SAN FRANCISCO—The U.S. Food and Drug Administration approved regorafenib, a multikinase inhibitor, for the treatment of patients with metastatic colorectal cancer that has progressed on all other standard therapies. The approval was based on the randomized Phase III CORRECT study, which showed significant improvement in overall survival from 5.0 months in the placebo control arm to 6.4 months in the patients receiving regorafenib.
Now, the CORRECT trial investigators report a detailed analysis of the time course of adverse events in the trial. The analysis, presented at a poster session here at the Gastrointestinal Cancers Symposium (Abstract 467), indicates that adverse events are most common early in treatment, before dose modifications, and that there is no evidence of cumulative toxicity associated with regorafenib.
The analysis, reported by Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, included the patients in the study who received at least one dose of the study medication (500 patients in the regorafenib arm and 253 in the placebo arm). Patients receiving regorafenib received an initial dose of 160 mg orally once daily for three weeks of a four-week cycle until disease progression, unacceptable toxicity, or a decision to stop treatment. Patients in the placebo arm received a matched pill on the same schedule.
The median time on therapy was 7.3 weeks and 7.0 weeks in the experimental and control arms, respectively, while the average time on therapy was 12.1 and 7.8 weeks.
About two thirds of patients in the regorafenib arm required dose modification due to adverse events, as did 22.5 percent of patients in the placebo arm. In the regorafenib arm, about 18 percent discontinued therapy due to adverse events, compared with 13 percent of patients in the control arm. The most common Grade 3 or higher adverse events were hand-foot skin reaction (17% in the regorafenib arm vs. 0.4% in the placebo arm), fatigue (10% vs. 5%), diarrhea (7% vs. 0.8%), hypertension (7% vs. 0.8%), and rash or desquamation (6% vs. 0%).
As expected, the mean daily regorafenib dose was highest in the first cycle (160 mg) before dose modifications might be introduced, and then decreased during cycles 2 (about 140 mg) and 3 (about 130 mg). The mean daily dose remained relatively constant thereafter, through cycle 8. Prespecified dose modifications for hand-foot skin reaction included an initial drop to 120 mg daily and then to 80 mg daily.
The frequency of adverse events largely followed that same pattern: For example, Grade 3 hand-foot skin reaction was highest in cycle 1, dropped to a nadir in cycle 5, jumped back up a bit in cycle 6, and then declined to zero in cycle 8. Grades 1 and 2 hand-foot skin reaction declined from cycle 1 to cycle 2 and then climbed back up to cycle 1 levels in cycle 5 before declining altogether.
Hypertension and rash/desquamation followed simpler curves, with all grades highest in cycle 1 and declining through cycle 3 or 4 and then remaining low. The curves for Grades 1 to 3 fatigue were more complex, bouncing up and down between cycles, but with an overall trend downward. Meanwhile, the incidence for Grade 2 and 3 diarrhea remained relatively flat throughout the study, while Grade 1 was relatively flat through cycle 4 and then declined steadily.
Grothey concluded that the majority of patients on regorafenib require dose modifications, but that close monitoring during the early days of treatment will allow prompt intervention and enable patients to stay on treatment to gain maximum potential benefit.
The study was supported by Bayer HealthCare AG.
The multidisciplinary symposium is co-sponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.