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Clinical Trial
. 2023 Nov;29(11):2835-2843.
doi: 10.1038/s41591-023-02583-2. Epub 2023 Oct 16.

Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial

John M Kirkwood  1 , Michele Del Vecchio  2 , Jeffrey Weber  3 , Christoph Hoeller  4 , Jean-Jacques Grob  5 , Peter Mohr  6 , Carmen Loquai  7 , Caroline Dutriaux  8 , Vanna Chiarion-Sileni  9 , Jacek Mackiewicz  10 , Piotr Rutkowski  11 , Petr Arenberger  12 , Gaelle Quereux  13 , Tarek M Meniawy  14 , Paolo A Ascierto  15 , Alexander M Menzies  16 , Piyush Durani  17 , Maurice Lobo  17 , Federico Campigotto  17 , Brian Gastman #  18 , Georgina V Long #  16
Affiliations
Clinical Trial

Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial

John M Kirkwood et al. Nat Med. 2023 Nov.

Erratum in

Abstract

Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 .

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Conflict of interest statement

J.M.K. reports research funding received by his institution from Amgen, Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore, Iovance Biotherapeutics, Lion Biotechnologies, Novartis, Takeda and Verastem; consulting fees from Amgen, Ankyra Therapeutics, Applied Clinical Intelligence, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore, iOnctura, Iovance Biotherapeutics, Istari Oncology, Jazz Pharmaceuticals, Magnolia Innovation, Merck, Natera, Novartis, OncoCyte Corporation, OncoSec Medical, PathAI, Pfizer, Regeneron, Replimune, Scopus BioPharma, SR One Capital Management, LP and Takeda; honoraria from Bristol Myers Squibb; meeting/travel support from Ankyra Therapeutics, Checkmate Pharmaceuticals, Iovance Biotherapeutics and Regeneron; participation on data safety monitoring/advisory boards for Axio Research and IQVIA; and leadership positions at AIM at Melanoma. M.D.V. reports consulting fees from Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis and Pierre Fabre; honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre; and meeting/travel support from Pierre Fabre. J.W. reports research funding received by his institution from Bristol Myers Squibb; consulting fees from AstraZeneca, Bristol Myers Squibb, Genentech, Incyte, Merck, Pfizer and Regeneron; honoraria from Bristol Myers Squibb; meeting/travel support from Bristol Myers Squibb; being named on a patent for a PD-1 inhibitor developed by Biodesix unrelated to this study; and being a shareholder of Biond, Evaxion, Instil Bio and OncoC4. C.H. reports research funding received by his institution from Amgen, BioNTech, Bristol Myers Squibb, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre and Regeneron; consulting fees from Almirall, Amgen, Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi; honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi; meeting/travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre; participation on data safety monitoring/advisory boards for Amgen; and leadership positions at the Austrian Society of Dermatology and Venerology, the European Association of Dermato-Oncology and the European Society for Medical Oncology Melanoma Group. J.-J.G. reports research funding received by his institution from Pierre Fabre; consulting fees from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre and Sanofi; honoraria from Bristol Myers Squibb, Novartis and Pierre Fabre; meeting/travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre; and participation on data safety monitoring/advisory boards for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre and Sanofi. P.M. reports research funding received by his institution from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; consulting fees from Almirall Hermal, Amgen, Beiersdorf, Bristol Myers Squibb, Immunocore, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi and Sun Pharma; honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma; meeting/travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Sun Pharma; and leadership positions at Melanom Info Deutschland. C.L. reports consulting fees from Almirall Hermal, BioNTech, Bristol Myers Squibb, Immunocore, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Sun Pharma; honoraria from Almirall Hermal, BioNTech, Bristol Myers Squibb, Immunocore, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Sun Pharma; meeting/travel support from Almirall Hermal, BioNTech, Bristol Myers Squibb, Immunocore, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Sun Pharma; and participation on data safety monitoring/advisory boards for Almirall Hermal, BioNTech, Bristol Myers Squibb, Immunocore, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Sun Pharma. C.D. reports consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma; honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma; and meeting/travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma. V.S.-C. reports meeting/travel support from Pierre Fabre and Sun Pharma and participation on advisory boards for Merck Sharp & Dohme and Pierre Fabre. J.M. reports honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche; meeting/travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche; and participation on data safety monitoring/advisory boards for Bristol Myers Squibb, Merck Sharp & Dohme and Novartis. P.R. reports consulting fees from Blueprint Medicines, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre and Sanofi and honoraria from AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre and Sanofi. T.M.M. reports research funding received by his institution from Bristol Myers Squibb; consulting fees from AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Merck, Merck Sharp & Dohme and Novartis; honoraria from AstraZeneca; meeting/travel support from AstraZeneca and Bristol Myers Squibb; and participation on data safety monitoring/advisory boards for AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Merck, Merck Sharp & Dohme and Novartis. P.A.A. reports research funding received by his institution from Array BioPharma, Bristol Myers Squibb, Genentech, Pfizer, Roche and Sanofi; consulting fees from 4SC, Array BioPharma, Bayer, Bio-Al Health, Bristol Myers Squibb, Genentech, Idera, Italfarmaco, Lunaphore, Medicenna, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi, Sun Pharma and ValoTx; meeting/travel support from Bio-Al Health, Pfizer and Replimune; and participation on data safety monitoring/advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, Genentech, Immunocore, iTeos, Merck Sharp & Dohme, Nouscom, Novartis, Oncosec, Regeneron, Roche and Seagen. A.M.M. reports consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre and QBiotics. P.D. reports being an employee and shareholder of Bristol Myers Squibb. M.L. reports being an employee and shareholder of Bristol Myers Squibb. F.C. reports being an employee and shareholder of Bristol Myers Squibb. B.G. reports research funding received by his institution from Bristol Myers Squibb. G.V.L. reports consulting fees from Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG, Highlight Therapeutics, Innovent Biologics USA, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, QBiotics Group Limited and Regeneron; honoraria from Bristol Myers Squibb and Pierre Fabre; and participation on advisory boards for Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG, Highlight Therapeutics, Innovent Biologics USA, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, QBiotics Group Limited and Regeneron. All other authors have no competing interests to disclose.

Figures

Fig. 1
Fig. 1. CONSORT flow diagram.
aThe most common reasons for no longer meeting study criteria included change in staging or residual disease on pathology (n = 24); recurrence, disease progression or metastasis before randomization (n = 16); lack of or missing baseline imaging before randomization (n = 14); and diagnosis of a second tumor type within 3 years before enrollment (n = 10). The remaining 44 patients no longer met study criteria for other varied reasons, including non-compliance with study procedures, disqualifying comorbidities and laboratory abnormalities. ITT, intention-to-treat.
Fig. 2
Fig. 2. Kaplan–Meier estimates of RFS in the intention-to-treat population (a) and in patients with stage IIB disease (b) and stage IIC disease (c).
aBased on Cox proportional hazards model stratified by AJCC 8th edition T category (T3b versus T4a versus T4b) with treatment group as a covariate. The two-sided log-rank P value was <0.0001. bBased on unstratified Cox proportional hazards model. mo, months; NA, not available; NR, not reached.
Fig. 3
Fig. 3. RFS according to subgroup.
Shown is a forest plot of unstratified HRs (estimated using an unstratified Cox proportional hazards model) for disease recurrence or death among subgroups of patients. Circles indicate HRs among subgroups of patients, horizontal lines indicate corresponding 95% CIs and the vertical dotted line indicates the HR for the overall population. aPer the statistical analysis plan, HR was not computed for subset categories with fewer than 10 events per treatment group.
Fig. 4
Fig. 4. Kaplan–Meier estimates of DMFS in the intention-to-treat population (a) and in patients with stage IIB disease (b) and stage IIC disease (c).
aBased on Cox proportional hazards model stratified by AJCC 8th edition T category (T3b versus T4a versus T4b) with treatment group as a covariate. bBased on unstratified Cox proportional hazards model. mo, months; NA, not available; NR, not reached.
Extended Data Fig. 1
Extended Data Fig. 1. RFS by T category.
Shown are Kaplan–Meier estimates of RFS in patients with T3b category disease (a), T4a category disease (b) and T4b category disease (c). aBased on unstratified Cox proportional hazards model. NA, not available; NR, not reached; RFS, recurrence-free survival; T, tumor.
Extended Data Fig. 2
Extended Data Fig. 2. RFS by histology and location of primary tumor.
Kaplan–Meier estimates of RFS according to location of primary tumor in patients treated with nivolumab (a) and placebo (b), as well as according to melanoma subtype in patients treated with nivolumab (c) or placebo (d). NA, not available; NR, not reached; RFS, recurrence-free survival.
Extended Data Fig. 3
Extended Data Fig. 3. Trial design.
RFS was defined as the time between randomization and first recurrence (recurrence events included local, regional, or distant recurrence, new primary melanomas [including in situ], and death [due to any cause]). Imaging assessments occurred every 26 weeks during years 1 through 3 and every 52 weeks in years 4 and 5. DMFS, distant metastasis-free survival (the time between randomization and first distant recurrence or death); FFR, freedom from relapse (with censoring patients who died from causes other than disease); IV, intravenous; OS, overall survival; PFS2, progression-free survival through next-line therapy; Q4W, every 4 weeks; RFS, recurrence-free survival; T, tumor.
See this image and copyright information in PMC

References

    1. National Cancer Institute. The Surveillance, Epidemiology, and End Results (SEER) cancer stat facts: melanoma of the skin. https://seer.cancer.gov/statfacts/html/melan.html (2023).
    1. Poklepovic AS, Luke JJ. Considering adjuvant therapy for stage II melanoma. Cancer. 2020;126:1166–1174. doi: 10.1002/cncr.32585. - DOI - PMC - PubMed
    1. Garbe C, et al. Prognosis of patients with primary melanoma stage I and II according to American Joint Committee on Cancer Version 8 validated in two independent cohorts: implications for adjuvant treatment. J. Clin. Oncol. 2022;40:3741–3749. doi: 10.1200/JCO.22.00202. - DOI - PMC - PubMed
    1. Gershenwald JE, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J. Clin. 2017;67:472–492. doi: 10.3322/caac.21409. - DOI - PMC - PubMed
    1. National Cancer Institute. The Surveillance, Epidemiology, and End Results (SEER)*Explorer: an interactive website for SEER cancer statistics. https://seer.cancer.gov/explorer (2023).

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