Adjuvant nivolumab versus ipilimumab (CheckMate 238 trial): Reassessment of 4-year efficacy outcomes in patients with stage III melanoma per AJCC-8 staging criteria.

Purpose: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8.
Patients and Methods: In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8.
Results: Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS).
Conclusions: CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JLa has worked in a consulting/advisory role for iOnctura, Apple Tree, Merck, Bristol Myers Squibb (BMS), Eisai, Debipharm, and Incyte; has received honoraria from AstraZeneca, BMS, Eisai, EUSA Pharma, GlaxoSmithKline (GSK), Incyte, Ipsen, Merck, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Merck Sharp & Dohme (MSD), Novartis, Aptitude, Pierre Fabre, Pfizer, Roche, Seagen, Inselgruppe, eCancer, Ultimovacs, Calithera, and Goldman Sachs; and has received research/grant support from Achilles Therapeutics, BMS, Immunocore, Aveo, Pharmacyclics, MSD, Nektar Therapeutics, Covance, Novartis, Pfizer, and Roche. JW has worked in a consulting/advisory role for, received honoraria from, and received institutional research/grant support from BMS; and is named on a patent for a PD-1 biomarker not used in the current trial. MDV has worked in a consulting/advisory role for and received honoraria from BMS, MSD, Novartis, and Pierre Fabre. HG has worked in a consulting/advisory role for Amgen, BMS, MSD, and Replimune; has received honoraria from BMS, MSD, Novartis, Sanofi, and Pierre Fabre; and has received research/grant support from Amgen, BMS, Iovance, MSD, Pfizer, and Replimune. AMA has worked in a consulting/advisory role for, and received honoraria from Pierre Fabre, Novartis, BMS, Merck, Roche, MSD, and Sanofi; and has served as a speaker/provided expert testimony for BMS, Merck, Pierre Fabre, Novartis, MSD, Sanofi, and Roche. SD has received research/grant support from BMS and MSD; has received travel/congress support from BMS; and has worked in an advisory role for MSD. CLC has worked in a consulting/advisory role for Merck, Novartis, Pfizer, Sanofi, and Eisai. MS has received research/grant support from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, BeiGene, Bioven, Clovis Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Tesaro. J-JG has worked in a consulting/advisory role for Amgen, BMS, MSD, Novartis, Philogen, Pierre Fabre, Roche, and Sanofi. VC-S has received honoraria from Pierre Fabre, Novartis, and BMS; and has received travel/congress support from Novartis and Pierre Fabre. IM-R has worked in a consulting/advisory role for AstraZeneca, Amgen, BMS, Incyte, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Highlight Therapeutics, Regeneron, and Sanofi; has received honoraria from BMS, MSD, Roche, Pierre Fabre, Novartis, and Sun Pharma; and has received travel/congress support from BMS, MSD, Novartis, Pierre Fabre, Roche, and Sun Pharma. MOB has worked in a consulting/advisory role for BMS, GSK, Immunocore, Merck, Novartis, Pfizer, Adaptimmune, Sun Pharma, Instil Bio, IOVANCE, Medison, LaRoche Possey, and Sanofi; has received research/grant support from Merck, Takara Bio, and Novartis; has received honoraria from Sanofi, BMS, Merck, and Novartis; and has served on the safety review board for Adaptimmune, and GSK. AMDG has worked in a consulting/advisory role for BMS, MSD, Pierre Fabre, Novartis, and Sanofi; has received honoraria from BMS, MSD, Pierre Fabre, and Sanofi; and has received travel/congress support from Pierre Fabre. MRM has worked in a consulting/advisory role for Novartis, BioLineRx, BMS, Immunocore, Kineta, Merck, and Silicon Therapeutics; and has received institutional research/grant support from Roche, Astrazeneca, GSK, Immunocore, BioLineRx, Pfizer, Regeneron, Replimune, and GRAIL. LDlC-M has received honoraria from BMS, Merck, MSD, Roche, AstraZeneca, and Gilead; and has received travel/congress support from Gilead. VA has worked in a consulting/advisory role for BMS, MSD, Nektar Therapeutics, Novartis, Pierre Fabre, and Q Biotics; has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Nektar Therapeutics, and Q Biotics; and has given expert testimony for BMS. AH is an employee of Tasman Oncology; has received honoraria from BMS; has received travel/congress support from BMS and Merck; and holds stock in Tasman Oncology. LAF has worked in a consulting/advisory role for Elsevier, and Via Oncology; has received cooperative group research/grant support from Array BioPharma and Pfizer; has received institutional research/grant support from Array BioPharma, BMS, EMD Serono, Incyte, Kartos Therapeutics, Merck, and Pfizer; has received honoraria from ASCO, and the Michigan Society of Hematology and Oncology; and has served on the data and safety monitoring board of the Hoosier Cancer Research Network. MMi has worked in a consulting/advisory role for BMS, Novartis, Roche, MSD, The Limbic, Takeda, Guardant Health, Beigene, Amgen, Merck, and Lilly; has received honoraria from BMS, Roche, and The Limbic; has received travel/congress support from AstraZeneca; and has served in a leadership position for Melanoma and Skin Cancer Trials Australia. NIK has received institutional research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience, Merck, Novartis, Regeneron, and Replimune; had received honoraria from Novartis and Replimune; holds stock in Amarin, Asensus, Bellicum, and Mazor Robotics; has served on the data and safety monitoring or advisory board of AstraZeneca, BMS, Castle Biosciences, Genzyme, Incyte, Instil Bio, Iovance, Merck, NCCN, Nektar Therapeutics, Novartis, and Regeneron; and has served in a leadership position for BMS, NCCN, Nektar Therapeutics, Regeneron, and Replimune. PQ has received honoraria from and served on the data safety monitoring board or advisory board of Novartis, Sun Pharma, Pierre Fabre, BMS, MSD, Merck, Sanofi, and Roche; and has received travel/congress support from MSD. GVL has worked in a consulting/advisory role for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG, Highlight Therapeutics, MSD, Novartis, OncoSec, Pierre Fabre, Provectus Australia, QBiotics, and Regeneron; and has received honoraria from BMS and Pierre Fabre. ML and MA are employees of BMS. PAA has worked in a consulting/advisory role for Array BioPharma, AstraZeneca, Boehringer Ingelheim, BMS, Idera Pharmaceuticals, Immunocore, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna, Bio-AI Health, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, 4SC, MSD, Merck Serono, Novartis, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, and Sun Pharma; and has received research/grant support from Array BioPharma, Pfizer, BMS, Sanofi, and Roche/Genentech. MMan has worked in a consulting/advisory role for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma; has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi, and Sun Pharma; and has received research/grant support from Novartis. All remaining authors have declared no conflicts of interest.
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