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. Patients and methods: 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-seq; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (Cycle 2 Day1, 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 mutation 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 C2D1 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 appears to have utility as a marker of prognosis and response in this population.
Exploratory Analysis of Biomarkers and Treatment Outcomes From the COLUMBUS Study in BRAF V600E/K-Mutant Advanced or Metastatic Melanoma
Mandala, Mario;
2026
Abstract
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. Patients and methods: 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-seq; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (Cycle 2 Day1, 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 mutation 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 C2D1 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 appears to have utility as a marker of prognosis and response in this population.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
