Association of BRAF V600E/K Mutation Status and Prior BRAF/MEK Inhibition With Pembrolizumab Outcomes in Advanced Melanoma: Pooled Analysis of 3 Clinical Trials.

Question Does BRAF V600E/K mutation status or previous BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy affect response to pembrolizumab in patients with advanced melanoma? Findings This post hoc analysis of 3 randomized clinical trials (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006) involved 1558 patients with advanced melanoma and known BRAF tumor status (BRAF wild-type or BRAF V600E/K-mutant melanoma) who had all been treated with pembrolizumab and some of whom had undergone prior treatment with BRAF inhibitors with or without MEK inhibitors. Patients with BRAF wild-type and BRAF V600E/K-mutant melanoma had objective response rates (ORRs) of 39.8% and 34.3%, respectively, and similar respective rates of 4-year progression-free survival (PFS; 22.9% and 19.8%) and overall survival (OS; 37.5% and 35.1%); patients with BRAF V600E/K-mutant melanoma who had vs had not received previous BRAFi with or without MEKi had baseline characteristics with worse prognosis: lower ORR (28.4% vs 44.2%), 4-year PFS (15.2% vs 27.8%), and OS (26.9% vs 49.3%). Meaning The results of this study support the use of pembrolizumab for the treatment of advanced melanoma regardless of BRAF V600E/K mutation status or prior BRAF inhibitor with or without MEK inhibitor therapy. This post hoc subgroup analysis examines the results of 3 randomized clinical trials to assess the association of BRAF V600E/K mutation status and previous BRAF inhibitor and MEK inhibitor therapy with response to treatment with pembrolizumab in patients with advanced melanoma. Importance The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. Objective To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. Design, Setting, and Participants This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab. Interventions Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. Main Outcomes and Measures End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. Results The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. Conclusions and Relevance Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.