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In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up., Methods: We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint., Results: The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group., Conclusions: The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma., Competing Interests: Declaration of Competing Interest Alexander MM Eggermont is an Editor-in-Chief for European Journal of Cancer and was not involved in the editorial review or the decision to publish this article. Susana Puig is an Editor for European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. Dirk Schadendorf is an Editor-in-Chief European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander C.J. van Akkooi: advisory board/consultancy honoraria from 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX; research grants from Amgen, Merck Serono-Pfizer, SkylineDX. Paolo A. Ascierto: a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon; research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi; travel support by Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. Victoria Atkinson: advisory board for and speeches fees from BMS, MSD, Novartis, Immunocore; travel support by Pierre Fabre. Christian U Blank: advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, Sandoz; research funding from BMS, Novartis, NanoString, 4SC; stock ownership of Flindr Therapeutics, Signature Oncology. Matteo Carlino: advisory boards or a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; honoraria from BMS, MSD, and Novartis. Stéphane Dalle: research grants to institution from MSD, BMS, Pierre Fabre; advisory board paid to institution by MSD and BMS; spouse employment Sanofi. Alexander MM Eggermont: honoraria for scientific advisory board or data monitoring committee activities from Agenus, Bioinvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Eurobio, GenOway, Imcheck, IO Biotech, Ipsen, IQVIA, ISA Pharmaceuticals, Merck KGA, Merck&Co/MSD, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, Sairopa BV, ScanCell, Scorpion Pharmaceuticals, Secarna, Sellas, SkylineDX BV, TigaTX, Thermosome, Trained Immunotherapeutics Discovery. Stock: IO Biotech, Sairopa BV, SkylineDX. Anna Maria Di Giacomo: advisor/board member for Merck, Roche, Bristol Myers Squibb, Incyte, Pierre Fabre, Sanofi, GlaxoSmithKline, SunPharma, Immunocore; honoraria from Merck, Bristol Myers Squibb, Sanofi, Pierre Fabre, GlaxoSmithKline, SunPharma. Immunocore. Dmitri Grebennik: employee of Merck & Co. Jean-Jacques Grob: advisory boards for Novartis, BMS, MSD, Philogen, Pierre Fabr, Sanofi, Roche, Amgen. Ralf Gutzmer: honoraria for lectures and advice from BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; support for participation in meetings from SUN Pharma, Boehringer Ingelheim and PierreFabre; research support (to institution) from Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal, Recordati. Andrew Haydon: advisory board member for BMS, MSD and Novartis. Rahima Jamal: honoraria for presentation and advisory board with Merck. PI in Merck-sponsored trials. Adnan Khattak: speaker honoraria, advisory board, and travel sponsorship from MSD. Michal Kicinski: research funding from MSD, BMS, Pierre Fabre, Immunocore, and JnJ. Clemens Kreplere: employee and shareholder of Merck & Co. James Larkin: relationships with the following companies: iOnctura, Apple Tree, Merck, BMS, MSD, Telix, Novartis, Philogen, Pfizer, Incyte, Eisai, Debipharm, GCO, TouchIME, Immatics, Insighter, Agence Unik, VJOncology, Royal College of General Practioners, Cambridge Healthcare Research, Royal College of Physicians, TouchExperts. Georgina V Long: consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Paul Lorigan: support for travel from MSD; research funding from Pierre Fabre and BMS; speakers bureau/consultancy for BMS and Pierre Fabre. Mario Mandala: advisory board and lectures for: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma; research grant from Novartis. Susana Puig: speaker for Almirall, BMS, Cantabria, ISDIN, La Roche Posay, Leo Pharma, MSD, Novartis, Pfizer, Roche, Regeneron, Sanofi, Sunpharma; advisory board of Almirall, BMS, ISDIN, La Roche Posay, Regeneron, Roche, Sanofi, Sun Pharma; involvement in research and trials of Abbvie, Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo Pharma, MSD, MEDA, Novartis, Polychem, Roche, Sun Pharma; husband has relationship with Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo, Mavig, Nevisence, Novartis, Polychem, Roche, Sun Pharma. Educational activities for Abbie, Lilly, and ISD; ownership of Athena Tech & Dermavision Solutions. Caroline Robert: consultant/advisory board of Pierre Fabre, Sanofi, BMS, MSD, Novaris, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; consultant steering committee for Novartis, Regeneron, Pfizer, IO Biotech; consultant IDMC for Ultimovacs; speaker for Pierre Fabre, Sanofi, BMS, MSD, Novaris; travel by Pierre Fabre. Piotr Rutkowski: honoraria for lectures and advisory boards from MSD, BMS, Novartis, Pierre Fabre, Genesis Pharma, Medison Pharma. Shahneen Sandhu: research funding from Novartis/AAA, AstraZeneca, Merck Sharp and Dohme, Amgen, Genentech, Senwha, Bristol-Myers Squibb, Merck Healthcare and Pfizer; participation on advisory boards for Merck Sharp and Dohme, AstraZeneca, Novartis, SkylineDx and Abbvie (fees for attending go to research funds at the institution); honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen (all paid to the institution); chair of DSMB for 2 Novartis/AAA sponsored Phase III trials (no fee accepted for chair role). Dirk Schadendorf: a member of the advisory board, consultant or received speakers´ honoraria from: Astra Zeneca, BMS, CureVac, Daiichi Sankyo, Erasca, Haystack, Immatics, Immunocore, InFlarX, Lapcorp, Merck-Serono, MSD, Neracare, Novartis, Novogenix, PamGene, Philogen, Pierre Fabre, Pfizer, Regeneron, Replimune, Sanofi, Seagen, Sun Pharma, UltraVacs; research funding from BMS, Roche, MSD, Amgen & Novartis. Stefan Suciu: DSMB member of the NADINA study. Alfonsus JM van den Eertwegh: study grant from Bristol-Myers Squibb, Idera; travel expenses by Ipsen; advisory board of Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV. The remaining authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)