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<p>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 <i>RAS/BRAF</i> mutations, intrinsic consensus molecular subtype (iCMS), and tumour sidedness in 439 profiled patients. Targeted sequencing identified <i>RAS</i> mutations in 57.5% and <i>BRAF</i> 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. <i>RAS/BRAF</i> wild-type tumours showed numerically improved overall survival (OS) and progression-free survival (PFS) with aflibercept, whereas no clear benefit was observed in <i>RAS</i>-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 <i>RAS/BRAF</i> 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, <i>q</i> = 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. <b>ClinicalTrials.gov number:</b> NCT00561470, registered 15 November 2007.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年1月13日

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  • Ting Pu,
  • Allyson M. Peddle,
  • Pratyaksha Wirapati,
  • Petros Tsantoulis,
  • Qian Wu,
  • Yourae Hong,
  • Leslie Samuel,
  • Jayesh Desai,
  • Maigo Riener,
  • Zacharenia Saridaki,
  • David Cunningham,
  • Sabine Tejpar

摘要

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.