HER-2 gene alterations as biomarker in patients with metastatic colorectal cancer treated with FOLFIRI + cetuximab: findings from the CAPRI-2 GOIM study

Background: Human epidermal growth factor receptor 2 (HER-2) overexpression/amplification is a known prognostic and predictive biomarker in breast and gastric cancer. However, its role in metastatic colorectal cancer (mCRC) is still debated. Patients and methods: We conducted an exploratory analysis to investigate the role of HER-2 amplifications/mutations in patients with RAS/BRAFV600 wild type (WT), microsatellite stable (MSS) mCRC enrolled in the CAPRI-2 GOIM trial, who received FOLFIRI/cetuximab as first-line therapy. At baseline, plasma and tumor tissue samples were collected for comprehensive genomic profiling using the FoundationOne CDx assay. HER-2 positive tumors were defined in case of HER-2 mutations or gene amplification, defined by using a gene copy number cut-off of ≥4. Results: Patients with HER-2 negative tumors had numerically higher objective response rates [78% versus 60%; odd-ratio, 1.95, 95% confidence interval (CI): 0.47-8; P = 0.4] compared with HER-2 positive tumors. Patients with HER-2 positive mCRC had worse median progression-free survival (PFS) [(7.54 months; 95% CI:4.99-Not evaluable (NE) versus 13.47 months (95% CI: 11.76-16.3); hazard ratio (HR): 2.47; 95% CI: 1.27-4.65; P = 0.007] as well as worse median overall survival [16.4 months (95% CI:9.4-NE) versus 33.4 (30.36-NE); HR: 2.54; 95% CI: 1.09-5.93; P = 0.031] compared with patients with HER-2 negative tumors. Of note, 6/7 cases with HER-2 mutations exhibited limited benefit from treatment with FOLFIRI plus cetuximab with PFS inferior to 8 months. Conclusion: Taken together, these results highlight the need to test HER-2 gene alterations for patients with RAS/BRAFV600 WT, MSS mCRC, who are candidates for anti-epidermal growth factor receptor therapies.