From bench to bedside and back: prognostic groups of Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial—A GISCAD study.

e15571 Background: Currently, no validated biomarkers are available for second-line anti-angiogenic treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR. Here, we present the results of a pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456) on prognostic groups identified with the combination of hematologic parameters and based on the association of clinical and translational biomarkers. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy receive FOLFIRI-aflibercept and are prospectively stratified in 2 groups according to Elisa-assessed baseline VEGFR2 plasma levels. Other circulating angiogenic factors are evaluated at specific timepoints. Clinical and laboratory data are collected to assess their correlation with outcome. Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression; cut-off: ROC curves). Results: Of 73 pts enrolled (04/2018-06/2020), 44 were eligible for interim analysis. Median OS was 11.9 months (m) (95% CI 10-14.2). We identified at first 2 prognostic groups: favorable prognosis (baseline monocytes ≤0.7x103/μL + RBC > 3.81x106/μL + MRR≤1528) and unfavorable prognosis (monocytes > 0.7x103/μL and/or RBC ≤3.81x106/μL and/or MRR > 1528). OS was 14.2 months (m) (95% CI 10.467-14.2) in the favorable prognosis group vs 6.9 m (95% CI 4.867-9.133) in the unfavorable prognosis group (HR 0.008, p < 0,0001). Then, we performed multivariate analysis on circulating angiogenic factors and on laboratory values; VEGFR2 levels at disease progression (PD) and baseline RBC maintained an independent role (Exp(b) 0.0891, p = 0.0464 and Exp(b) 0.1170, p = 0.0148, respectively). By combining these findings we separated pts in a favorable prognosis group (VEGFR2≤4ng/ml + RBC > 3.81x106/μL) and unfavorable prognosis group (VEGFR2 > 4ng/ml and/or RBC ≤ cut off). OS was significantly improved in the favorable prognostic group (14.2 m [95% CI 11.167-14.2] vs 9.1 m [95% CI 6. 367-10.067], HR 0.03, p = 0.0001). Conclusions: Our results showed the prognostic role of the combination of hematologic parameters and VEGFR2 levels + RBC count in RAS WT anti-EGFR resistant mCRC pts treated with FOLFIRI-Aflibercept. These findings represent a promising association of translational and clinical factors in predicting survival in the specific study population. Clinical trial information: NCT04252456.