Exploratory Analysis of Biomarkers and Treatment Outcomes from the COLUMBUS Study in BRAF V600E/K-Mutant Advanced or Metastatic Melanoma.

We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib.

我们回顾性分析了III期COLUMBUS试验的基因组和转录组数据，以确定与Encorafenib ± binimetinib治疗获益相关的分子标志物。

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.

在COLUMBUS研究中，共有921名BRAF V600E/K突变的局部晚期、不可切除或转移性黑色素瘤患者被随机分配接受恩考拉非尼联合比美替尼、恩考拉非尼或维莫非尼治疗。

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.

我们使用全外显子组测序（n = 666）、全转录组测序（RNA测序；n = 514）以及基线（n = 336）和治疗期间（第2周期第1天，n = 184）循环肿瘤DNA（ctDNA）的评估，来评估生物标志物与无进展生存和总生存的关联。

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).

在肿瘤突变负荷（TMB）较高以及肿瘤免疫浸润证据（即较高的细胞毒性评分、PD-L1表达或IFNγ基因签名评分）的患者中，恩曲替尼联合比尼替尼与维莫非尼相比，生存获益最大。

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.

基因表达谱的聚类分析识别出三个肿瘤亚组，包括一个与改善生存相关的“免疫”亚组。基线ctDNA中检测到BRAF V600变异与较短的生存期相关；第2周期第1天清除BRAF V600变异与各治疗组的改善生存相关。

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.

在高TMB和/或肿瘤免疫浸润证据的患者中，Encorafenib联合Binimetinib观察到最大的益处，这表明可能对疗效有免疫贡献，而这种贡献在Vemurafenib中并未观察到。

BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

ctDNA中BRAF V600的可检测性似乎作为这一人群预后和反应的标志物具有实用价值。