Circulating tumor DNA tumor fraction as a biomarker in refractory metastatic colorectal cancer: findings from the CAVE-2 GOIM trial.

Liquid biopsy guided anti-EGFR rechallenge therapy is gaining ground as a potential option for patient with refractory metastatic colorectal cancer. However, the identification of potential biomarkers to implement patient's stratification is required. The CAVE-2 GOIM trial investigated the role of rechallenge with cetuximab ± avelumab in patients with circulating tumor DNA (ctDNA) (assessed with the FoundationOne Liquid assay) RAS/BRAF wild type (WT) mCRC. Correlation with molecular profile, ctDNA tumor fraction (TF), and clinicopathological characteristics was performed. In patients with "negative" compared with "positive hyperselected" tumors the overall response rate was 12% vs 3%, median progression free survival (mPFS) mPFS 5.6 months (4.4-6.9) vs 3.65 months (2.8-4.8) (HR 0.61, 95%CI 0.41-0.91; P = 0.0155), median overall survival (mOS) 14.5 months (12.4-19.0) vs 11.6 months (8.5-15.6) (HR0.61, 95% CI 0.40-0.93; P = 0.023). Therefore, we explored potential biomarkers in patients with "negative hyperselected" tumors. Remarkably, among the investigated factors at multivariable analysis for PFS and OS only ctDNA TF retained significance. For patients with negative hyperselected tumors with ctDNA TF ≥ 10 compared with patients with ctDNA TF <10% mPFS was 4.8 months (3.4-3.9) vs 5.7 (4.4-6.9) (HR 1.74, 95% CI 1.20-2.53; P = 0.00382) and mOS 11.0 months (8.3-13.0) vs 21.3 months (HR 2.75, 95% CI 1.79-4.23; P = 0.00000418). This data suggests that a higher ctDNA shedding might better refine cancer aggressiveness and metastatic load than tumor burden. Taken together these results highlights the strong prognostic value of ctDNA TF and the potential role for treatment personalization.