@article{2999795,
    title = "Adjuvant nivolumab for stage III/IV melanoma: Evaluation of safety outcomes and association with recurrence-free survival",
    author = "Mandala, M. and Larkin, J. and Ascierto, P.A. and Del Vecchio, M. and Gogas, H. and Cowey, C.L. and Arance, A. and Dalle, S. and Schenker, M. and Grob, J.-J. and Chiarion-Sileni, V. and Marquez, I. and Butler, M.O. and Di Giacomo, A.M. and Lutzky, J. and De La Cruz-Merino, L. and Atkinson, V. and Arenberger, P. and Hill, A. and Fecher, L. and Millward, M. and Khushalani, N.I. and De Pril, V. and Lobo, M. and Weber, J.",
    journal = "Journal for ImmunoTherapy of Cancer",
    year = "2021",
    volume = "9",
    number = "8",
    publisher = "BMJ Publishing Group",
    issn = "2051-1426",
    doi = "10.1136/jitc-2021-003188",
    keywords = "ipilimumab;  nivolumab;  programmed death 1 receptor;  nivolumab, adult;  Article;  cancer adjuvant therapy;  cancer recurrence;  controlled study;  diarrhea;  disease duration;  double blind procedure;  drug efficacy;  drug safety;  eczema;  fatigue;  follow up;  human;  hypothyroidism;  immune-related gene;  immunosuppressive treatment;  immunotherapy;  major clinical study;  Medical Dictionary for Regulatory Activities;  melanoma;  overall survival;  phase 3 clinical trial;  progression free survival;  pruritus;  randomized controlled trial;  rash;  recurrence free survival;  skin toxicity;  vitiligo;  aged;  cancer staging;  disease free survival;  female;  melanoma;  mortality;  pharmacology;  treatment outcome, Aged;  Disease-Free Survival;  Female;  Humans;  Immune Checkpoint Inhibitors;  Melanoma;  Neoplasm Staging;  Nivolumab;  Treatment Outcome",
    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. ©"
}