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Advanced Melanoma: Pembrolizumab Effective Regardless of BRAF V600E/K Mutations

BRAF V600E-mutant melanoma.

In patients with advanced melanoma, pembrolizumab achieves efficacy regardless of BRAF V600E/K mutation status or prior treatment with BRAF and/or MEK inhibitors, according to the results of a new pooled analysis published in JAMA Oncology.

Approximately 40% of metastatic melanomas harbor a BRAF mutation, 90% of which are an activating BRAF V600E/K mutation. While targeted agents and immune checkpoint inhibitors, including pembrolizumab, have considerably improved outcomes for patients with advanced melanoma, limited data existed regarding the association of BRAF V600E/K mutation status and prior BRAF inhibitor treatment with response to pembrolizumab, until now.

A team of researchers led by first author Igor Puzanov, MD, Professor of Medicine at Roswell Park Cancer Institute in Buffalo, New York, investigated the efficacy of pembrolizumab in patients with advanced melanoma with or without BRAF-V600E/K mutations and with or without prior treatment with BRAF and/or MEK inhibitors. The post-hoc subgroup analysis included patients with advanced melanoma and known BRAF tumor status who were enrolled in one of three multinational clinical trials: KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006. Of 1,558 patients included in the analysis, 434 had BRAF V600E/K mutations; the remaining 1,124 had BRAF wild-type mutations. Patients received pembrolizumab 2 mg/kg every three weeks, 10 mg/kg every two weeks, or 10 mg/kg every three weeks. The primary end points of the analysis were objective response rate, four-year progression-free survival, and four-year overall survival.

In the overall population, pembrolizumab produced an objective response rate of 38.3%, a four-year progression-free survival rate of 22.0%, and a four-year overall survival rate of 36.9%. Patients with BRAF V600E/K experienced similar rates of objective response (34.3% vs 39.8%), progression-free survival (19.8% vs 22.9%), and overall survival (35.1% vs 37.5%) compared with patients with BRAF wild-type mutations. Patients with BRAF V600E/K mutations who had been previously treated with BRAF inhibitors with or without MEK inhibitors had baseline characteristics with worse prognosis and experienced lower rates of objective response (28.4% vs 44.2%), progression-free survival (15.2% vs 27.8%), and overall survival (26.9% vs 49.3%) compared with patients who had not undergone prior therapy with these agents. The safety profile of pembrolizumab was similar across all subgroups.

"Results of this post-hoc pooled subgroup analysis support the use of pembrolizumab for the treatment of patients with advanced melanoma regardless of BRAF V600E/K mutation status or use of BRAF inhibitors with or without MEK inhibitor therapy," conclude Dr. Puzanov and colleagues. "Results of well-designed randomized studies that evaluate potential determinants of outcome will help to determine optimal first-line agents for defined subgroups of patients with advanced melanoma."

For More Information

Puzanov I, Ribas A, Robert C, et al (2020). 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. [Epub ahead of print]. DOI:10.1001/jamaoncol.2020.2288

Image credit: Jensflorian. Licensed under CC BY-SA 4.0


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