Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in <i>RAS</i> Wild-Type Metastatic Colorectal Cancer.

Abstract

MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy. We investigated the predictive role of this biomarker in the FIRE-3 study population, including its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. MiR-31-3p expression was measured in primary tumors obtained from 340 patients with <i>RAS</i> WT mCRC enrolled in the FIRE-3 Trial. This included 164 patients randomized to receive FOLFIRI plus cetuximab (FOLFIRI+Cetux) and 176 to FOLFIRI plus bevacizumab (FOLFIRI+Beva). Patients were divided into subgroups defined by low or high miR-31-3p expression using a prespecified cut-off and by treatment arm. Analyses were performed to assess treatment efficacy by subgroup. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and Cox regression models. Investigator-assessed objective response (iOR), early tumor shrinkage at 6 weeks (ETS), and centrally reviewed objective response (cOR) were analyzed using logistic regression models. The predictive value of miR-31-3p expression level was assessed through a treatment interaction test using multivariate models adjusted for potential confounding factors. Low miR-31-3p expressers benefited from cetuximab compared with bevacizumab for PFS [HR, 0.74; 95% confidence interval (CI), 0.55-1.00; <i>P</i> = 0.05], OS (HR, 0.61; 95% CI, 0.41-0.88; <i>P</i> < 0.01), iOR (OR, 4.0; 95% CI, 1.9-8.2; <i>P</i> < 0.01), ETS (OR, 4.0; 95% CI, 2.1-7.7; <i>P</i> < 0.01 and cOR (OR, 4.9; 95% CI, 2.3-10.5; <i>P</i> < 0.01) in multivariate analyses. There was no difference in outcomes for high expressers between treatment arms. MiR-31-3p expression level was predictive of treatment effect for PFS (<i>P</i> = 0.03), OS (<i>P</i> = 0.05), iOR (<i>P</i> = 0.02), ETS (<i>P</i> = 0.04), and cOR (<i>P</i> < 0.01). MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for patients with <i>RAS</i> WT mCRC.