464PD - A multi-center, randomized, double-blind phase II trial of FOLFIRI + regorafenib or placebo for patients with metastatic colorectal cancer who fail...

Date 10 October 2016
Event ESMO 2016 Congress
Session Gastrointestinal tumours, colorectal
Topics Colon and Rectal Cancer
Presenter Bert O'Neil
Citation Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370
Authors B. O'Neil1, S. O'Reilly2, S. Kasbari3, R. Kim4, R. McDermott5, D. Moore6, W. Grogan7, A. Cohn8, T. Bekaii-Saab9, A. Ivanova6, O. Olowokure10, N. Fernando11, J. McCaffrey12, B. El-Rayes13, A. Horgan14, T. Ryan15, G. Yacoub16, G. Sherrill17, R.M. Goldberg18, H. Sanoff19
  • 1Oncology, Indiana University Simon Cancer Center, 46077 - Indianapolis/US
  • 2Medical Oncology, Cork University Hospital, Cork/IE
  • 3Oncology, SMOC, Wison/US
  • 4Clinical Oncology, H. Lee Moffitt Cancer Center University of South Florida, Tampa/US
  • 5Dept. Of Medical Oncology, AMNCH Adelaide and Meath Hospital, 24 - Dublin/IE
  • 6Biostatistics, University of North Carolina - Chapel Hill, Chapel Hill/US
  • 7Medical Oncology, Beaumont Hospital, 9 - Dublin/IE
  • 8Oncology, Rocky Mountain Cancer Centers U.S. Oncology Network, Denver/US
  • 9Hematology/oncology, Mayo Clinic, Phoenix/US
  • 10Hematology/oncology, University of Cincinnati, Cincinnati/US
  • 11Hematology/oncology, Georgia Cancer Centers, Atlanta/US
  • 12Medical Oncology, Irish Clinical Oncology Research Group, Cork/IE
  • 13Oncology, Emory University Winship Cancer Institute, Atlanta/US
  • 14Medical Oncology, University Hospital Waterford, Waterford/IE
  • 15Hematology/oncology, NYU Langone Medical Center, New York/US
  • 16Hematology/oncology, Wake Forest University Comprehensive Cancer Center, Winston Salem/US
  • 17Hematology/oncology, Moses Cone Health System, Greensboro/US
  • 18Division Of Medical Oncology, The Ohio State University Comprehensive Cancer Center and James Cancer Hospital, Columbus/US
  • 19Hematology/oncology, Lineberger Comprehensive Cancer Center University of North Carolina, Chapel Hill/US



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.

Clinical trial identification


Legal entity responsible for the study

University of North Carolina at Chapel Hill




B. O'Neil: Has consulted for Bayer in past 2 years and received honoraria totaling