Regorafenib Plus Nivolumab in Advanced Gastric and Colorectal Cancers

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In a Japanese phase Ib/dose-expansion trial reported in the Journal of Clinical Oncology, Fukuoka et al found that the combination of regorafenib and nivolumab showed activity in patients with previously treated gastric cancer and colorectal cancer with microsatellite stable/mismatch repair–proficient tumors.

As noted by the investigators, regorafenib may act to reduce mechanisms of immune suppression other than those associated with the programmed cell death protein 1/ programmed cell death ligand 1 (PD-L1) mechanisms.

Study Details

The study enrolled a total of 50 patients, including 25 with gastric cancer and 25 with colorectal cancer, between January 2018 and October 2018. All patients had received two or more previous lines of chemotherapy, including antiangiogenic inhibitors in 96% of patients and immune checkpoint inhibitors in seven patients with gastric cancer. All patients—except one with microsatellite instability (MSI)-high colorectal cancer—had microsatellite stable/mismatch repair–proficient tumors.

In the dose-finding phase of the trial, patients received regorafenib at 80 to 160 mg once daily for 21 days on/7 days off with nivolumab at 3 mg/kg every 2 weeks. In the expansion cohort, the regorafenib dose was reduced from 120 to 80 mg once daily due to frequent maculopapular rash at the higher dose. Overall, among all 50 patients, the regorafenib dose administered was 80 mg, 120 mg, and 160 mg once daily in 22, 25, and 3 patients, respectively.


In the dose-finding phase, three dose-limiting toxicities were observed at the 160 mg of regorafenib dose level, consisting of grade 3 colonic perforation, maculopapular rash, and proteinuria.

Among all 50 patients, grade ≥ 3 treatment-related adverse events occurred in 40% (27% vs 44% at regorafenib 80 mg vs 120 mg), with the most common being rash (in 12%), proteinuria (in 12%), and palmar-plantar erythrodysesthesia (in 10%). Grade 3 rash occurred in five vs no patients at 120 mg vs 80 mg of regorafenib. One treatment-related death, due to diabetic ketoacidosis, occurred in a patient with gastric cancer after approximately 9 months on combination treatment.


  • Objective response was achieved in 44% of patients with gastric cancer and 36% of those with colorectal cancer.
  • Median progression-free survival was 5.6 and 7.9 months.


Objective responses were observed in 20 patients (40%), including 11 (44%) with gastric cancer (44%) and 9 (36%) with colorectal cancer, including the one patient with MSI-high colorectal cancer. Response rates were 45.5% with regorafenib at 80 mg and 36.0% with 120 mg. Responses were ongoing at last analysis in six patients with gastric cancer and seven with colorectal cancer. Among 48 patients with PD-L1 combined positive score (CPS) data, response rates for those with CPS ≥ 1 vs < 1 were 60.0% vs 35.7% among patients with gastric cancer and 25% vs 43.8% among those with colorectal cancer. Among 47 patients with tumor mutational burden (TMB) data, response rates for those with TMB-high (top quartile) vs TMB-low were 50.0% vs 44.4% among patients with gastric cancer and 50.0% vs 35.3% among those with colorectal cancer. Median progression-free survival was 5.6 and 7.9 months in patients with gastric cancer and colorectal cancer, respectively.

The investigators concluded, “The combination of regorafenib [at] 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer[s], which warrants additional investigations in larger cohorts.”

Kohei Shitara, MD, of the Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bayer HealthCare Pharmaceuticals Inc and Ono Pharmaceuticals. For full disclosures of the study authors, visit

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