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

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. 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. 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 arm A vs 2% on B. 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.