In a single-institution phase I trial reported in JAMA Oncology, Marwan Fakih, MD, and colleagues found that the combination of regorafenib, ipilimumab, and nivolumab showed evidence of activity in patients with microsatellite-stable metastatic colorectal cancer who did not have liver metastases.
Study Details
Thirty-nine patients with disease progression after standard chemotherapy were enrolled in the study at City of Hope Comprehensive Cancer Center between May 2020 and January 2022. Patients received regorafenib daily for 21 days every 4 weeks, ipilimumab at 1 mg/kg every 6 weeks, and nivolumab at 240 mg every 2 weeks; treatment continued until disease progression, unacceptable toxicity, or completion of 2 years of therapy.
During the regorafenib dose-finding phase, nine patients received regorafenib at 80 mg daily, with no dose-limiting toxicities being observed. A dose of 80 mg/d was declared the recommended phase II dose (RP2D), and 20 patients were added to the RP2D cohort (n = 29). In addition, 10 patients were enrolled in a regorafenib dose-optimization cohort to explore a strategy to reduce skin-related toxicity.
Marwan Fakih, MD
Key Findings
Among the 29 patients in the RP2D cohort, the objective response rate (all partial responses) was 27.6%, and the disease control rate was 62.1%. Median progression-free survival was 4 months (95% confidence interval = 3–9 months) and median overall survival was 20 months (95% CI = 9 months to not reached).
In post hoc analysis, among 22 patients in the RP2D cohort without liver metastasis, the objective response rate was 36.4%, the disease control rate was 68.2%, median progression-free survival was 5 months (range = 1–28 months), and median overall survival was > 22 months (range = 2 months to not estimable). Among seven patients with liver metastasis, the objective response rate was 0%, the disease control rate was 42.9%, median progression-free survival was 2 months (range = 2–9 months), and median overall survival was 7 months (range = 4–23 months).
In the RP2D cohort, grade ≥ 2 skin toxicity occurred in 51.7% of patients, with grade 3 toxicity in 37.9%.
In the dose-optimization cohort, 10 patients received regorafenib at 40 mg/d in cycle 1 and 80 mg/d in cycle 2 and beyond. Compared with the RP2D cohort, the incidence of grade ≥ 2 skin toxicity (10.0% vs 51.7%) and the incidence of any other grade ≥ 2 immune-related adverse events (30.0% vs 65.5%) was lower in the dose-optimization cohort. However, no objective responses were observed in this cohort, with best response of stable disease seen in five patients (50.0%).
The investigators concluded, “Results of this nonrandomized clinical trial suggest that regorafenib, ipilimumab, and nivolumab at the RP2D demonstrated interesting clinical activity in patients with advanced microsatellite-stable colorectal cancer without liver metastases. These findings should be confirmed in randomized clinical trials.”
Dr. Fakih, of the Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by a National Cancer Institute grant and institutional funding from City of Hope Comprehensive Cancer Center. For full disclosures of the study authors, visit jamanetwork.com.
