Predictive biomarkers for cetuximab-based rechallenge therapy in metastatic colorectal cancer: a pooled analysis of the CAVE and CAVE-2 GOIM studies
Background Anti-epidermal growth factor receptor (EGFR) therapy is a therapeutic option in patients with molecularly selected metastatic colorectal cancer (mCRC). However, the identification of predictive factors represents an unmet need. Patients and methods We conducted a pooled analysis of individual patient data from the CAVE-GOIM (NCT04561336) and CAVE-2 GOIM (NCT05291156) studies to investigate the impact of several clinical variables on rechallenge with cetuximab with and without avelumab in circulating tumor DNA RAS/BRAF/EGFR-extracellular domain wild-type mCRC. Results Overall, 180 patients met the eligibility criteria: 136 received cetuximab–avelumab and 44 cetuximab. In patients receiving cetuximab monotherapy, median progression-free survival (mPFS) was 4.80 months [95% confidence interval (CI) 3.90-5.90] and median overall survival (mOS) 12.9 months (95% CI 11.1-not evaluable). Cetuximab activity was retained regardless of clinical factors. Patients treated with cetuximab–avelumab showed an mPFS of 5.00 months (95% CI 4.30-5.90) and mOS of 15.7 months (95% CI 13.0-19.9). In univariable analysis, a shorter progression-free survival was observed in patients with liver involvement [hazard ratio (HR) 2.19, 95% CI 1.51-3.20, P < 0.001] and anti-EGFR-free interval ≤16 months (HR 1.62, 95% CI 1.13-2.31, P < 0.008). Both variables retained statistical significance in multivariable analysis. In univariable analysis, lower overall survival was observed among patients treated with cetuximab–avelumab with >3 metastatic sites (HR 1.79, 95% CI 1.16-2.77, P < 0.009) and liver (HR 1.82, 95% CI 1.15-2.88, P < 0.011) and peritoneal metastases (HR 1.9, 95% CI 1.23-2.93, P < 0.004). In multivariable analysis, only liver and peritoneal metastases maintained statistical significance. Conclusions Single-agent cetuximab activity is not influenced by clinical factors. In cetuximab–avelumab therapy, the absence of liver metastases and longer anti-EGFR-free interval might represent potential biomarkers.