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.