Targeted therapy in advanced melanoma with rare BRAF mutations Journal Article


Authors: Menzer, C.; Menzies, A. M.; Carlino, M. S.; Reijers, I.; Groen, E. J.; Eigentler, T.; de Groot, J. W. B.; van der Veldt, A. A. M.; Johnson, D. B.; Meiss, F.; Schlaak, M.; Schilling, B.; Westgeest, H. M.; Gutzmer, R.; Pföhler, C.; Meier, F.; Zimmer, L.; Suijkerbuijk, K. P. M.; Haalck, T.; Thoms, K. M.; Herbschleb, K.; Leichsenring, J.; Menzer, A.; Kopp-Schneider, A.; Long, G. V.; Kefford, R.; Enk, A.; Blank, C. U.; Hassel, J. C.
Article Title: Targeted therapy in advanced melanoma with rare BRAF mutations
Abstract: PURPOSE: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
Journal Title: Journal of Clinical Oncology
Volume: 37
Issue: 33
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2019-11-20
Start Page: 3142
End Page: 3151
Language: English
DOI: 10.1200/jco.19.00489
PUBMED: 31580757
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 2 December 2019 -- Source: Scopus
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MSK Authors
  1. Christian Menzer
    2 Menzer