Comprehensive genomic profiling by liquid biopsy portrays metastatic colorectal cancer mutational landscape to predict antitumor efficacy of FOLFIRI plus cetuximab in the CAPRI-2 GOIM trial

Background: Limited evidence is currently available on the role of liquid biopsy (LBx) in predicting the efficacy of anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (mCRC). Methods: The CAPRI-2 GOIM is a phase II trial investigating the use of LBx-comprehensive genomic profiling (CGP)-guided, cetuximab-based treatment through three subsequent lines of therapy in patients with RAS/BRAF wild-type (WT) mCRC. LBx-CGP is carried out at baseline and at progressive disease to first- and second-line therapies. In case of RAS/BRAF WT circulating tumor DNA at progressive disease, EGFR therapeutic blockade is continued by combining cetuximab with a different chemotherapy backbone. The primary endpoint is overall response rate (ORR) by RECIST 1.1 criteria. Tumor molecular characteristics by LBx-CGP are correlated with treatment efficacy. Results: One hundred and ninety-two RAS/BRAF WT microsatellite stable mCRC patients treated with FOLFIRI plus cetuximab with baseline LBx-CGP and assessable for response were included in the analysis. One hundred and thirty-seven patients with WT tumors for potential anti-EGFR drug resistance genes (RAS/BRAF/EGFR/PIK3CA/MAP2K1/MET/RET/ALK/ROS1/NTRK/NF1/FGFR, and HER2 amplification; ‘negatively hyper-selected’ cases) had 78.1% ORR compared with 54.5% ORR for patients with mutations [odds ratio 2.95, 95% confidence interval (CI) 1.44-6.10, P = 0.001]. ‘Negatively hyper-selected’ patients had median progression-free survival of 12.35 months (95% CI 10.58-15.4 months) compared with 8.68 months (95% CI 4.87-12.1 months) for patients with mutations (hazard ratio 0.64, 95% CI 0.44-0.92, P = 0.017). High cancer cell clonality of pathogenic variants (PVs) correlated with worse median progression-free survival (3.55 months, 95% CI 2.57 months to NE) compared with low cancer cell clonality of PV (9.63 months, 95% CI 7.16 months to NE, P = 0.21). After first-line therapy failure, approximately one out of five patients had acquired PVs of potential anti-EGFR drug resistance genes, whereas RAS/BRAF WT circulating tumor DNA was maintained in most patients (78.5%). Conclusions: These results support the integration of LBx-CGP for implementing the efficacy and for optimizing the use of anti-EGFR therapies in RAS/BRAF WT mCRC.