Article révisé par les pairs
Résumé : Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 2013.

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