CMS4 Identified as Potential Biomarker of Anti-EGFR Benefit in RAS/BRAF Wild-Type Metastatic Colorectal Cancer
According to results from an individual patient data meta-analysis, consensus molecular subtype 4 (CMS4) may serve as a predictive biomarker for improved outcomes with anti-epidermal growth factor receptor (EGFR) therapy among patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC).
“Despite the best possible biomarker selection, anti–EGFR-directed therapy fails in at least 20% of all patients with mCRC, which emphasizes the need for further biomarkers,” stated Arndt Stähler, MD, Charité–Universitätsmedizin Berlin, Germany, and coauthors. “CMS4 might be an additional biomarker of anti-EGFR treatment efficacy in RAS (and BRAF) wild-type mCRC.”
In this study, researchers collected data from 790 patients classified as CMS1 (n = 77), CMS2 (n = 345), CMS3 (n = 74), or CMS4 (n = 294) who received fluoropyrimidine-, irinotecan-, or oxaliplatin-containing regimens in combination with anti-vascular endothelial growth factor (VEGF) or anti-EGFR monoclonal antibodies across 5 prospective trials (FIRE1, FIRE3, XELAVIRI, PanaMa, and TRIBE2). Primary end points included CMS-specific objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), evaluated using generalized estimating equation models and Cox regression accounting for within-trial clustering.
At analysis, between-trial heterogeneity was negligible. Compared with CMS1, CMS2 and CMS4 tumors demonstrated numerically higher ORR and significantly longer PFS and OS. Among patients with CMS4 tumors, treatment with anti-EGFR versus anti-VEGF therapy yielded clinically meaningful improvements in PFS (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.46 to 0.97; P = .03) and OS (HR, 0.49; 95% CI, 0.33 to 0.72; P <.001). This benefit was consistent among those with RAS/BRAF wild-type tumors (P = .004) and microsatellite-stable disease (P = .01). Interaction testing confirmed significant modification of PFS and OS treatment effects by CMS subtype.
As Dr Stahler et al concluded, “our findings nevertheless justify the development of simplified diagnostical approaches for the detection of CMS4 tumors by, for instance, proteomics or image-guided analysis, and prospective investigation in larger clinical trials.”
“These data provide insights on the clinical utility and therapeutic relevance of transcriptomic signatures for subtyping colorectal cancer and support preferential initial therapy with an anti-EGFR strategy in RAS [wild-type] CMS4 subtype,” added Journal of Clinical Oncology associate editor Eileen O’Reilly, MD, Memorial Sloan Kettering Cancer Center, New York, New York.
Source:
Stahler A, Modest DP, Stintzing S, et al. Individual patient data meta-analysis of consensus molecular subtypes as biomarkers of first-line treatment in RAS wild-type metastatic colorectal cancer. J Clin Oncol. Published online: November 18, 2025. doi: 10.1200/JCO-25-00596
