Conversations in Oncology November 12-13 Kerry Hotel Pudong, Shanghai China
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
Immunotherapy in Scientific News 2013 2014 2015 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
Mutational Heterogeneity in Cancer Lawrence MS et al. Nature. 2013;499:214-218. 4
Immune Checkpoints Mellman. Nature. 2011. 5
Summary of Phase II Trials on PD-1 and PD-L1 Inhibitors Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab N 129 475 175 228 184 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;33:2004-2012; Herbst R. Nature. 2014;515:563-567; Soria JC. ESMO 2013; Garon E. NEJM. 2015;372:2018-2028; Rizvi N. ASCO 2015; Guley LJ. ASCO 2015. 7
Checkmate 017 and 057 on Nivolumab Overall Survival Squamous Ca HR 0.59 (95% CI, 0.44-0.79) P<0.001 Brahmer J et al. NEJM. 2015;373:123. Non-squamous NSCLC HR 0.73 (95% CI, 0.59-0.89) P=0.002 Borghaei H et al. NEJM. 2015;373:1627. 8
CheckMate 017: Progression-Free Survival PFS per investigator. Spigel DR et al. ASCO 2015. 9
CheckMate 057: Progression-free Survival Symbols represent censored observations. Paz-Ares L et al. ASCO 2015. 10
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, 0.36-0.70) P<0.0001 Pembrolizumab 2 mg/kg q3wks : HR 0.54 (95% CI, 0.38-0.77) P=0.0002 ITT Population Pembrolizumab 10 mg/kg q3wks: HR 0.61 (95% CI, 0.49-0.75) P=0.0001 Pembrolizumab 2 mg/kg q3wks: HR 0.71 (95% CI, 0.58-0.88) P=0.0008 Herbst R et al. Lancet. 2015, online December 19. 11
Pembrolizumab vs Docetaxel Keynote 010 Docetaxel Relevant to PD-L1 Expression 12
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
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. http://tago.ca/9hh. 14
Barlesi F et al. ESMO 2016. Abstract LBA44_PR
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
Phase 3 CheckMate 026 Study Design: Nivolumab vs Chemotherapy in 1st-line NSCLC 19
CHECKMATE 026: PFS and OS in 5% PD-L1+ Socinski M et al. ESMO 2016. Abstract LBA7_PR 20
Socinski M et al. ESMO 2016. Abstract LBA7_PR 21
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, 2016 6:45 am EDT www.mercknewsroom.com Reck M et al. ESMO 2016. Abstract LBA8_PR 22
KEYNOTE 024 Baseline Charactistics Reck M et al. ESMO 2016. Abstract LBA8_PR 23
KEYNOTE 024: PFS Reck M et al. ESMO 2016. Abstract LBA8_PR 24
KEYNOTE 024: OS and Objective Response Reck M et al. ESMO 2016. Abstract LBA8_PR 25
KEYNOTE 024: AE and Exposure Data Cutoff: May 9, 2016 Reck M et al. ESMO 2016. Abstract LBA8_PR 26
PD-L1 Expression (IHC) 34% of Patients were TPS <1% 27
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 2016. 28
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 2016. 29
NR = not reached. Gadgeel et al. ASCO 2016.
KEYNOTE 021: COHORT G STUDY Langer LJ et al. ESMO 2016. Abstract LBA46_PR 31
KEYNOTE 021: COHORT G Baseline Characteristics Langer LJ et al. ESMO 2016. Abstract LBA46_PR 32
KEYNOTE 021: COHORT G Overall Responses and by PD-L1 TPS Langer LJ et al. ESMO 2016. Abstract LBA46_PR 33
KEYNOTE 021: COHORT G PFS and OS Langer LJ et al. ESMO 2016. Abstract LBA46_PR 34
KEYNOTE 021: COHORT G Exposure and AE Data Cutoff Aug 8, 2016 Langer LJ et al. ESMO 2016. Abstract LBA46_PR 35
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
Checkmate 012: Safety Profile ESMO 2016. 37
Nivolumab + Ipilimumab: Efficacy with Increasing Levels of PD-L1 Expression Hellman M et al. ASCO 2016. Abstract 3001 38
Checkmate 012 39
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PD-L1 Expression Within the Tumour in Relation to Efficacy of PD-1/PD-L1 Blocker # of Cases 42 44 34 94 30 53 113 129 65 55 411 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 2014. 41
Challenges in PD-L1 Detection: Currently, 4 Methods Are Used 42
High Mutational Burden Predicts Response to Pembrolizumab (anti-pd1) in NSCLC Rizvi. Science. 2015. 43
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;348:124. 44
Prospective in Personalised Immunotherapy *Possible hypothetical algorithm. 45
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
Thanks for Your Attention 47