Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

BACKGROUND

In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively.

METHODS

Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes.

RESULTS

At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE.

CONCLUSIONS

Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement A.M.M.E.—consulting fees: Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, GSK, IO Biotech, ISA Pharmaceuticals, Merck/MSD, Nektar, Novartis, Pfizer, SAiRoPA, Sellas, SkylineDx, TigaTx, TTxDiscovery; payment or honoraria: Biocad, BMS, Merck/MSD, Novartis; payment for expert testimony: Novartis; support for attending meetings and/or travel: BMS; participation on a Data Safety Monitoring Board or Advisory Board: GSK, Novartis and Pfizer; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences Gerrman Cancer Aid; stock or stock options: SkylineDx and SAiRoPA P.L.—personal fees, advisory, speaker, trial grants: BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre Fabre, NeraCare, Roche and Oncology Education Canada. N.I.—stock or stock options: Merck stock; other financial interest: employee Merck & Co. M.K.—study funding from Merck to institution; grants or contacts: Pierre Fabre; sponsor and provider of an academic grant for different melanoma studies (money paid to the author’s institution); BMS Sponsor and provider of an academic grant for different melanoma studies (money paid to the author’s institution). S.S.—Merck is the sponsor of this study; payment was made to the author’s institution; grants or contracts: BMS, Pierre Fabre—sponsor and provider of academic grants to other EORTC melanoma studies; payments were made to the author’s institution. C.R.—consulting fees: occasional consultant for Roche, Novartis, Pierre Fabre, MSD, BMS, Sanofi, Pfizer; payment or honoraria: occasional consultant for Roche, Novartis, Pierre Fabre, MSD, BMS, Sanofi and Pfizer. A.M.—grants or contracts: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb; payment or honoraria: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb; support for attending meetings: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb. V.A.—payment or honoraria: BMS, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche and Limbic Ad Boards. C.K.—stock or stock options: Merck & Co. C.B.—grants or contracts: BMS, Novartis and NanoString Payments were made to the author’s institution; consulting fees: BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre; payments were made to the author’s institution. Third Rock Venture: payments were made to the author; stock or stock options: Unity Cars—Stocks; Immagene BV - Co-founder. A.C.J.v.A.—grants or contracts from any entity: Amgen, Merck-Pfizer, all paid to the institute and unrelated to current work; participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, all paid to the institute and unrelated to current work M.M.—payment or honoraria: BMS, MSD, Novartis, Pierre Fabre and Sanofi. G.V.L. is a consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., specialised Therapeutics Australia Pty Ltd; payment or honoraria: Bristol Myers Squibb—personal—one hour lecture of the author’s own slides; Pierre Fabre—personal—one hour lecture of the author’s own slides. A.M.D.G.—payment or honoraria: BMS, MSD, Sanofi, Pierre Fabre; compensated educational activities; support for attending meetings and/or travel: Pierre Fabre and BMS; participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Pierre Fabre, Sanofi, Incyte, GSK and Novartis. S.S.—grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Merck Serono, Genentech, AstraZeneca; funding to the institution; consulting fees: Amgen, Merck Sharp & Dohme, Merck Serono, AstraZeneca and Bristol Myer Squibb (funding to the institution). R.K.—consulting fees: Merck, Array/Pfizer, BMS and Regeneron; participation on a Data Safety Monitoring Board or Advisory Board: Merck, Array/Pfizer, Regeneron and BMS P.L.O.R.—patents planned, issued or pending: PLCG1 for T-cell lymphoma. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Takeda, Kyowa, 4SC, Helsinn, Recordati Rare Diseases, Innate Pharma, MIRAGEN advisory boards; payments to the author, receipt of equipment, materials, drugs, medical writing, gifts or other services: MEDA (Viatris) support for the investigator-initiated clinical trial. I.M.S.—all support for the present manuscript: MSD/EORTC partly covering of trial-associated expenses to the author’s institution; consulting fees: MSD - Webpage text, personal fee; support for attending meetings and/or travel: MSD—Conference in oncology; participation on a Data Safety Monitoring Board or Advisory Board: Roche/Genentech—IDSM, personal fee, Pierre Fabre; Novartis—Adv board, personal fee. S.P.—grants or contracts from any entity: Almirall—to the author’s institution; ISDIN—to the author’s institution; La Roche-Posay—to the author’s institution; consulting fees: ISDIN, Almirall—to the author; Sanofi, Sun Pharma—to the author; Pfizer, Roche and Regeneron—to the author; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche-Posay—to the author; Pfizer, Roche and Regeneron—to the author. BMS, Sun Pharma—to the author; support for attending meetings and/or travel: Almirall—to the author; participation on a Data Safety Monitoring Board orAdvisory Board: Roche and Sanofi—to the author; Sun Pharma and Almirall—to the author; ISDIN, Pfizer and Novartis—to the author. Pi.Q.—payment or honoraria: BMS, MSD, Pierre Fabre, Novartis and Roche; support for attending meetings and/or travel: BMS, MSD, Pierre Fabre, Novartis and Roche. Pa.Q.—payment or honoraria: Roche, Novartis, Sun Pharma, Sanofi, BMS, MSD, Merck Serono and Pierre Fabre. P.M.—payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Allmiral-Hermal, Beiersdorf, BMS, Medac, MSD, Pierre Fabre, Novartis, Roche and Sanofi Genzyme; support for attending meetings and/or travel: Amgen, Allmiral-Hermal, Beiersdorf, BMS, Medac, MSD, Pierre Fabre, Novartis, Roche and Sanofi Genzyme; participation on a Data Safety Monitoring Board or Advisory Board: CureVac AG. M.H.—payment or honoraria: MSD, BMS, Novartis; lecture at MSD symposium; payment for expert testimony: Pierre Fabre—A written statement to the Finnish Pricing Board; Participation on a Data Safety Monitoring Board or Advisory Board: MSD, BMS, Novartis, Varian—Participation on National and Nordic advisory boards A.H.—Grants or contracts from any entity: clinical trial support (grant to the institution): MSD/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; consulting fees: clinical trial support (grant to the institution): MSD/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; Payment or honoraria: MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; Participation on a Data Safety Monitoring Board or Advisory Board: MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Immunocore, Replimune and Seagen. N.Y.—grants or contracts from any entity: ONO Pharmaceuticals, Bristol Myers Squibb, Novartis Pharma K.K.，MSD K.K, Merck Serono Co., Ltd.; payment or honoraria: ONO Pharmaceuticals, Bristol-Myers Squibb, Novartis Pharma K.K.，MSD K.K., Merck Serono Co., Ltd. and Takeda Pharmaceutical Co., Ltd. The other authors have no disclosures.