Data demonstrate efficacy of more flexible dose of regorafenib to relieve side-effects in mCRC patients

This international trial, led by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD), included 299 patients from over a dozen hospitals in Spain, Italy and France. The average age of the participants was 64 and they had received an average of four treatment lines prior to inclusion in the trial with regorafenib between July 2016 and September 2017.

"Regorafenib has been approved since 2013 for patients with metastatic colorectal cancer (mCRC) who have progressed to standard treatments," said study author, Dr. Guillem Argiles, medical oncologist and clinical investigator, Gastrointestinal & Endocrine Tumors Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

"Its adverse toxicity profile often limits its use in routine clinical practice. This clinical trial attempted to show the usefulness of different dose strategies in order to improve its tolerability and quality of life in patients who can benefit from the medicine in the context of advanced disease."

In the trial, patients were randomised 1:1:1: standard dose 160 mg/day for three weeks followed by a week off; reduced dose of 120 mg/day for three weeks followed by a week off (reduced dose group); or intermittent dose of 160 mg/day a week, followed by a week off (intermittent dose group). The patients in the latter two groups (reduced or intermittent dose) were escalated to the standard of care dose if, after a first treatment cycle, no limiting toxicities that prevented to continuing to stay in the trial occurred. "We reduced the dose in the first cycle and then escalated because it has been shown that the toxicity is higher in the first and second months of treatment," explained Argiles.

The investigators observed that flexible dosing showed numerical improvement on several parameters that improved tolerance, such as fatigue, hypertension or hand-foot syndrome (reaction due to redness, swelling and pain caused in the palms), although REARRANGE did not meet its primary endpoint of improving regorafenib global tolerability in the reduced and intermittent dose groups. The average treatment duration was 3.2 months in the standard group; 3.7 in the reduced dose group; and 3.8 in that with alternating weeks. Median progression-free survival was not different across groups (approximately 2 months).

"Although statistical significance was not achieved, we did observe a numerical reduction in some side-effects that can be very troublesome for the patients," explained Argiles. "These results, interpreted in the context of other trials, like the American study ReDOS, tell us that the more flexible doses of regorafenib are an effective alternative in order to improve quality of life in patients with metastatic refractory colorectal cancer."

Commenting on the results, Prof. Eric Van Cutsem, from the University Leuven, Belgium, said: "This study will change clinical practice with regard to the use of regorafenib in patients with metastatic colorectal cancer, because it demonstrates and supports something that many clinicians have already observed and were carrying out in regular clinical practice." In his opinion, the trial shows that this reduction in regorafenib initial dose limits the drug toxicity while maintaining its efficacy.