COREGO: drug-drug interaction analysis on the efficacy and safety of regorafenib in patients with a sarcoma: pooled analysis of the data from the REGOSARC and REGOBONE trials.

BACKGROUND

Regorafenib, an antiangiogenic multikinase inhibitor (MKI), showed antitumour activity in the second line of treatment for sarcomas in the phase II, randomised versus placebo, multicentre clinical trials REGOSARC (NCT01900743) and REGOBONE (NCT02389244). MKIs are drugs with a narrow therapeutic index subject to drug-drug interactions. The co-medications were not included in the trials' analyses.

MATERIALS AND METHODS

We conducted an ancillary exploratory analysis of the two trials to evaluate the interactions between regorafenib and patients' co-medications administered at baseline in terms of efficacy [progression-free survival (PFS)] and toxicity. The efficacy analysis was stratified according to histology groups.

RESULTS

Overall, 289 patients were included in the efficacy analysis and 339 in the toxicity analysis. Of the entire population, 71.7% of patients had at least one co-medication (median = 2, range 0-14). Overall, we found an improvement in PFS with regorafenib versus placebo (hazard ratio 0.40, 95% confidence interval 0.30-0.53, P < 0.0001). In the multivariate model adjusted on sex, histological grade, and performance status, we did not find any significant interaction between treatment effect (regorafenib versus placebo) and the co-medications on PFS. In the safety analysis, we observed no significant interaction analysis between treatment effect (regorafenib versus placebo) and the co-medications, for all the adverse events, even when considering co-medications with treatments known to be at risk of similar toxicities, or with co-medications at risk of pharmacological overdose (like cytochrome P-450 3A4 inhibitors, organic anion-transporting polypeptide inhibitors, UDP-glucuronosyltransferase inhibitors, treatments competing on protein binding). We did not find any significant interaction between regorafenib and anti-acid drugs either in the efficacy analysis (P = 0.35) or in the toxicity analysis (P = 0.53).

CONCLUSION

We did not find any significant unfavourable interaction between regorafenib and patients' co-medications, from any pharmacological class (e.g. anti-acid), either in terms of efficacy or regarding the occurrence of adverse events. These results are reassuring for the safety of regorafenib administered in association with co-medications.