheckMate 057 October 2015 Positive results announced for KEYNOTE-010 study (pembrolizumab vs docetaxel in PD-L1 + previously treated NSCLC patients)

62 CheckMate 017 & 057 Study Design Stage IIIB/IV SQ (017) or non-sq (057) NSCLC Pretreatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0 1 Failed 1 prior platinum doublet Prior maintenance therapy allowed a Prior TKI therapy allowed for known ALK translocation or EGFR mutation 057 Randomize 1:1 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity Primary Endpoint OS Additional Endpoints ORR b PFS b Safety Efficacy by tumor PD-L1 expression Quality of life (LCSS) PD-L1 expression measured using the Dako/BMS automated IHC assay Fully validated with analytical performance having met all predetermined acceptance criteria for sensitivity, specificity, precision, and robustness a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator. Brahmer J, et al. N Engl J Med. 2015;373: Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

63 Overall Survival CheckMate 017 Nivolumab Docetaxel N = 135 N = mos mo, (95% CI) 9.2 (7.3, 13.3) 6.0 (5.1, 7.3) # events HR = 0.59 (95% CI: 0.44, 0.79), P = OS (%) yr OS rate = 42% Nivolumab yr OS rate = 24% Docetaxel Time (months) Number of Patients at Risk: Nivolumab Docetaxel Symbols represent censored observations Brahmer J, et al. N Engl J Med. 2015;373:

64 Overall Survival CheckMate mos mo, (95% CI) Nivolumab Docetaxel N = 292 N = HR= 0.73 (96% CI: 0.59, 0.89), P = OS (%) yr OS rate = 39% 1-yr OS rate = 51% Nivolumab Number of Patients at Risk: Time (months) Docetaxel 27 Nivolumab Docetaxel Symbols represent censored observations. Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

65 Treatment Effect on OS in Predefined Subgroups CheckMate 057 Unstratified HR N (95% CI) Overall (0.62, 0.91) Age Categorization (years) < (0.62, 1.04) 65 and < (0.45, 0.89) (0.43, 1.87) Gender Male (0.56, 0.96) Female (0.58, 1.04) Baseline ECOG PS (0.44, 0.93) (0.63, 1.00) Smoking Status Current/Former Smoker (0.56, 0.86) Never Smoked (0.64, 1.61) EGFR Mutation Status Positive (0.69, 2.00) Not Detected (0.51, 0.86) Not Reported (0.51, 1.06) 0.25 Nivolumab Docetaxel All randomized patients (nivolumab, n = 292; docetaxel, n = 290) Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

66 Secondary Endpoints CheckMate 017 & 057 CheckMate-017 CheckMate-057 Nivolumab Docetaxel Nivolumab Docetaxel ORR P value DOR (mo) NR Med TTR (mo) PFS HR/p 0.62/ /0.39 ORR overall response rate DOR duration of response TTR time to tumor response PFS progression-free survival Brahmer J, et al. N Engl J Med. 2015;373: Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

67 Nivolumab PI Complementary Diagnostic The proportion of patients (n=455) in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmdx assay were: 46% PD-L1 negative (defined as <1% of tumor cells expressing PD-L1) 54% had PD-L1 expression (defined as 1% of tumor cells expressing PD-L1) Among patients with tumors expressing PD-L1, 26% had 1%, but <5% tumor cells with positive staining 7% had 5% but <10% tumor cells with positive staining 67% had greater > 10% tumor cells with positive staining

68 CheckMate-017 OS and PFS by PD-L1 Expression Survival benefit with nivolumab was independent of PD-L1 expression level PD-L1 Expression Patients, n Nivolumab Docetaxel Unstratified HR (95% CI) OS 1% (0.45, 1.05) <1% (0.37, 0.92) 5% (0.31, 0.89) <5% (0.47, 1.02) 10% (0.28, 0.89) <10% (0.48, 1.01) Not quantifiable (0.19, 0.82) PFS 1% (0.44, 1.01) <1% (0.43, 1.00) 5% (0.32, 0.90) <5% (0.52, 1.08) 10% (0.33, 1.02) <10% (0.49, 0.99) Not quantifiable (0.23, 0.89) Interaction P- value PD-L1 positive expression PD-L1 negative expression Not quantifiable Nivolumab Docetaxel PD-L1 expression was measured in pre-treatment tumor biopsies (DAKO automated IHC assay) 15 Brahmer J, et al. N Engl J Med. 2015;373:

69 CheckMate-057 OS and PFS Hazard Ratios by Baseline PD-L1 Expression Patients, n PD-L1 Expression Nivolumab Docetaxel Unstratified HR (95% CI) Interaction P value OS 1% (0.43, 0.82).0646 <1% (0.66, 1.24) 5% (0.30, 0.63).0004 <5% (0.77, 1.34) 10% (0.26, 0.59).0002 <10% (0.76, 1.31) Not quantifiable (0.61, 1.35) PFS 1% (0.53, 0.94).0227 <1% (0.88, 1.61) 5% (0.39, 0.76) <.0001 <5% (1.01, 1.71) 10% (0.37, 0.75).0002 <10% (0.96, 1.61) Not quantifiable (0.73, 1.56) PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable 0.25 Nivolumab Docetaxel a Interaction p-value from Cox proportional hazard model with treatment, PD-L1 expression and treatment by PD-L1 expression interaction. Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

70 ORR by PD-L1 Expression CheckMate 057 PD-L1 Expression Level Nivolumab ORR, a % Docetaxel 1% <1% % <5% % <10% Not quantifiable 13 9 Interaction P value Median DOR was longer with nivolumab vs docetaxel in both PD-L1 expressors and non-expressors across all expression levels ORR was not different in CheckMate 017 based on level of PD-L1 expression a CR+PR as per RECIST v1.1 criteria. Confirmation of response required (investigator assessment) Paz-Ares L, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA109.

71 Friday, October 9, :02 pm EDT Public Company Information: PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company Bristol-Myers Squibb has partnered with Dako, an Agilent Technologies company, to develop PD-L1 IHC 28-8 PharmDx, a test which was used to assess PD-L1 expression in the CheckMate -057 trial. This test is now approved by the FDA as a complementary diagnostic, which will provide additional information for physicians. These tests are distinct from companion diagnostics, which are essential for safe and effective use of a drug. Biomarker testing is not required for [nivolumab].

72 Treatment-Related AEs Reported in 10% of Patients Nivolumab (n = 287) Docetaxel (n = 268) Any Grade, % Grade 3-4, a % Any Grade, % a No grade 5 events were reported at DBL; 1 grade 5 event was reported for nivolumab post-dbl. Grade 3-4, a % Total patients with an event Fatigue Nausea Decreased appetite Asthenia 10 < Diarrhea Peripheral edema <1 Myalgia 2 < Anemia 2 < Alopecia < Neutropenia < Febrile neutropenia Leukopenia

73 Treatment-Related Select AEs Nivolumab (n = 287) Docetaxel (n = 268) Any Grade, % Grade 3-4, a % Any Grade, % Grade 3-4, a % Endocrine, % Hypothyroidism Gastrointestinal, % Diarrhea Hepatic, % ALT increased AST increased <1 1 1 <1 0 Pulmonary, % Pneumonitis 3 1 <1 <1 Skin, % Rash Pruritus Erythema < Hypersensitivity/Infusion reaction, % Infusion-related reaction <1 Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention Includes events reported in 2.5% of patients. a No grade 5 events were reported at DBL;1 grade 5 event for nivolumab was reported post-dbl.

74 Pembrolizumab PI October 2015 Pembrolizumab is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of: Patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established

75 NSCLC Expansion Cohorts of KEYNOTE-001: N = 495 PD-L1 status assessed by a prototype IHC assay using the 22C3 antibody clone (Merck) Positivity defined as Membranous staining in >1% of cells (both neoplastic and intercalated mononuclear inflammatory cells) within tumor nests OR A distinctive band of stromal staining adjacent to tumor nests caused by mononuclear inflammatory cells infiltrating the stroma *The first 11 patients were randomized to pembrolizumab 2 mg/kg Q3W vs 10 mg/kg Q3W. The remaining 90 patients were randomized to pembrolizumab 10 mg/kg Q3W vs 10 mg/kg Q2W. 1. Garon EB, et al. Presented at: 2014-IASLC on Joint Conference on Molecular Origins of Lung Cancer; January 6-9, 2014; San Diego, CA.

76 Baseline Characteristics Characteristics, % N = 495 Age, median (range), years 64 (28-93) Male 52.7 Race White 82.0 Asian 12.9 Black or African American 4.0 Other 1.0 ECOG performance status Unknown 0.4 Histology Squamous 17.2 Nonsquamous 81.0 Adenosquamous 1.4 Unknown 0.4 Characteristics, % N = 495 Smoking history Current 8.3 Former 66.3 Never 25.5 Molecular alterations EGFR mutation (n = 478) 15.5 KRAS mutation (n = 295) 26.1 ALK translocation (n = 438) 2.0 No. of unique prior therapies >4 20.6

77 ORR In All Treated Patients Because of small patient numbers, data for patients treated with pembrolizumab 2 mg/kg Q3W (n = 6) and those with other histology (n = 9) are not shown. ORR was assessed per RECIST v1.1 by central review. Analysis cut-off date: August 29, 2015.

78 Comparison of Antitumor Activity at 2 mg/kg with Published Data for 10 mg/kg in Previously Treated Patients Safety profiles appear equivalent 1 For patients with PD-L1 TPS >50% (2 mg/kg vs 10 mg/kg 1 ) 6-mo PFS rate b : 46.8% vs 50.4% 6-mo OS rate b : 71.2% vs 71.4% PK/PD modeling data support a flat relationship between pembrolizumab exposure and antitumor activity Tumor size was assessed per RECIST v1.1 by independent review. a Regardless of PD-L1 status. b From the Kaplan-Meier method for censored data. Garon EB, et al. N Engl J Med. 2015;372(21):

79 Longitudinal Outcomes in All Treated Patients N at risk N at risk *Assessed per RECIST v1.1 by central review Analysis cut-off date: August 29, 2014

80 Pembrolizumab PI- Companion Diagnostic A prospectively defined sub-group was retrospectively analyzed using an analytically validated test for PD-L1 expression tumor proportion score (TPS). This retrospectively identified sub-group of 61 patients accounts for 22% of the 280 patients in the cohort. Patients included in this sub-group had a PD-L1 expression TPS of greater than or equal to 50% tumor cells as determined by the PD-L1 IHC 22C3 pharmdx Kit. Table 5: Efficacy Results Endpoint N = 61 Overall Response Rate ORR %, (95% CI) 41% (29, 54) Complete Response 0% Partial Response 41%

81 Examples of PD-L1 IHC Staining of NSCLC Samples Using the Clinical Trial Assay PS <1% PS 1%-49% PS >50% 5X magnification 40x magnification Brown chromogen: PD-L1 staining; Blue color: hematoxylin counterstain Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference; April 19, 2015; Philadelphia, PA. Abstract CT 104.

82 ORR by PD-L1 Proportion Score: CTA-Evaluable Validation Set Patients with Measurable Disease When measurable disease is NOT required, the ORR (95% CI) in the PS > 50% subgroups are: 42.3%, 41.0%, and 47.1% in the total, previously treated, and treatment-naïve populations d A n = 73, 103, and 28, respectively. b N = 57, 77, and 22, respectively. c N = 16, 26, and 6, respectively. d N = 78, 61, and 17, respectively. ORR was assessed per RECIST v1.1 by central review in the biomarker-evaluable population (ie, patients with measurable disease per RECIST v1.1 by central review at baseline whose slides were cut within 6 months of staining and for which a proportion score could be assigned). Analysis cut-off date: August 29, Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference.; April 19, 2015; Philadelphia, PA. Abstract CT 104.

83 Prevalence of PD-L1 Positivity and ORR by Quartiles of PD-L1 Proportion Score Prevalence, all screened patients, n a (%) 323 (39.2) 255 (31.0) 55 (6.7) 71 (8.6) 120 (14.6) ORR in CTA-evaluable patients, n (%) [95% CI] 7 (8.1) [ ] 19 (12.9) [ ] 6 (19.4) [ ] 13 (29.6) [ ] 39 (45.4) [ ] Prevalence and ORR (RECIST v1.1 by central review) assessed in patients whose samples were evaluable by the CTA, regardless of the interval between cutting and staining. Analysis cut-off date: August 29, Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference.; April 19, 2015; Philadelphia, PA. Abstract CT 104.

84 Maximum Change From Baseline in Target Lesions: Biomarker-Evaluable Population Maximum change from baseline was assessed per RECIST v1.1 by central review in patients in the validation set with measurable disease per RECISv1.1 by central review at baseline whose slides were cut within 6 months of staining and for which a proportion score could be assigned. Analysis cut-off date: August 29, Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference.; April 19, 2015; Philadelphia, PA. Abstract CT 104.

85 OS by PD-L1 Expression, CTA Evaluable Patients by Prior Treatment N at risk N at risk OS was assessed in all patients whose samples were stained within 6 months of cutting. Analysis cut-off date: August 29, Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference.; April 19, 2015; Philadelphia, PA. Abstract CT 104.

86 Treatment-Related AEs With Incidence >2% in the Treated Population Potentially immune-mediated AEs are presented regardless of investigator-designated attribution. The following immunerelated AEs were not observed in any patients: adrenal insufficiency, hepatic, myocarditis, myositis, neuropathy, pancreatitis, renal, thyroiditis, type 1 diabetes mellitus, and uveitis. Analysis cut-off date: August 29, Garon EB, et al. Presented at: 2015 American Association for Cancer Research Conference.; April 19, 2015; Philadelphia, PA. Abstract CT 104.

87 Pembrolizumab Shows Superior Overall Survival Compared to Chemotherapy in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 Regulatory submissions planned in the US in late 2015 and in the European Union in early 2016 Monday, October 26, :00 am EDT

88 Agents With Clinical Data Anti PD-1 Nivolumab (MBS936558) Anti PD-L1 MPDL3280A Pembrolizumab (MK3475) MEDI4736

89 POPLAR: A Randomized All- Comer Phase II Study Metastatic or locally advanced NSCLC (2L/3L) Disease progression on a prior platinum therapy N = 287 Stratification Factors PD-L1 IC expression (0 vs 1 vs 2 vs 3) a Histology (squamous vs non-squamous) Prior chemotherapy regimens (1 vs 2) R 1:1 Atezolizumab 1200 mg IV q3w until loss of clinical benefit Docetaxel 75 mg/m 2 IV q3w until disease progression Primary study objective: Estimate OS in PD-L1 selected and ITT populations Secondary study objectives: Evaluate PFS, ORR and DOR in PD-L1 selected and ITT populations Evaluate safety Interim analysis is based on 153 events with a minimum follow-up 10 months a Archival or fresh tissue required for pre-dose testing.

90 POPLAR: All Patient Efficacy ITT OS (N = 287) Minimum follow up = 13 months HR a = 0.73 (0.53, 0.99) P value =.040 Median 9.7 mo (8.6, 12.0) Median 12.6 mo (9.7, 16.4) + Atezolizumab Docetaxel Censored Event/patient ratio: 60% (54% for atezolizumab, 66% for docetaxel) a Stratified HR.. Data cut-off May 8, Vansteenkiste J, et al. Eur J Cancer. 2015;51(Suppl 3): 14LBA.

91 Immunotherapy - Conclusions Clearly established as a new therapeutic paradigm in the 2 nd + line setting, and will likely be part of 1 st -line therapy in the near future Biomarkers are available and can be helpful clinically - predict likelihood of response - may reassure MD or patient in the setting of toxicity - utility may differ depending on histology PD-1/PD-L1 inhibitors have greater activity in PD-L1+ patients but still have activity in PD-L1-negative patients Toxicity patterns are unique; grade >3 toxicities occur in <5% of patients Education at all levels (MD,PA/NP, nurses and patients & caregivers) about the nature of immune-related adverse events is necessary

92 A A Thank you

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