1078MO - Pembrolizumab (pembro) vs placebo as adjuvant therapy for high-risk stage II melanoma: Long-term follow-up, rechallenge, and crossover in KEYNOTE-716

Background

Adjuvant pembro significantly prolonged RFS and DMFS vs placebo in patients (pts) with resected stage IIB or IIC melanoma in the phase III KEYNOTE-716 study (NCT03553836). We present updated data, including rechallenge and crossover to pembro.

Methods

Pts aged ≥12 y with resected stage IIB or IIC melanoma were randomly assigned 1:1 to pembro 200 mg (2 mg/kg up to 200 mg for pts <18 y) or placebo Q3W for ≤17 cycles (∼1 y). The primary end point was RFS. Secondary end points were DMFS and safety. PRFS2 was exploratory. Pts with recurrence >6 mo after 17 cycles of pembro or at any time following placebo in part 1 were eligible to be rechallenged with or crossover to pembro in part 2 (≤17 cycles for resectable disease; ≤35 cycles for unresectable). Part 2 assessed RFS (resectable disease), progression-free survival (PFS; unresectable disease), and safety.

Results

Of 976 pts, 487 were assigned to pembro and 489 to placebo. With a median follow-up of 52.8 mo, pembro prolonged RFS (HR, 0.62 [95% CI, 0.50-0.78]; 48 mo, 71% vs 58%) and DMFS (HR, 0.59 [95% CI, 0.45-0.77]; 48 mo, 81% vs 70%) vs placebo. Median PRFS2 was not reached (NR) in either arm (HR, 0.75 [95% CI, 0.56-1.01]). Of all pts, 9 of 487 (2%) in the pembro group were rechallenged and 71 of 489 (15%) in the placebo group crossed over to pembro. Median follow-up for part 2 was 35.2 mo. Of pts with resectable disease, 0% (0/6) of rechallenged pts and 41% (17/41) of crossover pts had an RFS event (medians, NR). Among pts with unresectable disease, ORR was 0% (0/3; 95% CI, 0-71) in the rechallenge group and 43% (13/30; 95% CI, 26-63) in the crossover group; 33% (1/3) of rechallenge pts and 47% (14/30) of crossover pts had a PFS event (medians, NR and 22 mo). The part 1 safety profile was consistent with prior reports. In part 2, 67% of rechallenged pts and 61% of crossover pts had treatment-related AEs (grade 3/4, 11% and 10%; no grade 5). Immune-mediated AEs or infusion reactions occurred in 0% of rechallenged pts and 30% of crossover pts (grade 3/4, 0% and 6%; no grade 5).

Conclusions

With >4 y of follow-up, pembro continued to show prolonged RFS and DMFS and had promising PRFS2. OS data were immature and will be reported in the future.

Clinical trial identification

NCT03553836; June 12, 2018.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Jemimah Walker, PhD, and Rob Steger, PhD, of ApotheCom (Yardley, PA, USA).

Legal entity responsible for the study

Merck Sharp & Dohme LLC.

Funding

Merck Sharp & Dohme LLC.

Disclosure

P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, Novartis, Merck Serono, Sun Pharma, Sanofi, Sandoz, Immunocore, Boehringer Ingelheim Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant, Advisory Role and Travel support: MSD, Pierre Fabre; Financial Interests, Personal, Other, Consultant and Advisory Role.Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Consultant Role: Pfizer, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role.Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Personal, Other, Consultant and Advisory: Erasca; Financial Interests, Personal, Other, Consultant: Philogen; Financial Interests, Personal, Advisory Board: BionTech, Anaveon; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR. M.A. Khattak: Financial Interests, Personal, Advisory Board: Moderna; Financial Interests, Personal, Invited Speaker: MSD, Evaxion; Financial Interests, Personal, Other, Conference sponsorship: Evaxion; Financial Interests, Personal, Other, Advisory role: One Clinical Research. P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfzer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Member of Board of Directors: Polish Society of Surgical Oncology; Non-Financial Interests, Member of Board of Directors, President: Polish Oncological Society. M. Del Vecchio: Financial Interests, Personal, Advisory Board, Advisor and Consultant and Invited Speaker: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Immunocore; Non-Financial Interests, Principal Investigator, Clinical Trials: Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore. F. Spagnolo: Financial Interests, Personal, Advisory Board: Novartis, Merck Sharp & Dohme, Sun Pharma, Pierre Fabre, Philogen; Financial Interests, Personal, Invited Speaker: Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre, Merck, Sanofi, Sun Pharma, IGEA. J. Mackiewicz: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Novartis; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre; Other, Other, Travel grant: Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre. L. de la Cruz Merino: Financial Interests, Personal and Institutional, Advisory Board: MSD-Merck, Novartis; Financial Interests, Personal and Institutional, Research Grant: MSD-Merck; Financial Interests, Personal and Institutional, Principal Investigator: MSD-Merck, Novartis; Financial Interests, Personal and Institutional, Advisory Role: MSD-Merck; Financial Interests, Personal and Institutional, Speaker’s Bureau: Novartis. V. Chiarion Sileni: Financial Interests, Personal, Other, Travel, registration, and accommodation to attend ASCO annual meetings: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre, Immunocore; Financial Interests, Personal, Other, Medical Congress Travel, registration and accommodation: Sanofi. J.M. Kirkwood: Financial Interests, Personal, Advisory Board: Ankyra Therapeutics, Bristol Myers Squibb, Iovance Biotherapeutics, Istari Oncology, Jazz Pharmaceuticals, Inc, Merck, Natera, Inc, Novartis Pharmaceuticals, OncoCyte Corporation, Regeneron Pharmaceuticals, Inc, Replimune, Inc, Scopus BioPharma, Inc; Financial Interests, Personal, Other, Data Safety Monitoring Board: Axio Research, LLC, IQVIA; Financial Interests, Personal, Advisory Role: CytomX Therapeutics, Magnolia Innovation, Inc, PathAI, Inc, Pfizer, Inc, Piper Sandler & Co, PyrOjas Corporation, Takeda, Valar Labs, Inc; Financial Interests, Personal, Other, Leader of Consensus Conference: DermTech; Financial Interests, Personal, Advisory Role, Leader of Consensus Conference: iOnctura; Financial Interests, Personal, Other, Data Safety Committee: Lytix Biopharma AS; Financial Interests, Institutional, Principal Investigator: Amgen, Inc, Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co, Immunocore, Ltd, Iovance Biotherapeutics, Lion Biotechnologies, Inc, Lytix Biopharma AS, Novartis Pharmaceuticals, Takeda, Verastem, Inc. C. Robert: Financial Interests, Personal, Advisory Board, Consultancy fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, Pfizer, Sun Pharma, Merck, Ultimovacs, Regeneron, EGLE, Philogen, MAAT Pharma; Financial Interests, Personal, Other, Steering Committee: Novartis, Regeneron, Pfizer, IO Biotech; Financial Interests, Personal, Other, IDMC: ULTIMOVACS; Financial Interests, Personal, Invited Speaker: Pierre Fabre, Sanofi, BMS, MSD, Novartis. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, MSD, Merck Serono, Sanofi, Neracare, SunPharma; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare, InFlarX, BioAlta, Daiichi Sanyko, NoviGenix, Anaveon, AstraZeneca, PamGene, BioNTech, Immatics, CureVac, Erasca, Formycon, Replimune, Seagen, SunPharma, Ultimovacs; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG; Non-Financial Interests, Leadership Role, Founding member and SC chair: European Melanoma Registry (EuMelaReg). F. De Galitiis: Financial Interests, Personal, Other, Invited Speaker, Expert Testimony, Advisory Board: BMS, Novartis. M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre Fabre, Eisai, Nektar, Regeneron. A. Odeleye-Ajakaye, M. Kalabis: Financial Interests, Institutional, Full or part-time Employment: Merck. C. Krepler: Financial Interests, Personal, Full or part-time Employment: Merck& Co; Financial Interests, Personal, Stocks/Shares: Merck& Co. A.M.M. Eggermont: Financial Interests, Personal, Advisory Board: Agenus, BioInvent, Boehringer Ingelheim Ingelheim, BioNTech, Brenus, CatalYm, Galecto, Egle, Eikon Therapeutics, Imcheck, IO Biotech, ISA Pharmaceuticals, Merck&Co, MSD, Pfizer, Pierre Fabre, IQVIA, Pierre Fabre, GenOway, Sairopa, Scancell, SkylineDX, Scorpion, TigaTX, Trained Therapeutics DIscovery; Financial Interests, Personal, Stocks/Shares: IO Biotech, Sairopa, SkylineDX. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L, IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. All other authors have declared no conflicts of interest.