Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)

J Clin Oncol. 2020 Jun 20;38(18):2053-2061. doi: 10.1200/JCO.19.03296. Epub 2020 Apr 28.


Purpose: This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer.

Patients and methods: Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose.

Results: Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability-high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair-proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively.

Conclusion: The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

Trial registration: NCT03406871.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • B7-H1 Antigen / analysis
  • Biomarkers, Tumor / analysis
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nivolumab / administration & dosage
  • Nivolumab / adverse effects
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / adverse effects
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / mortality


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • Phenylurea Compounds
  • Pyridines
  • regorafenib
  • Nivolumab

Associated data