Regorafenib Dose-Escalation Strategy Potentially a New Standard in Metastatic Colorectal Cancer

Wayne Kuznar

Gastrointestinal Cancers


San Francisco, CA—A starting dose of regorafenib (Stivarga) 80 mg daily with dose escalation to 160 mg daily was better tolerated than starting at 160 mg daily, with a trend toward improved survival in the management of patients with metastatic colorectal cancer.

More patients starting at 80 mg daily were able to start their third cycle of therapy, and the rates of grade 3 or 4 fatigue and hand/foot skin reactions were lower when starting at the lower dose, said Daniel H. Ahn, DO, MS, Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, at the 2018 Gastrointestinal Cancers Symposium. These results potentially establish a new standard for optimization of regorafenib dosing, he said.

“From the phase 3 data, we usually start people at 160 mg, but when you look at the real-world practice, most oncologists would not feel comfortable starting with the full dose, mainly due to toxicity, mostly fatigue,” Dr Ahn observed. “The premise of the study was to understand if we started at a low dose with close follow-up and went to a dose-escalation scheme, and whether or not that would improve tolerance. We saw a doubling of the patients who were able to take it into cycle 3, which is the primary end point.”

Toxicities such as palmar-plantar erythrodysesthesia syndrome (PPES), fatigue, and hypertension have limited the use of regorafenib. To minimize toxicities, various dosing schemes or interval scheduling have been implemented without data to support them.

Study Details

In this phase 2 clinical trial, 123 patients were randomly assigned to receive regorafenib 80 mg daily with weekly dose escalation to 160 mg daily (arm A; N = 54) or to a standard dose starting at 160 mg daily (arm B; N = 62). Each arm was also randomly assigned to receive either reactive or preemptive clobetasol in an attempt to manage PPES. Dr Ahn presented outcomes data for arm A versus arm B; further data on outcomes of preemptive versus reactive clobetasol strategies are still undergoing analysis, he added.

Of the 123 patients, 116 were evaluable for the primary end point, which was the proportion of patients who completed 2 cycles of treatment and initiated the third cycle. Overall, 43% of patients achieved the primary end point in arm A compared with 25% of patients in arm B (P = .028).

“This model kind of proves that if we have close follow-up and do appropriate dose escalation, this would probably make many more oncologists less fearful to use a drug like regorafenib, where there can be severe adverse events,” Dr Ahn said. In addition, “when you look at our secondary end point, there was nearly a 3-month difference in overall survival, and while it didn’t reach statistical significance, it was trending toward it, so potentially there may be a survival benefit in addition to better tolerance.”

The median overall survival was 9 months in arm A and 5.9 months in arm B (hazard ratio, 0.65; P = .094). Median progression-free survival was 2.5 months in arm A versus 2.0 months in arm B (P = .553).

During week 1 of treatment cycle 2, the mean percentage of the planned regorafenib dose actually received was 99.6% in arm A versus 78.0% in arm B. In week 2 of cycle 2, it was 95.1% and 76.7%, respectively, and in week 3, 84.8% and 69.9%, respectively.

Grade 3 fatigue was reported in 13.0% of patients in arm A versus in 17.7% of those in arm B. In arm A versus arm B, other rates of grade 3 toxicities included, respectively: hand/foot skin reaction, 14.8% and 16.1%; abdominal pain, 16.7% and 6.5%; hypertension, 7.4% and 14.5%; and an increase in bilirubin, 3.7% and 8.1%. Multiple quality-of-life parameters favored arm A over arm B, primarily at week 2 of the first treatment cycle.