Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

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Déclaration de conflit d'intérêts

Conflict of interest statement A. Hepner is currently employed by AstraZeneca R&D since August 2020, Cambridge, UK and has received honoraria from Novartis and travel expenses from Roche; V.G.A. has served on advisory boards for BMS, MSD, Merck Novartis, Nektar, Pierre Fabre, Roche and QBiotics and received honoraria from BMS, MSD, Novartis, Pierre Fabre, Merck and Roche; J.L. reports institutional research support from BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics and Aveo, has a consultancy role in Achilles, AZ, Boston Biomedical, BMS, Eisai, EUSA Pharma, GSK, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna and Vitaccess and reports support from NIHR RM/ICR Biomedical Research Centre for cancer; R.A.B. has no conflict of interests to report; M.S.C. has served on advisory boards for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai and QBiotics and reports honoraria from Bristol Myers Squibb, MSD and Novartis; D.B.J. has served on advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis and Oncosec and has received research funding from Bristol Myers Squibb and Incyte; L.Z. reports honoraria from Roche, BMS, MSD, Novartis and Pierre Fabre; a consultant or advisory role for BMS, Novartis, Pierre Fabre, Sun Pharma, Sanofi and MSD; research funding from the institution Novartis and travel support from BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sun Pharma; K.K.T. has received institutional research funding from Array/Pfizer, OncoSec, Parker Institute for Cancer Immunotherapy, Regeneron and Replimune; O.K. reports travel support from BMS and speaker fee from BMS and MSD; S.N.L. has no conflict of interest to report; A. Haydon has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre and QBiotics; P.B. has received sponsorship from MSD; M.L. and L.P. have no conflicts of interest; I.P.d.S. reports travel support by BMS and MS and speaker fee by Roche, BMS and MSD; C.G. has no conflicts of interest; O.M. is the beneficiary of research funding from Merck Sharp & Dohme, Bristol Myers Squibb and Roche and/or is a consultant or participated to advisory boards for Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Roche and GlaxoSmithKline; G.V.L. is a consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. and SkylineDX B.V.; A.M.M. has received honoraria for serving on advisory boards for BMS, MSD, Novartis, Roche, Pierre Fabre and QBiotics.