Liquid Biopsy Detects Early Molecular Response and Predicts Benefit to First-Line Chemotherapy plus Cetuximab in Metastatic Colorectal Cancer: PLATFORM-B Study

Purpose: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy. Experimental Design: Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/ MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. Results: One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/ BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with early molecular response (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P< 0.001) compared with patients with early molecular progression (increase in trunk and/or increase in resistant mutations). Conclusions: ctDNA detects early molecular response and pre-dicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.

Automated summary

This study aimed to determine the usefulness of ctDNA in assessing early response in patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving first-line anti-EGFR therapy. The results showed that a decrease in ctDNA trunk mutations correlated with longer progression-free survival, while an increase in RAS/BRAF mutations at C3 was associated with shorter survival. The combined analysis of trunk and resistant mutations at C3 was found to be the best predictor of treatment response.