Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival

Abstract

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.

Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.

Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.

Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.

Trial registration number: NCT02388906.

Keywords: adjuvants; immunologic; immunotherapy; melanoma; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: MM: Consulting or Advisory Role: Bristol Myers Squibb, Novartis, MSD Oncology, Pierre Fabre, Roche/Genentech; Honoraria: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, Roche/Genentech; Research Funding: Novartis, Roche/Genentech; JL: Grants: Achilles Therapeutics, Aveo, Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess, Covance, Immunocore; Personal Fees: Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, Imugen, Incyte, Ipsen, iOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess; PAA: Grant: Array, Bristol Myers Squibb, Roche/Genentech; Personal Fees: 4SC, Array, AstraZeneca, Bristol Myers Squibb, Idera, Immunocore, Incyte, Genmab, Medimmune, MSD, NewLink Genetics, Novartis, Merck Serono, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, Syndax, Sun Pharma, Ultimovacs; Advisory/consultant role and travel support: MSD; MDV: Consultant/Advisory Boards: Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, Sanofi; HG: Consulting or Advisory Role: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche, Pierre Fabre; Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche; Honoraria: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche; Research Funding: Bristol Myers Squibb, MSD Oncology, Roche, Novartis; CLC: Nothing to disclose; AA: Personal Fees: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; Travel Grant: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; SD: Consulting or Advisory Role: MSD; Research Funding: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Travel, Accommodations, Expenses: Bristol Myers Squibb; Stock Ownership/Employment: Sanofi Pasteur (immediate family member); MS Grant: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung; J-JG: Personal Fees: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sanofi, SunPharma; VC-S: Advisory Board: Incyte, Merck-Sorono, MSD; Meeting Expenses: Bristol Myers Squibb, Pierre Fabre; Speaker Fee: Novartis; IM: Grant: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Roche; Personal Fees: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Regeneron, Roche, Sanofi; Non-financial Support: BionCoTech, Bristol Myers Squibb, MSD, Roche; MOB: Consulting or Advisory Role: Adaptimmune, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Genzyme, Immunocore, Immunovaccine, Merck, Novartis; Expert Testimony: Merck; Honoraria: Bristol Myers Squibb, Merck, Novartis, Roche; Research Funding: Takara Bio, Merck; AMDG: Consulting or Advisory Role: Bristol Myers Squibb, Incyte, MSD, Pierre Fabre; JL: Consulting or Advisory Role: Array BioPharm, Bristol Myers Squibb, Novartis; Speakers’ Bureau: Array BioPharm, Novartis, Regeneron; Travel, Accommodations, and Expenses: Bristol Myers Squibb, Novartis, Pfizer; Research Funding: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Elios Pharmaceutical, Genentech/Roche, Incyte, Merck Seronon, Merck, Novartis, Pfizer, Viralytics; LDLC-M: Nothing to disclose; VA: Personal Fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec; PA: Nothing to disclose; AH: Nothing to disclose; LF: Grant: Bristol Myers Squibb, EMD Serono, Incyte, Kartos, Merck, Pfizer, Array; Consulting or Advisory Role: Elsevier/Via Oncology, Hoosier Cancer Research Network; MM: Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, MSD, Novartis, Pfizer, Roche; Travel, Accommodations, and Expenses: AstraZeneca, Bristol Myers Squibb, MSD, Roche; NIK: Consulting or Advisory Role: Array BioPharma, AstraZeneca, Bristol Myers Squibb, EMD Serono, Immunocore, HUYA Bioscience International, Genentech, Merck, Regeneron; Research Funding: Amgen, HUYA Bioscience International, GlaxoSmithKline, Merck, Novartis, Regeneron; Stock/Other Ownership Interests: Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, TransEnterix; VdP: Employee: Bristol Myers Squibb; Stock Ownership: Bristol Myers Squibb; ML: Employee: Bristol Myers Squibb; Stock Ownership: Advaxis Immunotherapies, Bristol Myers Squibb; JW: Consulting or Advisory Role: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Research Funding: Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte Corporation, Merck, Novartis, Roche; Travel, Accommodations, and Expenses: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, GlaxoSmithKline, Merck, Novartis, Pieris Pharmaceuticals, Inc, Roche; Honoraria: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Stock/Ownership Interests: Biond; Patents: Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker; named on a patent submitted from Biodesix for a PD-1 antibody biomarker.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Frequencies of first-occurrence select treatment-related adverse events reported in ≥2% of nivolumab-treated patients during any time interval. (A) Any-grade occurring on treatment. (B) Any-grade events occurring from the last dose to 100 days after the last dose. (C) Grade 3–4 events, of those shown in panel A. (D) Grade 3–4 events, of those shown in panel B. TRAEs were coded using the Medical Dictionary for Regulatory Activities, V.20.0, and preferred terms may not be mutually exclusive. ALT; alanine aminotransferase. AST; aspartate aminotransferase.

Figure 2

Time to onset (A) and time to resolution (B) of any grade select treatment-related adverse events from first dose of nivolumab to 100 days after the last dose; time to onset (C) and time to resolution (D) of grade 3–4 select treatment-related adverse events from first dose of nivolumab to 100 days after the last dose. *Numbers of patients with onset of an adverse event. †Numbers of patients whose adverse event resolved out of the numbers of patients with onset of an adverse event. GI, gastrointestinal; NR, not reached.

Figure 3

Three-month landmark analysis of RFS in nivolumab-treated patients with and without early select TRAEs. NIVO, nivolumab; NR, not reached; RFS, recurrence-free survival; TRAE, treatment-related adverse event.