Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial.

Abstract

e15503 Background: Data on anti-angiogenic second line treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR drug are lacking and no validated biomarkers are available. We present the pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456), a biologically enriched, prospectively stratified phase 2 study assessing the aflibercept use in this setting. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy and candidates for second-line FOLFIRI/aflibercept are eligible for the DISTINCTIVE trial. Pts are prospectively allocated to a favorable (F) or unfavorable (U) prognostic group, according to Elisa-assessed baseline (BL) VEGFR2 plasma levels (PL). Other circulating angiogenic factors are evaluated at BL, first tumor assessment (TA1) and disease progression (PD). 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). Sample size: 151 pts (one-sided test, α: 0.1, β: 0.2). Results: From 04/2018 to 06/2020, 73 pts were enrolled. Complete data from 44 pts were available for interim analysis. 33 pts (75%) achieved DCR (26 pts/59% SD, 7 pts/16% PR). Globally, median OS was 11.9 months (m) (95%CI 10 – 14.2). 24 (54.5%) pts were prospectively assigned to F group (VEGFR2 PL > 4 ng/ml) and 20 (45.5%) to U group (VEGFR2 PL ≤4 ng/ml). OS in F group was 13.1 m (95%CI 9.6 – 14.2) vs 11.9 m (95%CI 6.8 – 11.9) in U group (HR 0.76 p = 0.6218). PFS was 9.8 m [95%CI 5.7 – 24.2] in F group vs 4.2 m [95%CI 2.5 – 14.2] in U group (HR 0.41 p = 0.0105). We also found preliminary correlation with PD as shown in table. Conclusions: Interim analysis showed high activity of FOLFIRI/aflibercept in RAS WT anti-EGFR pretreated mCRC pts. VEGFR2 showed promising ability to predict aflibercept efficacy. Our data on circulating angiogenic biomarkers are likely to further compose the landscape of anti-angiogenic activity in mCRC pts. Clinical trial information: NCT04252456. [Table: see text]