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?
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%).
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.
The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established.
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.
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.
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.
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Puzanov I, Ribas A, Robert C, et al. Association of BRAF V600E/K Mutation Status and Prior BRAF/MEK Inhibition With Pembrolizumab Outcomes in Advanced Melanoma: Pooled Analysis of 3 Clinical Trials. JAMA Oncol. 2020;6(8):1256–1264. doi:10.1001/jamaoncol.2020.2288
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