Purpose: Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K–mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib. Experimental Design: In COLUMBUS, patients with BRAF V600E/K–mutant locally advanced, unresectable, or metastatic melanoma (n = 921) were randomized to receive encorafenib plus binimetinib, encorafenib, or vemurafenib. We used whole-exome sequencing (n = 666), whole-transcriptome sequencing (RNA sequencing; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (cycle 2 day 1, n = 184) to evaluate biomarker associations with progression-free and overall survival. Results: Survival benefits with encorafenib plus binimetinib versus vemurafenib were greatest in patients with higher tumor mutational burden (TMB) and those with evidence of tumor immune infiltration (i.e., higher cytolytic score, PD-L1 expression, or IFNγ gene signature scores). Clustering of gene expression profiles identified three tumor subgroups, including an “immune” subgroup associated with improved survival. Detection of BRAF V600 alterations in baseline ctDNA was associated with shorter survival; clearance of BRAF V600 alterations at cycle 2 day 1 was associated with improved survival across arms. Conclusions: The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

PFS and OS for encorafenib plus binimetinib or encorafenib vs. vemurafenib by (A and B) ERBB2 expression level and (C and D) PI3K pathway mutation status. Bini, binimetinib; BM, biomarker; Enco, encorafenib; Vemu, vemurafenib.

Purpose:Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K–mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib.Experimental Design:In COLUMBUS, patients with BRAF V600E/K–mutant locally advanced, unresectable, or metastatic melanoma (n = 921) were randomized to receive encorafenib plus binimetinib, encorafenib, or vemurafenib. We used whole-exome sequencing (n = 666), whole-transcriptome sequencing (RNA sequencing; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (cycle 2 day 1, n = 184) to evaluate biomarker associations with progression-free and overall survival.Results:Survival benefits with encorafenib plus binimetinib versus vemurafenib were greatest in patients with higher tumor mutational burden (TMB) and those with evidence of tumor immune infiltration (i.e., higher cytolytic score, PD-L1 expression, or IFNγ gene signature scores). Clustering of gene expression profiles identified three tumor subgroups, including an “immune” subgroup associated with improved survival. Detection of BRAF V600 alterations in baseline ctDNA was associated with shorter survival; clearance of BRAF V600 alterations at cycle 2 day 1 was associated with improved survival across arms.Conclusions:The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

PFS and OS by detection of BRAF V600 alterations in ctDNA at (A and B) baseline and (C and D) on treatment. Only patients with BRAF V600 alteration detections at baseline are shown in C and D. Bini, binimetinib; D, detectable; Enco, encorafenib; ND, nondetectable; Vemu, vemurafenib.

Characterization of tumor samples to identify candidate molecular subtypes by K-means clustering and distribution of subtypes by biopsy site. A, Heatmap showing K-means cluster and the expression of key marker genes (AXL and MITF) and cell type scores generated by xCell. B, Distribution of K-means subgroups across biopsy sites. C, OS by K-means subgroup and treatment arm. Bini, binimetinib; Vemu, vemurafenib.