Tolerance and Efficacy of Regorafenib according to UGT Pharmacogenetical Status in the Treatment of Metastatic Refractory Colorectal Cancer

Introduction: Regorafenib is a multi tyrosin-kinase inhibitor prescribed in metastatic refractory colorectal cancer treatment. Its toxicity is significant but inconstant. The metabolism of regorafenib includes oxydation via cytochrome P3A4, then glucuroconjugation. A pharmacogenetical approach of mutational status of Uridine-Diphospho-Glucuronosyltransfersase (UDP-glucuronosyl-transferase, UGT) could be a strategy to optimise the use of regorafenib. Patients and Method: This is a restrospective, unicentric study. All adult patients treated with regorafenib for a metastatic colorectal cancer in our center between 2013 and 2017 were analysed. UGT1A1 polypmorphism was previously researched in the laboratory after written informed consent. Results: Thirty-five patients received regorafenib during the study period. A TA repetition in UGT1A1 gene was present for 16 patients including two Gilbert syndrome. There were no more adverse events on patients with a heterozygous TA repetition or with a Gilbert syndrome compared with patients without UGT polymorphism, whatever the dosage at initiation of regorafenib. Adverse events grade 2 or superior, and grade 3 or superior tended to be more noticeable when the starting dose was 120 or 160 mg per day compared to 80 mg per day, but not statistically significant. No difference was observed on progression-free survival neither depending on UGT status nor depending on initating dose of regorafenib. Conclusion: This is a preliminary study evaluating safety of regorafenib according to UGT1A1 polymorphism. Larger and prospective studies are needed to evaluate dose-escalation strategy in patients with variable activity of glucuroconidation, especially Gilbert syndrome, or with abnormalities in other UGT enzymes such as UGT1A9.