Nivolumab Plus Regorafenib Regimen Active in Gastrointestinal Cancers

The combination of nivolumab and regorafenib demonstrated promising antitumor activity in patients with gastric and colorectal cancer.

Shota Fukuoka, MD, PhD

The combination of the PD-1 inhibitor nivolumab (Opdivo) and the multikinase inhibitor regorafenib (Stivarga) demonstrated promising antitumor activity and tolerability in patients with gastric and colorectal cancer (CRC), according to findings from the phase 1b REGONIVO trial (EPOC1603) published in the Journal of Clinical Oncology.

Among 50 evaluable patients, the objective response rate (ORR) was 40%, comprising 44% in patients with gastric cancer and 36% in patients with CRC. The median progression-free survival (PFS) was 5.6 months in the gastric cohort and 7.9 months in the CRC cohort.

“The combination of regorafenib [at] 80 mg plus nivolumab demonstrated manageable safety profiles and encouraging antitumor activity in patients with [gastric cancer] and CRC. Additional investigations in larger cohorts are warranted,” first study author Shota Fukuoka, MD, PhD, of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, and coauthors wrote.

Overall, the study accrued 50 patients, 25 each with gastric cancer and CRC. The median age was 61 years (range, 31-80), 80% of patients were male, and 98% had an ECOG performance status of 0. All patients had received at least 2 prior lines of therapy, and 72% of patients had received ≥3 prior lines. Almost all (96%) patients had received an angiogenesis inhibitor, and 14% had prior anti—PD-1/PD-L1 therapy. There was 1 patient with microsatellite instability–high CRC, with all other patients having microsatellite stable or mismatch repair–proficient disease.

Regorafenib was administered once daily at 80 mg to 160 mg for 21 days on, 7 days off, and nivolumab was administered at 3 mg/kg every 2 weeks. The 160-mg regorafenib dose caused 3 dose-limiting toxicities (DLTs): grade 3 colonic perforation, maculopapular rash, and proteinuria. The were no DLTs reported with the other 2 doses used, 80 mg and 120 mg; however, the regorafenib dose was reduced from 120 mg to 80 mg in the dose-expansion part of the trial due to the common occurrence of maculopapular rash. The investigators concluded that 80 mg is the optimal dose to use in further research.

The 40% overall ORR comprised 20 patients, including 11 with gastric cancer and 9 with CRC. The ORR was 45.5% at the 80-mg regorafenib dose and 36% at the 120-mg dose. At the time of the analysis, 13 of 20 responders had ongoing responses. The disease control rate across all 50 patients was 86%.

The 1-year PFS rate was 41.8% in patients with CRC and 22.4% in those with gastric cancer. The median overall survival (OS) had not been reached in the CRC group (95% CI, 9.8—not reached) and was 12.3 months (95% CI, 5.3–not reached) in the gastric cancer group. The 1-year OS rates were 68% and 55.3%, respectively.

The most frequently occurring grade ≥3 adverse events (AEs) were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Grade ≥3 AEs were reported in 27% of the 80-mg regorafenib group and 44% of the 120-mg group. Grade 3 rash occurred in 5 patients receiving 120 mg of regorafenib and none of the patients receiving the 80-mg dose.

Fukuoka et al reported that there was 1 treatment-related death, occurring in a patient with gastric cancer. It was due to diabetic ketoacidosis, following about 9 months of receiving treatment.

“Although VEGF inhibition and PD-1 blockade has been investigated in several clinical trials, randomized studies in CRC did not demonstrate significant improvement in PFS or OS. Moreover, regorafenib targets the VEGF pathway as well as other molecules, such as CSF1R. Additional biomarker analyses are required to identify the molecules that play key roles in the modulation of the tumor immune microenvironment to enhance the efficacy of the PD-1 blockade,” Fukuoka et al wrote in their conclusion.

Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): an open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603) [published online April 28, 2020]. J Clin Oncol.