Regorafenib Dose-Optimization Study (ReDOS): A Phase 2 Randomized Study to Evaluate Dosing Strategies for Regorafenib in Patients with Refractory Metastatic Colorectal Cancer - An ACCRU Network Study

Abstract

Background: Regorafenib confers an overall survival benefit in refractory metastatic colorectal cancer (mCRC) patients. The adverse event (AE) profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. Methods: In this randomized phase 2 study (NCT02368886), adults with refractory mCRC received a dose-escalation strategy (starting dose 80 mg/day with weekly escalation to standard-dose regorafenib; arm A) if no significant drug-related AEs occurred, or standard-dose regorafenib (160 mg/day; arm B) for 21 days of a 28-day cycle. Patients were randomized (1:1) to arms A and B. The primary endpoint was the proportion of patients initiating cycle 3 in arm A vs B. Superiority for arm A was declared if the one-sided p-value with Fisher's exact test was <0.2. Quality of life (QOL) measures were assessed. Findings: In total, 123 patients were randomized (116 were evaluable: A=54, B=62). The primary endpoint was met: 43% of patients in the dose-escalation arm initiated cycle 3 vs 26% in the standard-dosing arm (one-sided p=0·043). The main reason in both arms for not initiating cycle 3 was progressive disease (arm A vs B: 37% vs 47%). There was a trend toward improved median overall survival in arm A vs B (9·8 vs 6·0 months; p=0·124). In cycle 1, rates of grade 2-3 hand-foot skin reaction (38·9% vs 43·5%) and grade 3 fatigue (13·0% vs 17·7%) or hypertension (7·4% vs 14·5%) were lower in arm A vs B. QOL appeared more favorable in arm A vs B. Interpretation: The dose-escalation strategy was superior to standard dose in terms of the proportion of patients who entered a third treatment cycle, and may represent an alternative approach for optimizing regorafenib dosing with comparable efficacy and lower AE rates. Funding: Bayer HealthCare Pharmaceuticals. Declaration of Interest: TBS has received research funding from Bayer; and has served as consultant for Bayer, Taiho, Genentech, Bristol-Myers Squibb, and Amgen. F-SO has nothing to disclose. DA has served as a consultant for Eisai Co., Ltd. and Astellas. PB has received research funding from Merck, Boehringer Ingelheim. Ipsen, Merrimack, Advaxis, Theradiag, Athenex, Boston Biomedical, MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Incyte, Amgen, Sanofi, Array Biopharma Daiichi Sankyo and Nucano; has received honoraria from Sirtex and Boston Biomedical. KC has received research funding to her institution from Bayer, Pfizer and Boston Medical; has received honoraria from Bayer. EH has nothing to disclose. TD has nothing to disclose. NJ has nothing to disclose. BP has nothing to disclose. JC has received research funding from Merck and Tesero; has been a consultant for Bristol-Myers Squibb; and has received travel expenses from Bristol-Myers Squibb, Roche and Agios. JM has nothing to disclose. JMcC has nothing to disclose. KP Dr. Pedersen reports grants from Mayo Foundation for Medical Education and Research during the conduct of the study; personal fees from Bayer, non-financial support from Beigene, nonfinancial support from Array Pharmaceuticals, grants from Mayo Foundation for Medical Education and Research, grants from BiolineRx outside the submitted work. AB has nothing to disclose. GC has received research funding from Boehringer Ingelheim, Celgene, Stemline, Ignyta, Incyte, Eli Lilly and Merck; has received honoraria from Halozyme, Vicus, Ipsen, Five Prime, Exelixis, AstraZeneca and Seattle Genetics. JS has nothing to disclose. ML has received royalties from Legacy Healthcare Services, Adgero Bio Pharmaceuticals, Amryt Pharmaceuticals, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson and Johnson, Novocure Inc., Lindi, Merck Sharp and Dohme Corporation, Helsinn Healthcare SA, Janssen Research & Development, LLC, Menlo Therapeutics, Novartis Pharmaceuticals Corporation, F. Hoffman-La Roche AG, Abbvie Inc., Boehringer Ingelheim Pharma Gmbh & Ci. KG, Allergn Inc., Amgen Inc., E.R. Squibb & Sons, L.L.C., EMD Serono, Inc., AstraZeneca Pharmceuticals LP, Genentech, Inc., Leo Pharma, Inc., Seattle Genetics, Bayer, Manner SAS, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva Mexico, Parexel, OnQuality Pharmaceuticals Ltd., Novartis, Our Brain Bank; has received research funding from Veloce, US Biotest, Berg, Bristol-Myers Squibb, Lutris, Paxman and Novocure. H-JL has received honoraria from Bristol-Myers Squibb, Bayer, Merck KG, and Genentech; and has a patent pending. AG has received research funding to his institution (at the time) from Bayer, as well as travel expenses to attend advisory board meetings. Ethical Approval: The protocol was approved by the institutional review board at each participating center and all patients provided written informed consent. This study is registered with ClinicalTrials.gov (number NCT02368886).