A multi-center, randomized, double-blind phase II trial of FOLFIRI + regorafenib or placebo for patients with metastatic colorectal cancer who failed one prior line of oxaliplatin-containing therapy

Abstract

Background: Regorafenib (rego) is a multi-kinase inhibitor that inhibits angiogenesis (VEGFR 2/3, TIE-2), and growth and proliferation (BRAF), and is active in chemotherapy-refractory mCRC. This international investigator-initiated trial assessed the efficacy of second-line FOLFIRI +/- rego given on an intermittent dosing strategy (week on, week off ) in patients with mCRC. Methods: Patients with mCRC were recruited from 45 sites in the US and Ireland (ICORG). Key eligibility included progression on first-line OX and fluoropyrimidine, measurable disease, ECOG PS 0-1, and adequate organ function. Patients were randomized 2:1 (double blind), stratified by prior bevacizumab, to receive rego 160 mg (arm A) or placebo (arm B) on days 4-10 and 18-24 with FOLFIRI given on days 1-2 and 15-16 of every 28 day cycle. Treatment was continued until progression or toxicity. The primary endpoint was PFS; secondary endpoints included RR (CR + PR) and OS. With n = 180 (120 A, 60 B) 75% event rate yielded 135 events required to achieve 90% power for a 60% improvement in PFS with a one-sided alpha of 0.1. Results: 181 patients were enrolled from 4/11 to 8/15 (120 rego, 61 placebo). Arms were balanced for age, sex, prior adjuvant, prior bev. 118 (65.2%) had prior anti-VEGF, 14 (7.7%) had prior anti-EGFR in 1stline (2 patients received both). Median PFS was 6.14 mo for arm A and 5.29 mo for arm B, (HR 0.69, log-rank p = 0.02). Median OS was 13.2 mo for A and 12.0 mo for B (HR 1.06, p = 0.76). RR in evaluable pts was 32% (95% CI 23, 42) for A, 19% (95% CI 10, 32) for B, p = 0.10. RR in ITT population was 27% versus 18% (p = 0.11). Grade ≥ 3 adverse events occurring in > 5% of pts (A v. B) included neutropenia (40% v. 30%), diarrhea (14% v. 5%), hypophosphatemia (14% v 0), fatigue (11% v. 7%), mucositis (9% v. 10%), HTN (8% v. 2%), elevated lipase (8% v. 3%). Hand-foot syndrome grade ≥was 5% on armAvs 2% on B. Conclusions: The addition of rego on an intermittent schedule to FOLFIRI was tolerable, and resulted in a statistically significant prolongation of PFS compared to FOLFIRI alone. The study was underpowered to definitively evaluate OS, and potentially influenced by post-protocol crossover to regorafenib.