Targeted therapy for rare BRAF-mutated melanoma: Updated multicenter analysis and launch of a publicly accessible online outcome database
- PMID: 40850313
- DOI: 10.1016/j.ejca.2025.115703
Targeted therapy for rare BRAF-mutated melanoma: Updated multicenter analysis and launch of a publicly accessible online outcome database
Abstract
Introduction: While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database.
Patients and methods: A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations. Treatments included BRAF/MEK inhibitor combination therapy (BRAFi/MEKi) and the respective monotherapies. Clinical outcomes concerning overall response rate (ORR), progression-free (PFS), and overall survival (OS) were collected.
Results: Included patients had a median age of 65 years (range 20-93), 101 (71 %) were male. Most patients (n = 92, 64 %) received BRAFi/MEKi, 42 (29 %) BRAFi monotherapy, and 9 (6 %) MEKi monotherapy. The ORR was 35 % and higher in V600-nonE/K (45 %) than non-V600 melanomas (26 %, p = 0.025). Median duration of response was similar, with 8.2 months (range 2.9-53.1 +) for V600-nonE/K and 7.4 months (range 0.8-73.8 +) for non-V600. Combination therapy achieved best results in both groups, however, differences between V600-nonE/K and non-V600mutation were only found in ORR (51 % vs. 33 %, p = 0,11) and median PFS (6.5 vs. 3.2 months, p = 0.01). Patients with the longest PFS (> 50 months) had V600D/R, V600_K601D/E/N or K601E/N-, L597V/S/R/Q/P/K- mutations. OS was similar in both groups (16.1 vs. 11.7 months, p = 0.96). Of note, in non-V600 melanomas MEKi monotherapy revealed similar response rates as combination treatment (ORR 33 %, PFS 3 months); however, median OS was shorter (6.6 months, p = 0.02).
Conclusions: This updated analysis reinforces the benefit of BRAFi/MEKi therapy in rare BRAF mutations. A database for ongoing data collection was developed and is available at https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen.
Keywords: BRAFi; MEKi; Melanoma; Non-V600; Rare BRAF mutation; Targeted therapy; V600.
Copyright © 2025. Published by Elsevier Ltd.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CM has received grant funding from the Society of MSK and the German Research Foundation (DFG); he has served on advisory boards, as a consultant, or given educational presentations for MSD-Sharp and Dohme, Bristol-Myers-Squibb, Kyowa Kirin, Recordati Rare Diseases, AstraZeneca, and Pierre Fabre Pharma. He has received support for travel and meetings from Sun Pharma, Kyowa Kirin, and Novartis. CB has had an advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, and Senya. He has received research funding from BMS, Novartis, NanoString, and 4SC. Stock ownerships: co-founder Flindr Therapeutics to develop TNF sensitizers to clinicPatents (incl. submitted): WO 2021/177822 A1 (pending) US 2023/0114276 A1 (pending) > national phase, EP 4114450 A1 (pending) > national phase, WO 2023/022596 A1 (pending), US (submitted by AOMB, not published yet) > national phase, EP 4387683 A1 (pending) > national phase. MS has no relevant conflicts of interest related to this manuscript. He has served on advisory boards, as a consultant for MSD, Bristol-Myers-Squibb, Novartis, Immunocore and Pierre Fabre Pharma. He has received support for travel and meetings from Sun Pharma and Pierre Fabre Pharma. KB has had consulting/advisory relationships with Abbvie, and Sairopa; received research funding from TigaTx, Bristol Myers Squibb, Philips, Genmab, and Pierre Fabre; and received honoraria from Bristol Myers Squibb - all relationships are not related to this work and were paid to the institution. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. DBJ has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, and Teiko, and has received research funding from BMS and Incyte, and has patents pending for use of MHC-II as a biomarker for immune checkpoint inhibitor response, and abatacept as treatment for immune-related adverse events. CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. FM served as consultant and/or has received honoraria from Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. BS received personal honoraria from SUN Pharma, Immunocore, Bristol-Myers Squibb, Sanofi, Regeneron, Pierre Fabre Pharma, Novartis and Blueprint Medicines for participation in advisory boards or for speaking engagements. RG declares honoria for lectures/advice from BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, Delcath, and Sanofi/Regeneron; support of meeting participation from SUN Pharma, and PierreFabre; and research support (to institution) from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal, and Recordati. KMT has received speaker or consultant honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Regeneron, Immunocore, Sanofi, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, Candela, Lilly, Abbvie, and Johnson & Johnson. AMM has served on advisory board for BMS, MSD, Novartis, Pierre-Fabre, Roche and QBiotics. MSC has served a consultant for Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck Sharpe & Dohme, Medison, Moderna, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, Merck KGaA, Sanofi, and Strand therapeutics and received honoraria from Bristol Myers Squibb, Merck Sharpe & Dohme, and Novartis. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Fortiva Biologics (USA) Inc, GI Innovation Inc, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Biologics USA Inc, Iovance Biotherapeutics Inc, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals, Scancell Limited, SkylineDX B.V. AvdV has served on advisory boards (all paid to the institute) for BMS, MSD, Esai, Pfizer, Novartis, Roche, Pierre Fabre, Ipsen, and Sanofi, and received travel support from Ipsen. TE has served as a consultant for MSD, Novartis, Regeneron / Sanofi, Anaveon, CureVac, Pierre Fabre, BMS, SunPharma, and Merck Darmstadt; he declares stock ownership for CureVac, and Genmab. JCH has received honoraria for talks from BMS, Delcath, Immunocore, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma; and honoraria for advisory boards from Onkowissen and Sunpharma. SDB, MB, IR, EJG, JE, FM, TH, AKS, MM, JWBdG, MSdB, CP, and KH have no potential competing interests to declare.
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