Regorafenib has demonstrated in two multicenter phase III randomized clinical trials a significant benefit in overall survival (OS) in metastatic colorectal cancer (mCRC) patients treated with regorafenib at 160mg/day 3 weeks/4 (3w/4). However, more than 50% of patients had severe adverse events (grade 3-4), leading to temporary or definitive discontinuation of treatment in 2/3 of the patients and a reduction of the dosing in 20% of them. Thus, a part of the therapeutic failures could be explained by an insufficient exposure to regorafenib because of an early toxicity potentially linked to an initial overexposure. The recent randomized phase II ReDOS study has shown that a gradual increase in the dose of regorafenib (from 80 mg to 160 mg/day 3w/4) led to a significantly greater proportion of patients starting a third cycle of regorafenib and showed a trend toward improvement in overall survival of patients when compared to the standard administration schedule (160 mg/day 3 w/4). These results favored the dose-escalation strategy. However, due to the low correlation between dose and concentration, a concentration-controlled study might be of better relevance.

Regorafenib pharmacokinetics is characterized by a hepatic metabolism leading to the production of two main pharmacologically active metabolites (M-2 and M-5) that may induce therapeutic and adverse effects. The production of these metabolites shows a large inter-individual variability. Pharmacokinetic data from phase III studies have suggested the existence of a relationship between exposure to regorafenib and its metabolites and the occurrence of some therapeutic and adverse effects. In an ancillary pharmacokinetic study of the phase II prospective TEXCAN study in which regorafenib was evaluated in its mCRC indication, it was shown a major benefit in OS in patients with an accumulation of M-2 between the first (C1) and the second (C2) cycle of regorafenib (M2 C2/C1). A significant correlation between M-2 C2/C1 ratio and the sum of trough concentrations of regorafenib, M-2 and M-5 measured at D15C1 (C Sum (Rego+M-2+M-5)) was found, which could be a pharmacological marker of efficacy, earlier than the M-2 C2/C1 ratio. The assessment of the relationship between C Sum and in OS according to a Restricted Cubic Spline analysis showed that the benefit is optimal for a concentration between 2.5 mg/L and 5.5 mg/L (median OS of 10.6 months versus 3.3 and 4.0 months in patients with a concentration \<2.5 mg/L and ≥5.5 mg/L, respectively). The rate of serious adverse events was also lower in the group in the range \[≥2.5; \<5.5 mg/L\] (0% vs 43% and 20% respectively). This interval seems to allow limiting the severe toxicities that cause treatment discontinuations and/or early progressions that could explain the over-risk of death when the concentrations are outside.

The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of Csum and secondly the occurrence of toxicity during treatment. This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients, using the previously defined Csum therapeutic range.