Exploratory biomarker analysis of RAS/BRAF somatic mutations and gene expression signatures for predicting treatment effects of aflibercept in the velour trial

The phase III VELOUR trial demonstrated improved outcomes with aflibercept plus FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin-based regimens. We retrospectively evaluated the prognostic and predictive impact of RAS/BRAF mutations, intrinsic consensus molecular subtype (iCMS), and tumour sidedness in 439 profiled patients. Targeted sequencing identified RAS mutations in 57.5% and BRAF mutations in 10.0% of evaluable tumours; 34.2% of tumours with complete genotyping were RAS/BRAF wild-type. Transcriptomic profiling classified 66.5% of tumours as iCMS2 and 33.5% as iCMS3. RAS/BRAF wild-type tumours showed numerically improved overall survival (OS) and progression-free survival (PFS) with aflibercept, whereas no clear benefit was observed in RAS-mutant tumours. iCMS subtyping was strongly prognostic, with iCMS2 patients demonstrating longer OS and PFS than iCMS3 (OS HR 0.57, 95%CI 0.45-0.72; PFS HR 0.70, 95%CI 0.56-0.88). Exploratory integrated analyses suggested OS benefit in RAS/BRAF wild-type iCMS2 tumours (HR 0.56, 95%CI 0.33-0.96) and a significant PFS advantage in bevacizumab-pretreated iCMS3 tumours (HR 0.41, 95%CI 0.20-0.85, q = 0.032). Right-sided tumours were associated with poorer OS, but no significant treatment interaction was observed. These findings support integrating genomic and transcriptomic biomarkers to refine patient selection for anti-VEGF therapy, warranting validation in prospective studies. ClinicalTrials.gov number: NCT00561470, registered 15 November 2007.