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Results of KEYNOTE-240: Phase 3 Study of Pembrolizumab vs Best Supportive Care for Second-Line T herapy in Advanced Hepatocellular Carcinoma.

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  1. Results of KEYNOTE-240: Phase 3 Study of Pembrolizumab vs Best Supportive Care for Second-Line Therapy in Advanced Hepatocellular Carcinoma Richard S. Finn,1 Baek-Yeol Ryoo,2 Philippe Merle,3 Masatoshi Kudo,4 Mohamed Bouattour,5Ho-Yeong Lim,6Valeriy Breder,7 Julien Edeline,8 Yee Chao,9 Sadahisa Ogasawara,10 Thomas Yau,11 Marcelo Garrido,12 Stephen L. Chan,13 Jennifer Knox,14 Bruno Daniele,15 Scot W. Ebbinghaus,16Erluo Chen,16 Abby B. Siegel,16 Andrew X. Zhu,17 Ann-Lii Cheng,18 for the KEYNOTE-240 Investigators 1University of California, Los Angeles, Los Angeles, CA, USA; 2Asan Medical Center University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Lyon North Hospital, Hepatology Unit, Lyon, France; 4Kindai University Faculty of Medicine, Osaka, Japan; 5Beaujon University Hospital, APHP, Clichy, France; 6Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 7NN Blokhin National Medical Research Center of Oncology of MoH, Moscow, Russian Federation; 8Centre Eugène Marquis, Rennes, France; 9 Taipei Veterans General Hospital,Taipai, Taiwan; 10Chiba University Graduate School of Medicine, Chiba, Japan; 11The University at Hong Kong, Hong Kong, China; 12 Pontificia Universidad Catolica de Chile,Santiago, Chile; 13State Key Laboratory of Translation Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong, China; 14Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada; 15Ospedale del Mare, Napoli, Italy; 16Merck & Co., Inc., Kenilworth, NJ, USA; 17Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 18National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan

  2. Disclosures Richard S. Finn, MD • Consultant/advisor: Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Eisai, Lilly, Genentech/Roche, AstraZeneca, and Exelixis • Research Funding to Institution: Pfizer, Bayer, Novartis, Eisai, Merck Sharp & Dohme Corp., Bristol-Myers Squibb, and Roche/Genentech • Expert Testimony: Novartis

  3. Pembrolizumab and Hepatocellular Carcinoma • Available treatment options for HCC • First-line: sorafenib and lenvatinib1,2 • Second-line: regorafenib, cabozantinib and the monoclonal antibody ramucirumab3-5 • HCC is often associated with inflammation and a suppressed immune environment6 • Immune checkpoint inhibitors have shown promising results in previously treated patients with advanced HCC • Pembrolizumab demonstrated encouraging antitumor activity and manageable safety in the phase 2 KEYNOTE-224 study in patients with sorafenib-treated advanced HCC • US FDA granted accelerated approval to nivolumab and pembrolizumab in this population7,8 • KEYNOTE-240 (NCT02702401) is a phase 3 trial designed to confirm the efficacy and safety of pembrolizumab in this HCC population 1. Llovet JM, et al. N Engl J Med 2008; 359(4): 378-90. 2. Kudo M et al. Lancet 2018; 391(10126): 1163-73. 3. Bruix J et al. Lancet 2017; 389(10064): 56-66. 4. Abou-Alfa GK et al. N Engl J Med 2018; 379(1): 54-63. 5. Zhu AX et al. Lancet Oncol 2019; 20(2): 282-96. 6. Ringelhan M et al. Nat Immunol 2018; 19(3):222-32. 7. Zhu AX et al. Lancet Oncol 2018; 19(7): 940-52. 8. El-Khoueiry AB et al. Lancet 2017; 389(10088): 2492-502.

  4. KEYNOTE-240 Study Design Pembrolizumab 200 mg Q3W + BSC • Key Eligibility Criteria • Pathologically/radiographically confirmed HCC • Progression on/intolerance to sorafenib • Child Pugh class A • BCLC stage B/C • ECOG PS 0-1 • Measurable disease per RECIST v1.1 • Main portal vein invasion was excluded Randomized 2:1 N = 413 Saline-placebo Q3W + BSC • Stratification Factors • Geographic region (Asia w/o Japan vs non-Asia w/Japan) • Macrovascular invasion (Y vs N) • AFP level (≥200 vs <200 ng/mL) • Enrollment May 31, 2016 – November 23, 2017

  5. Study Endpoints • Primary • OS • PFS (RECIST v1.1, central review) • Secondary • ORR, DOR, DCR and TTP (all RECIST v1.1, central review) • Safety and tolerability • Response was assessed Q6W

  6. Statistical Considerations • Overall Type I error ()=0.025 controlled across testing of PFS, OS and ORR1 • Initial  allocation • PFS =0.002; OS =0.023   • ORR =0.0 (tested only if OS or PFS criteria met) •  re-allocated per multiplicity strategy specified in the protocol • OS testing by group sequential design •  controlled over 2 interim and final efficacy analyses (O’Brien-Fleming spending function2) • Primary analysis of PFS and ORR at 1st interim cut-off • Efficacy boundaries • p=0.0174 for OS (final analysis cutoff, Jan 2, 2019, based on 284 observed events) • p=0.0020 for PFS (at 1st interim cutoff, Mar 26, 2018) • Study power • 92% for OS with 273 deaths at α=2.3%, HR=0.65 • 94% for PFS with 331 PFS events at α=0.2%, HR=0.60 1. Maurer W, Bretz F. Stat Biopharm Res 2013; 5(4): 311-20. 2. Lan KKG, Demets DL. Biometrika 1983; 70(3): 659-63.

  7. Patient Disposition • Number screened • N = 588 • Randomly allocated (2:1) • N = 413 Placebo N = 135* Pembrolizumab N = 278* 5 completed treatment 28 ongoing 245 discontinued 173 progressive disease 48 adverse event 12 clinical progression 5 physician decision 6 withdrawal by patient 1 complete response 1 completed treatment 4 ongoing 130 discontinued 100 progressive disease 11 adverse event 12 clinical progression 3 withdrawal by patient 2 physician decision 1 protocol violation 1 excluded medication *Allocated and treated. Data cut-off: Jan 2, 2019.

  8. Baseline Demographics aIncludes Argentina, Australia, Canada, Chile, Colombia, Israel, Mexico, Norway, Russian Federation, and Turkey. Data cut-off: Jan 2, 2019.

  9. Baseline Characteristics a163 (58.6%) and 85 (63.0%) uninfected patients in pembrolizumab and placebo groups respectively. bTime from stopping until 1st dose of study medication. Data cut-off: Jan 2, 2019.

  10. Overall Survival Pre-specified p=0.0174 required for statistical significance Data Cutoff: Jan 2, 2019.

  11. Overall Survival in Subgroups Data cutoff: Jan 2, 2019.

  12. Regional Differences in Overall Survival Other includes: Argentina, Australia, Canada, Chile, Colombia, Israel, Mexico, Norway, Russian Federation and Turkey. Data cutoff: Jan 2, 2019.

  13. Progression-Free Survival Final Analysis Primary Analysis Pre-specified p=0.002 required for statistical significance Data cutoff: Mar 26, 2018 for PFS primary analysis and Jan 2, 2019 for OS final analysis.

  14. Progression-Free Survival in Subgroups Data cutoff: Jan 2, 2019.

  15. Time-to-Progression Data Cutoff: Jan 2, 2019.

  16. Objective Response Rate at Final Analysis(RECIST 1.1, BICR) • Duration of response, median (range)b,c: • Pembrolizumab: 13.8 mo (1.5+ mo − 23.6+ mo) • Placebo: not reached (2.8 mo−20.4+ mo) aNominal one-sided P-value based on the Miettinen and Nurminen method stratified by randomization factors. bFrom product-limit (Kaplan-Meier) method for censored data. C “+” indicates no PD by the time of last disease assessment. Data cutoff: Jan 2, 2019.

  17. Maximum Percentage Changes from Baseline in Size of Target Lesions Pembrolizumab Placebo Based on RECIST v1.1 by central radiology review in patients who had both pre- and post-treatment image measurements. Dashed line represents threshold for response. Changes greater than 100% were truncated at 100%. Data cutoff: Jan 2, 2019.

  18. Summary of Adverse Events aAttributed to treatment by the investigator. bOne grade 5 event occurred in 1 patient (death) in the pembrolizumab group.cDeath attributed to malignant neoplasm progression, possibly related to study treatment by investigator. dAnyatttribution. eNo grade 5 immune-mediated AEs reported. fBased on sponsor assessment; no HBV/HBC viral flares identified. Data cutoff: Jan 2, 2019.

  19. Adverse Events of Any Attribution: Frequency ≥15% aAEs listed in descending order of frequency in the pembrolizumab group. No grade 5 events reported in ≥15% of patients. Data cutoff: Jan 2, 2019.

  20. Treatment-Related Adverse Events: Frequency ≥5% aAEs attributed to treatment by the investigator. bNo grade 5 AEs occurred in ≥5% of patients; one grade 5 event occurred in 1 (0.4%) patient (death) in the pembrolizumab group, attributed to malignant neoplasm progression, possibly related to study treatment by investigator. Data cutoff: Jan 2, 2019

  21. Immune-Mediated Adverse Events and Infusion Reactions Event of any attribution in order of decreasing frequency for pembrolizumab. No grade 5 immune-mediated events reported. Data cutoff: Jan 2 , 2019

  22. Post-study Anticancer Therapy aIncluded both with/without prior exposure to other post-treatment anticancer medications. bIncluded regorafenib, lenvatinib, cabozantinib, and ramucirumab. Data cut-off: Jan 2, 2019.

  23. Exploratory Sensitivity Analyses: Impact of Post-Treatment Anticancer Medications on OS Adjusted for treatment switches in both arms. IPCW, inverse probability of censoring weighting.aHR based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, macrovascular invasion and AFP (ng/mL), and bootstrap 95% CI for both the 2-stage model and IPCW. bOne-sided p-value based on the IPCW log-rank test; based on stratified log-rank test, adjusted for treatment switch for the 2-stage model. c p=0.0090 and d p=0.002, one-sided p-values based on bootstrap percentiles.

  24. Relationship Between PD-L1 Expression and Outcomes • 76 patients on Pembro arm had tissue available for PDL-1 staining • Baseline characteristics between those with tissue and without were similar • PD-L1 CPS and TPS were not significantly associated with clinical response to pembrolizumab in this small subset of pts (one-sided p>0.10) • An association of PD-L1 CPS with clinical response was previously observed in KEYNOTE-2241 aPD-L1 expression was assessed using PD-L1 IHC 22C3 pharmDx kit, scored by CPS in tumor cells, lymphocytes, and macrophages and by TPS in tumor cells. bConfirmed best overall response. cOne-sided Wald test p-value from logistic regression for BOR and Cox regression for PFS and OS. PD-L1 CPS and TPS were on a square root scale. Regression adjusted for ECOG (0 vs 1+). 1. Zhu AX et al. Lancet Oncol 2019; 20(2): 282-96. Data cut-off: Jan 2, 2019.

  25. Effect of Pembro vs Placebo by PD-L1 Expression Status • Treatment effects for pembrolizumab vs placebo for ORR, PFS and OS did not appear to be larger in pts with PD-L1+ (CPS ≥1) tumors than those with PD-L1– tumors (CPS <1) aPD-L1 expression was assessed using PD-L1 IHC 22C3 pharmDx kit and scored by combined positive score (CPS) in tumor cells, lymphocytes, and macrophages. bConfirmed best overall response. PD-L1 CPS was on a square root scale. Regression adjusted for ECOG (0 vs 1+). Data cut-off: Jan 2, 2019.

  26. Summary • Pembrolizumab reduced the risk of death by 22% and improved PFS over placebo in patients with advanced HCC • HR=0.781 (P=0.0238) for OS; HR=0.718 (P=0.0022) for PFS • Prespecified efficacy boundaries were not reached • ORR was higher for pembrolizumab (18.3%) than placebo (4.4%) • Responses to pembrolizumab were durable (13.8 months) • The safety profile, including incidence of immune-mediated events and hepatitis, was similar to that of pembrolizumab in other tumor types; no HBV or HCV viral flares were identified

  27. Conclusions • KEYNOTE-240 did not meet the statistical criteria for either of the dual endpoints • The magnitude of benefit as captured by the HR for OS and PFS, the ORR and response duration are consistent with the findings of KEYNOTE-224 • Taken together, these data support that the risk-benefit balance for pembrolizumab is favorable in the second-line setting for HCC • An additional phase 3 study evaluating pembrolizumab as second-line therapy in previously treated patients with advanced HCC is ongoing in the Asia-Pacific region (KEYNOTE-394; NCT03062358)

  28. Acknowledgments • Patients and their families • Investigators and site personnel from 119 medical centers in 27 countries • Argentina:Silva M, Gadano A, Barrabino M; Australia: Roberts S, Strasser S, Sievert W, Ng W; Belgium:Verslype C, Borbath I, Van Vlierberghe H, Laethem, J-L Van; Canada:Asselah J, Ramjeesingh R, Tam V, Goel R, Zbuk K, Ko Y-J, Asselah J; Chile:Garrido M; Colombia: Restrepo Gutierrez JC, Cardona A; Denmark:Vistisen K, Weber, B; France:Merle P, Peron, J-M, Anty R, Ozenne V, Decaens T, Bouattour M, Boige V, Gilabert M, Edeline J; Germany: Galle P, Springfeld C, Vogel A, Folprecht G, Bitzer M;Hong Kong:Chan L, Tai Y-P, Yau C-C; Hungary: Geczi L, Arkosy, P, Kahan Z, Mahr K, Mangel L, Lohinszky J;Ireland:McDermott R;Israel: Geva R, Stemmer S; Italy:Daniele B, Fanello S, Rimassa L; Japan: Hasegawa K, Isoda N, Morimoto M, Ogasawara S, Kuromatsu R, Aikata H, Ohkawa K, Ishigami M, Kudo M, Numata K, Yamashita T, Uchida S, Nakajima T, Karino Y, Furuse J, Tada T, Itoh Y, Kurosaki M, Ogawa K; Mexico:Diaz Romero, M del, Hernandez Hernandez C; Norway:Dajani O; Phillipines:Lao-Tan J, Ong J; Poland: Szutowicz-Zielinska E, Kraj L; Puerto Rico: Velez-Cortes H, Rodriguez-Monge E; Russia:Breder V, Barannikova T, Moiseyenko V, Manikhas G, Kostorov V, Akhmetzyanov F; South Korea:Lim HY, Ryoo B-Y, Lee, Myung A, Kim YH, Lee K-H, Choi HJ; Taiwan: Cheng A-Li, Chao Y, Lin S-M, Chen, Y-H, Chiu C-F, Chen C-H; Thailand:Tanasanvimon S, Ativitavas T, Korphaisarn K, Dechaphunkul A, Chewaskulyong B; Turkey: Cicin I, Sumbul A, Harputluoglu H, Goker E, Seker M, Saglam S, Cabuk Ozcan D; United Kingdom: Sarker D, Palmer D, Punia P, Sharma R, Zubair S; United States: Finn R, Karwal M, Kaseb A, Damjanov N, Vaccaro G, Acoba J, Carney J, Ramirez R, Iyer R, Lee J, Zhu, AX, Baron A, Li D, Kaubisch A, Heyne K, Reske T, Al-Rajabi R, Dhanarajan A, Noel M, Tesfaye A, Saylors G, Chaudhry A, Xiao G, Braiteh F, He R, Raj M, Emmons S, Menter A, Sanabria J, Klempner S, Olowokure O, Thota R, Zakari A, Huber M, Treisman J, Lawitz E, Kim E, Costin D, Lammers P, Sahai V. • Merck & Co., Inc.: • Olga Kuznetsova, Melissa Buckland, Himanshu Patel, Kristel Vandormael, Rachid Massaad, Andrea Webber, Anran Wang, Heng Zhou, Joanne E Tomassini • Study Funding: • Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

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