<i>BRAF</i> and <i>NRAS</i> Mutation Status and Response to Checkpoint Inhibition in Advanced Melanoma.

Abstract

Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma. All patients with advanced melanoma treated with first-line anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to <i>BRAF</i> and <i>NRAS</i> status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for <i>BRAF</i>-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with <i>NRAS</i>-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, <i>BRAF</i>-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for <i>BRAF</i>-mutant melanoma compared with <i>NRAS</i>-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. Ipilimumab-nivolumab-treated patients with <i>BRAF</i>-mutant melanoma display improved PFS and OS compared with patients with <i>NRAS</i>-mutant and double wild-type melanoma. <i>BRAF</i> mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.