Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial.

BACKGROUND

Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics.

METHODS

Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm

RESULTS

Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm

CONCLUSIONS

In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma.

TRIAL REGISTRATION NUMBER

ClinicalTrials.gov, NCT03553836.

Informations de copyright

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: DS reports being an invited speaker for BMS, Merck Serono, MSD, Novartis, Roche, and Sanofi; having advisory board roles with BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, and Sanofi/Regeneron; research grants from BMS and MSD; being a steering committee member for BMS, MSD, and Novartis; being a coordinating PI for BMS, MSD, Novartis, and Pierre Fabre; being a local PI for Philogen and Sanofi; and being member of the board of directors for EORTC-MG (non-financial). JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; having two provisional patents (serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)); participating on a data safety monitoring board or advisory board for AbbVie, Immutep, and Evaxion; having leadership or a fiduciary role in the Society for Immunotherapy of Cancer; and having stock or stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest. PAA reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, and Bayer; support for attending meetings and/or travel from Pfizer, Bio-Al Health, and Replimmune; and participating on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, and Erasca. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, and Regeneron. PR reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicine; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, AstraZeneca, Philogen and Blueprint Medicine. AK reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing or educational events from MSD and support for attending meetings and/or travel from MSD. MDV reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore. LdlC-M reports grants or contracts from Roche, Celgene, and MSD; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, MSD-Merck, Novartis, Roche, AstraZeneca, Incyte, and Gilead; and support for attending meetings and/or travel from Gilead. JM reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; support for attending meetings and/or travel from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; and participation on a data safety monitoring board or advisory board for MSD, Bristol Myers Squibb, and Novartis. VCS reports consulting fees from Pierre Fabre, Novartis, Merck-Serono, and Bristol Myers Squibb; support for attending meetings and/or travel from Pierre Fabre and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for Merck Sharp and Dohme and Pierre Fabre. JMK reports consulting fees from Amgen Inc., Ankyra Therapeutics, Applied Clinical Intelligence LLC, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore LLC, iOnctura, Iovance Biotherapeutics, Istari Oncology, Jazz Pharmaceuticals Inc., Magnolia Innovation LLC, Merck, Natera Inc, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc, PathAI Inc, Pfizer Inc, Regeneron Pharmaceuticals Inc, Replimune Inc, Scopus BioPharma Inc, SR One Capital Management LP, and Takeda; research trial support to institution from Amgen Inc, Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co, Immunocore Ltd, Iovance Biotherapeutics, Lion Biotechnologies Inc, Novartis Pharmaceuticals, Takeda, and Verastem Inc; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS; support for attending meetings and/or travel from Checkmate Pharmaceuticals, BMS, Regeneron, Ankyra Therapeutics, and Iovance Biotherapeutics; and participation on a data safety monitoring board or advisory board for Axio Research and IQVIA. CR reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Merck, MSD, Sun Pharma, and AstraZeneca; participation on a data safety monitoring board or advisory board for BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck, MSD, and AstraZeneca; and stock or stock options in Ribonexus. J-JG reports grants or contracts from Pierre Fabre (institution); consulting fees from Novartis, BMS, MSD, Pierre Fabre, Amgen, Sanofi, and Philogen; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, Novartis, and Pierre Fabre; support for attending meetings and/or travel from BMS, Novartis, MSD, and Pierre Fabre; and participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Philogen. RD reports consulting fees from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and TouchIME; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME. MSC reports consulting fees from MSD, BMS, Novartis, Amgen, Eisai, Ideaya, Nektar, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, BMS, and Novartis. YZ reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. MK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. CK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. AE reports consulting fees from Agenus, BioInvent, BioNTech, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GenOway, IO Biotech, IQVIA, ISA Pharmaceuticals, MSD, Pierre Fabre, Pfizer, Scorpion Pharmaceuticals, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS and MSD; support for attending meetings and/or travel from BMS; participation on a data safety monitoring board or advisory board for BioNTeck, IQVIA, and Pfizer; and stock or stock options in IO Biotech, Sairopa, and SkylineDX. RAS reports consulting fees from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen Inc., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline.