Conversations in Oncology. November Kerry Hotel Pudong, Shanghai China

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1 Conversations in Oncology November Kerry Hotel Pudong, Shanghai China

2 Immunotherapy of Lung Cancer Professor Caicun Zhou All materials are for scientific exchanges. Afatinib and nintedanib are not launched in China yet and are still under application. 2

3 Immunotherapy in Scientific News Former US President Jimmy Carter said in a statement that a recent brain MRI showed his original melanoma brain metastases have disappeared; he will continue to receive treatment with Keytruda. 3

4 Mutational Heterogeneity in Cancer Lawrence MS et al. Nature. 2013;499:

5 Immune Checkpoints Mellman. Nature

6

7 Summary of Phase II Trials on PD-1 and PD-L1 Inhibitors Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab N RR Squamous Non-Squamous 17% 18% 23.5% 19% 27% 21% 21% 13% 14% Treatmentrelated AEs: All grades Grade 3/4 41% 4.7% 71% 9.5% 66% 11% 50% 8% 77% 12% RR PDL-1 + PDL-1-16% 13% 42% (>50%) 10% (<1%) 34% IC 2/3 or TC 2/3 (half if 3 used) Gettinger S. J Clin Oncol. 2015;33: ; Herbst R. Nature. 2014;515: ; Soria JC. ESMO 2013; Garon E. NEJM. 2015;372: ; Rizvi N. ASCO 2015; Guley LJ. ASCO

8 Checkmate 017 and 057 on Nivolumab Overall Survival Squamous Ca HR 0.59 (95% CI, ) P<0.001 Brahmer J et al. NEJM. 2015;373:123. Non-squamous NSCLC HR 0.73 (95% CI, ) P=0.002 Borghaei H et al. NEJM. 2015;373:

9 CheckMate 017: Progression-Free Survival PFS per investigator. Spigel DR et al. ASCO

10 CheckMate 057: Progression-free Survival Symbols represent censored observations. Paz-Ares L et al. ASCO

11 Keynote 010: Overall Survival (Pembrolizumab 2 or 10 mg/kg vs Docetaxel) PD-L1 50% Pembrolizumab 10 mg/kg q3wks: HR 0.50 (95% CI, ) P< Pembrolizumab 2 mg/kg q3wks : HR 0.54 (95% CI, ) P= ITT Population Pembrolizumab 10 mg/kg q3wks: HR 0.61 (95% CI, ) P= Pembrolizumab 2 mg/kg q3wks: HR 0.71 (95% CI, ) P= Herbst R et al. Lancet. 2015, online December

12 Pembrolizumab vs Docetaxel Keynote 010 Docetaxel Relevant to PD-L1 Expression 12

13 Overall Survival in POPLAR Phase 2 Atezolimab vs Docetaxel ECOG 0 32%, ECOG 1 68%; Adeno 66%, Squamous 34% Fehrenbacher L et al. Lancet. 2016, March 9. 13

14 Phase III Oak Study Design a A prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup ( 1% PD-L1 expression). TC = tumour cells; IC = tumour-infiltrating immune cells. Barlesi et al. Atezolizumab Phase III OAK Study. 14

15 Barlesi F et al. ESMO Abstract LBA44_PR

16 Strategies of Immunotherapy in 1st-line Setting Monotherapy High PD-L1 expression In combination with chemotherapy Low PD-L1 expression In combination with other agents Targeted therapies Bevacizumab Immune checkpoint inhibitors Other immunotherapies 18

17 Phase 3 CheckMate 026 Study Design: Nivolumab vs Chemotherapy in 1st-line NSCLC 19

18 CHECKMATE 026: PFS and OS in 5% PD-L1+ Socinski M et al. ESMO Abstract LBA7_PR 20

19 Socinski M et al. ESMO Abstract LBA7_PR 21

20 Pembrolizumab as First-Line Therapy in Patients With High Levels of PD-L1: KEYNOTE-024 Merck s KEYTRUDA (pembrolizumab) demonstrates superior-progression-free survival and overall survival compared to chemotherapy as first-line therapy in patients with advanced non-small cell lung cance.r Press release, Thursday, June 16, :45 am EDT Reck M et al. ESMO Abstract LBA8_PR 22

21 KEYNOTE 024 Baseline Charactistics Reck M et al. ESMO Abstract LBA8_PR 23

22 KEYNOTE 024: PFS Reck M et al. ESMO Abstract LBA8_PR 24

23 KEYNOTE 024: OS and Objective Response Reck M et al. ESMO Abstract LBA8_PR 25

24 KEYNOTE 024: AE and Exposure Data Cutoff: May 9, 2016 Reck M et al. ESMO Abstract LBA8_PR 26

25 PD-L1 Expression (IHC) 34% of Patients were TPS <1% 27

26 KEYNOTE-021 (Phase I/II): Study Design Stage IIIB/IV NSCLC No systemic therapy for recurrent disease ECOG PS 0-1 (n=308) Cohort A: Pembrolizumab + carboplatin + paclitaxel (n=25) Cohort B: Pembrolizumab + carboplatin + paclitaxel + bevacizumab (n=25) Cohort C: Pembrolizumab + carboplatin + pemetrexed (n=25) Maintenance pembrolizumab Maintenance pembrolizumab + bevacizumab Maintenance pembrolizumab + pemetrexed Pembrolizumab dose: 2 or 10 mg/kg iv q3w; Carboplatin dose: AUC 6 iv (cohort A and B), AUC 5 iv (cohort C); Paclitaxel dose: 200 mg/m 2 iv q3w; Bevacizumab dose:15 mg/kg iv q3w; Pemetrexed dose: 500 mg/m 2 iv q3w Primary endpoint ORR Secondary endpoints OS PFS DoR Gadgeel et al. ASCO

27 KEYNOTE-021: Response Cohort A: Pembrolizumab + carboplatin + paclitaxel (n=25) Cohort B: Pembrolizumab + carboplatin + paclitaxel + bevacizumab (n=25) Cohort C: Pembrolizumab + carboplatin + pemetrexed (n=25) *Patients with TPS 50%. Gadgeel et al. ASCO

28 NR = not reached. Gadgeel et al. ASCO 2016.

29 KEYNOTE 021: COHORT G STUDY Langer LJ et al. ESMO Abstract LBA46_PR 31

30 KEYNOTE 021: COHORT G Baseline Characteristics Langer LJ et al. ESMO Abstract LBA46_PR 32

31 KEYNOTE 021: COHORT G Overall Responses and by PD-L1 TPS Langer LJ et al. ESMO Abstract LBA46_PR 33

32 KEYNOTE 021: COHORT G PFS and OS Langer LJ et al. ESMO Abstract LBA46_PR 34

33 KEYNOTE 021: COHORT G Exposure and AE Data Cutoff Aug 8, 2016 Langer LJ et al. ESMO Abstract LBA46_PR 35

34 CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1 Nivo 1 mg/kg IV Q3W x 4 Nivo 1 mg/kg IV Q2W Nivo 3 mg/kg IV Q2W Nivo 3 mg/kg IV Q2W Ipi 1 mg/kg IV Q3W x 4 Ipi 1 mg/kg IV Q6W Ipi 1 mg/kg IV Q12W Ipi 1 mg/kg IV Q6W Nivo 3 mg/kg IV Q2W until disease progression or unacceptable toxicity a Until disease progression or unacceptable toxicity a Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wks Exploratory endpoints: OS; efficacy by PD-L1 expression Here, we report results from new cohorts explored to permit synergistic activity and acceptable safety profile of combination treatment with nivolumab and ipilimumab a Patients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit. 36

35 Checkmate 012: Safety Profile ESMO

36 Nivolumab + Ipilimumab: Efficacy with Increasing Levels of PD-L1 Expression Hellman M et al. ASCO Abstract

37 Checkmate

38 40

39 PD-L1 Expression Within the Tumour in Relation to Efficacy of PD-1/PD-L1 Blocker # of Cases Response Rates Unselected 21% 32% 29% 22% 23% 23% 40% 19% 26% 18% 40% PD-L1 Expression Level PD-L1+ 36% 67% 44% 39% 27% 46% 49% 37% 43% 46% 49% PD-L1-0% 19% 17% 13% 20% 15% 13% 11% 11% 11% 13% From Callahan: ASCO

40 Challenges in PD-L1 Detection: Currently, 4 Methods Are Used 42

41 High Mutational Burden Predicts Response to Pembrolizumab (anti-pd1) in NSCLC Rizvi. Science

42 Mutation Burden and PD-1 Inhibition Total Exonic Mutation Burden DCB = Durable clinical benefit (n=14) NDB = Non-durable clinical benefit (n=17) NR = No response (n=3) Rizvi et al. Science. 2015;348:

43 Prospective in Personalised Immunotherapy *Possible hypothetical algorithm. 45

44 Conclusions Immunotherapy standard 2nd-line therapy for advanced NSCLC Better OS compared with docetaxel Phase III trials: Nivolumab, Pembrolizumab, Atezolizumab 1st-line pembrolizumab better than doublet chemotherapy in those with PD-L1 >50%: OS, PFS, ORR, and safety profile Adverse events controllable and different from chemotherapy Biomarkers needed in personalised immunotherapy 46

45 Thanks for Your Attention 47