Background: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown., Methods: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated., Results: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001)., Conclusions: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AH has received honoraria from Novartis and L.E.K, travel expenses from Roche, and is currently employed by Clinical Development, AstraZeneca Pharmaceuticals, United States. YJ: conference sponsorship: Bristol-Myers Squibb, MSD and Novartis. PB: conference sponsorship: Roche, Bristol-Myers Squibb, MSD, Novartis; paid speaker: Novartis, Bristol-Myers Squibb. BN: personal financial compensation from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis for public speaking, consultancy and participation in advisory board meetings; my institution (UZ Brussel) received research funding related to research projects conducted by my team from Pfizer, Novartis, Roche, Merck-Serono. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Roche, Bristol Myers Squibb and Pierre Fabre and has received travel support from Ultrasun, L′oreal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre outside of the submitted work. AS: Advisory Board Bristol-Myers Squibb, Immunocore, Novartis. Institutional Research Support from Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Polaris, Pfizer, Alkermes, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics. ABW: has/had a consultant/advisory role for Bristol-Myers Squibb, Immatics, Instil Bio, Iovance, Lyell Immunopharma, Novartis, Pfizer. PAA: has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer. MSC: consultant advisor: Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche; honoraria: Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis. LZ: declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. CL: consultancy for BMS MSD Sanofi Pierre Fabre Novartis. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. SS: consultant advisor: Bristol-Myers Squibb, Merck Sharp and Dohma and AstraZeneca. Grant funding to undertake investigator-initiated trials: Advanced Accelerators Applications a Novartis company, Genentech, Amgen, Merck Sharp and Dohme, Pfizer, Senwha, and AstraZeneca. CUB: Advisory role: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures. Research funding: BMS, Novartis, NanoString, 4SC. Stockownership: co-founder Immagene BV and Signature Oncology. Patents (incl. submitted): WO 2021/177822 A1, N2027907, P091040NL2. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics.All remaining authors had no disclosures to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)