Dose escalation strategy trumps standard starting dose for regorafenib in mCRC
A weekly dose escalation of regorafenib was superior to starting with the standard dose of 160 mg/day for patients with refractory metastatic colorectal cancer (mCRC), according to the ReDOS* trial presented at the ASCO GI Cancers Symposium 2018.
Although survival benefit has been shown with regorafenib in previous trials, associated toxicities such as hand-foot skin reaction or palmar-plantar erythrodysesthesia syndrome (PPES), which usually occur during the first 2 weeks of treatment, and fatigue may have limited its use, according to lead author Dr Tanios Bekaii-Saab of the Mayo Clinic in Phoenix, Arizona, US.
“There is a need to optimize the dose of regorafenib in patients with refractory mCRC to allow maintenance of the observed anti-tumour benefits while improving the tolerability profile,” he said.
The phase II trial randomized 123 patients with refractory mCRC to regorafenib dose escalation (Arm A; starting at 80 mg/day followed by weekly dose escalation provided no significant drug-related toxicities, up to 160 mg/day) or standard dose of 160 mg/day (Arm B) for 21 days of a 28-day cycle. Of these, 116 patients (median age 61 years, 61 percent males; n=54 and 62 in Arms A and B, respectively) were evaluable and constituted the modified intent-to-treat population. [ASCO GI 2018, abstract 611]
Significantly more patients in Arm A met the primary endpoint of having completed two cycles of treatment and were initiating the third cycle of treatment than Arm B (43 percent vs 25 percent, one-sided p=0.028), with Arm A showing superiority over B as defined by a one-sided p-value of <0.2.
Improvements in overall survival (median, 9.0 vs 5.9 months, hazard ratio [HR], 0.65; p=0.094) and progression-free survival (median, 2.5 vs 2.0 months; HR, 0.89; p=0.553) were also observed in Arms A vs B, although the difference between groups were not statistically significant.
Importantly, lower rates of grade 3/4 toxicities overall were observed with dose escalation vs starting with standard dose (13 percent vs 18 percent for fatigue, 15 percent vs 16 percent for PPES, and 7.4 percent vs 15 percent for hypertension).
“These results potentially establish a new standard for optimizing regorafenib dosing through a dose escalation strategy,” said Bekaii-Saab.
Also, various measures of quality of life (QoL) were improved in Arm A compared with Arm B, particularly at week 2 of the first cycle.
“At 2 weeks from initiation of therapy, the dose escalation strategy did not appear to compromise QoL unlike the standard dose administration,” added Bekaii-Saab.
Additionally, patients in each Arms A and B were further randomized to pre-emptive corticosteroid clobetasol for PPES or reactive clobetasol, outcome data of which are currently being analysed and will be presented in future meeting, according to the researchers.