PMID- 37965433 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240404 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 65 DP - 2023 Nov TI - Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study. PG - 102290 LID - 10.1016/j.eclinm.2023.102290 [doi] LID - 102290 AB - BACKGROUND: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. METHODS: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. FINDINGS: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. INTERPRETATION: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. FUNDING: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study. CI - (c) 2023 The Author(s). FAU - Bai, Xue AU - Bai X AD - Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. AD - Massachusetts General Hospital, USA. FAU - Shaheen, Ahmed AU - Shaheen A AD - Newcastle University Centre for Cancer, UK. FAU - Grieco, Charlotte AU - Grieco C AD - Skin Unit, The Royal Marsden NHS Foundation Trust, London, UK. FAU - d'Arienzo, Paolo D AU - d'Arienzo PD AD - Skin Unit, The Royal Marsden NHS Foundation Trust, London, UK. FAU - Mina, Florentia AU - Mina F AD - Skin Unit, The Royal Marsden NHS Foundation Trust, London, UK. FAU - Czapla, Juliane A AU - Czapla JA AD - Massachusetts General Hospital, USA. FAU - Lawless, Aleigha R AU - Lawless AR AD - Massachusetts General Hospital, USA. FAU - Bongiovanni, Eleonora AU - Bongiovanni E AD - Dermatologic Clinic, Department of Medical Sciences, University of Turin Medical School, Italy. FAU - Santaniello, Umberto AU - Santaniello U AD - Dermatologic Clinic, Department of Medical Sciences, University of Turin Medical School, Italy. FAU - Zappi, Helena AU - Zappi H AD - Alfred Health, Australia. FAU - Dulak, Dominika AU - Dulak D AD - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. FAU - Williamson, Andrew AU - Williamson A AD - The Christie NHS Foundation Trust, Manchester, UK. FAU - Lee, Rebecca AU - Lee R AD - Division of Cancer Sciences, University of Manchester and Christie NHS Foundation Trust, Manchester, UK. FAU - Gupta, Avinash AU - Gupta A AD - The Christie NHS Foundation Trust, Manchester, UK. FAU - Li, Caili AU - Li C AD - Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. FAU - Si, Lu AU - Si L AD - Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. FAU - Ubaldi, Martina AU - Ubaldi M AD - University of Perugia, Italy. FAU - Yamazaki, Naoya AU - Yamazaki N AD - Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Ogata, Dai AU - Ogata D AD - Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Johnson, Rebecca AU - Johnson R AD - Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. FAU - Park, Benjamin C AU - Park BC AD - Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Jung, Seungyeon AU - Jung S AD - Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Madonna, Gabriele AU - Madonna G AD - Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. FAU - Hochherz, Juliane AU - Hochherz J AD - Department of Dermatology, University Skin Cancer Center, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany. FAU - Umeda, Yoshiyasu AU - Umeda Y AD - Department of Skin Oncology/Dermatology, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Saitama, Japan. FAU - Nakamura, Yasuhiro AU - Nakamura Y AD - Department of Skin Oncology/Dermatology, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Saitama, Japan. FAU - Gebhardt, Christoffer AU - Gebhardt C AD - Department of Dermatology, University Skin Cancer Center, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany. FAU - Festino, Lucia AU - Festino L AD - Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. FAU - Capone, Mariaelena AU - Capone M AD - Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. FAU - Ascierto, Paolo Antonio AU - Ascierto PA AD - Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. FAU - Johnson, Douglas B AU - Johnson DB AD - Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Lo, Serigne N AU - Lo SN AD - Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia. FAU - Long, Georgina V AU - Long GV AD - Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. FAU - Menzies, Alexander M AU - Menzies AM AD - Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia. FAU - Namikawa, Kenjiro AU - Namikawa K AD - Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Mandala, Mario AU - Mandala M AD - University of Perugia, Italy. FAU - Guo, Jun AU - Guo J AD - Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. FAU - Lorigan, Paul AU - Lorigan P AD - Division of Cancer Sciences, University of Manchester and Christie NHS Foundation Trust, Manchester, UK. FAU - Najjar, Yana G AU - Najjar YG AD - UPMC Hillman Cancer Center, Pittsburgh, PA, USA. FAU - Haydon, Andrew AU - Haydon A AD - Alfred Health, Australia. FAU - Quaglino, Pietro AU - Quaglino P AD - Dermatologic Clinic, Department of Medical Sciences, University of Turin Medical School, Italy. FAU - Boland, Genevieve M AU - Boland GM AD - Massachusetts General Hospital, USA. FAU - Sullivan, Ryan J AU - Sullivan RJ AD - Massachusetts General Hospital, USA. FAU - Furness, Andrew J S AU - Furness AJS AD - Skin Unit, The Royal Marsden NHS Foundation Trust, London, UK. FAU - Plummer, Ruth AU - Plummer R AD - Newcastle University Centre for Cancer, UK. FAU - Flaherty, Keith T AU - Flaherty KT AD - Massachusetts General Hospital, USA. LA - eng PT - Journal Article DEP - 20231031 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 EIN - EClinicalMedicine. 2024 Mar 27;71:102564. PMID: 38572079 PMC - PMC10641479 OTO - NOTNLM OT - Adjuvant therapy OT - BRAF V600 mutation OT - Dabrafenib/trametinib OT - Melanoma OT - PD-1 COIS- Dr. Alexander Menzies is on advisory boards of BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. Dr. Andrew J.S. Furness has a patent (WO2019008375A1) (co-inventor of methods for identifying responders to cancer treatment), has participated on Data Safety Monitoring Boards or advisory boards of Achilles Therapeutics, GSK, Immunocore and Neogene; and has speaker's bureau and educational events from BMS, Eisai, Ipsen, Merck, and Pfizer. Dr. Andrew Haydon has received payments for advisory boards from BMS, MSD, Novartis. Dr. Christoffer Gebhardt has received research support by BMS, Novartis, Pierre-Fabre, and Sanofi; is a member of the advisory board of BMS, Immunocore, MSD, Novartis, Pierre-Fabre, Sanofi, SUN Pharma, Sysmex; and has received honoraria by BMS, GSK, Immunocore, MSD, Novartis, Pierre-Fabre, Sanofi, SUN Pharma, Sysmex. He has received travel expenses by BMS, Pierre-Fabre, SUN Pharma. He is a member of the advisory board of BMS, Immunocore, MSD, Novartis, Pierre-Fabre, Sanofi, SUN Pharma, Sysmex; a board member of the DeCOG (ADO), unpaid; he is a board member of the Hiege Foundation, unpaid. He is board member of the Roggenbuck Foundation, unpaid. He is a Co-Founder of Dermagnostix and Dermagnostix R&D. Dr. Douglas Johnson has received grants or contracts from BMS, Incyte; consulting fees from Teiko, Targovax, Mosaic ImmunoEngineering; has participated on a Data Safety Monitoring Board or Advisory Board of BMS, Merck, Novartis, and Pfizer. Dr. Genevieve M. Boland has received grants or contracts from Olink Proteomics, Teiko Bio, InterVenn Biosciences, Palleon Pharaceuticals; consulting fees from Merck, InterVenn Biosciences, Ankyra Therapeutics. She has received visiting professorships, payment from legal review, support as an invited speaker, and has a patent pending (not related to current content). She is on Board of Trustees, Karin Grunebaum Cancer Research Foundation. She has stock of Ankyra Therapeutics. Dr. Georgina Long has received consulting fees from Agenus Inc, Amgen Inc, Array Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L, Innovent Biologics USA Inc, Merck Sharp & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals. She has received payment or honoraria for lectures from BMS, Pierre Fabre. Dr. Jun Guo is the member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, Oriengene. Dr. Keith Flaherty has received grants or contracts from Sanofi, Novartis; consulting fees from Clovis Oncology, Strata Oncology, Checkmate Pharmaceuticals, Kinnate Pharmaceuticals, Scorpion Therapeutics, PIC Therapeutics, Apricity, Fog Pharma, Vibliome; participated on a Data Safety Monitoring Board or advisory board of PIC Therapeutics, Apricity, Fog Pharma, Tvardi, xCures, Monopteros, Vibliome, ALX Oncology, OMRx, Soley Therapeutics, Alterome, IntrECate, and Quanta Therapeutics. He is on Board of Directors: Clovis Oncology, Strata Oncology, Checkmate Pharmaceuticals, Kinnate Pharmaceuticals and Scorpion Therapeutics. He owns stock from Clovis Oncology, Strata Oncology, Checkmate Pharmaceuticals, Kinnate Pharmaceuticals Scorpion Therapeutics, PIC Therapeutics, Apricity, Fog Pharma, Tvardi, xCures, Monopteros, ALX, Oncology, OMRx, Soley Therapeutics, Alterome, IntrECate, and Quanta Therapeutics, Transcode Therapeutics. Dr. Kenjiro Namikawa has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono pharmaceutical, Novartis, BMS, and MSD. He has participated on an Data Safety Monitoring Board or advisory board of Novartis and MSD. Dr. Lu Si has received speakers' honoraria from MSD, Roche, Novartis, Shanghai Junshi Biosciences and Oriengene. Dr. Mario Mandala (please confirm that I read your handwriting right; section 1 of all support is a bit har to read) has received consulting fees from MSD, BMS, Novartis, Sanofi, Suw Pharma. Dr. Naoya Yamazaki has received grants or contracts from Ono Pharmaceutical CO., LTD., BMS, Novartis Pharma K.K., Amgem Inc; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono Pharmaceutical CO., LTD., BMS, Novartis Pharma K.K., MSD K.K., Maruho CO., LTD; and participated on a Data Safety Monitoring Board or Advisory Board of Ono Pharmaceutical CO., LTD and Chugai Pharmaceutical CO., LTD. Dr. Paolo A. Ascierto has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer, Bio-Al Health, Replimmune. Dr. Paul Lorigan has received consulting fees from Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche; support for attending meetings and/or travel from BMS, MSD. He works as Chair, EORTC Melanoma Group (unpaid). Dr. Pietro Quaglino has received speaker fee and is advisory board of Novartis, BMS, MSD, Pierrefabre; support for attending meetings and/or travel from Novartis, BMS, MSD, Pierrefabre. Rebecca Johnson has received speaking honoraria from Novartis. Dr. Rebecca Lee is on advisory board of Pierre Fabre. Dr. Ruth Plummer has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from MSD, BMS. She has participated on a Data Safety Monitoring Board or Advisory Board of GSK. Dr. Ryan Sullivan has received grants or contracts from Merck (to institution); consulting fees from BMS, Novartis, Merck, Pfizer, Replimune, Marengo; participated on a Data Safety Monitoring Board or Advisory Board of Yale University, Duke University. Dr. Yana Najjar has the following disclosure: consulting/advisory board: immunocore, merck, BMS, pfizer, novartis, intervenn bio; speaker's bureau: immunocore; research (to institution): merck, bms, pfizer, replimune. Dr. Yasuhiro Nakamura has received grants or contracts from Torii (to institution), consulting fees from Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers-Squibb, Kyowa Kirin, Maruho, MSD, Novartis, Ono, Leo Pharma Sun Pharma, Tanabe-Mitsubishi Pharma, Torii, Sanofi, Alexion Pharma. Dr. Yoshiyasu Umeda has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Maruho and BMS. The rest of the authors have no declaration of interests. EDAT- 2023/11/15 06:42 MHDA- 2023/11/15 06:43 PMCR- 2023/10/31 CRDT- 2023/11/15 04:26 PHST- 2023/05/25 00:00 [received] PHST- 2023/10/10 00:00 [revised] PHST- 2023/10/11 00:00 [accepted] PHST- 2023/11/15 06:43 [medline] PHST- 2023/11/15 06:42 [pubmed] PHST- 2023/11/15 04:26 [entrez] PHST- 2023/10/31 00:00 [pmc-release] AID - S2589-5370(23)00467-4 [pii] AID - 102290 [pii] AID - 10.1016/j.eclinm.2023.102290 [doi] PST - epublish SO - EClinicalMedicine. 2023 Oct 31;65:102290. doi: 10.1016/j.eclinm.2023.102290. eCollection 2023 Nov.