Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAF V600 -mutant resectable melanoma: the randomized phase 2 NeoTrio trial.

Autor: Long GV; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au.; Royal North Shore Hospital, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au.; Mater Hospital, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au.; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au., Carlino MS; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Westmead Hospital, Westmead, New South Wales, Australia.; Blacktown Hospital, Blacktown, New South Wales, Australia., Au-Yeung G; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia., Spillane AJ; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Royal North Shore Hospital, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia., Shannon KF; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia.; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.; Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.; Concord Repatriation Hospital, Concord, New South Wales, Australia., Gyorki DE; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia., Hsiao E; Royal North Shore Hospital, Sydney, New South Wales, Australia., Kapoor R; Mater Hospital, Sydney, New South Wales, Australia.; I-MED Radiology Network, Mater Hospital, Sydney, New South Wales, Australia., Thompson JR; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Batula I; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Howle J; Westmead Hospital, Westmead, New South Wales, Australia., Ch'ng S; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia.; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.; Chris O'Brien Lifehouse, Sydney, New South Wales, Australia., Gonzalez M; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia., Saw RPM; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia.; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia., Pennington TE; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia.; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia., Lo SN; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Scolyer RA; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.; Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.; NSW Health Pathology, Sydney, New South Wales, Australia., Menzies AM; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Royal North Shore Hospital, Sydney, New South Wales, Australia.; Mater Hospital, Sydney, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2024 Sep; Vol. 30 (9), pp. 2540-2548. Date of Electronic Publication: 2024 Jun 21.
DOI: 10.1038/s41591-024-03077-5
Abstrakt: Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF V600 -mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 .
(© 2024. The Author(s).)
Databáze: MEDLINE
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