Regorafenib with nivolumab and chemotherapy gave tumor response in 22 of 30 gastric cancer patients

A team led by Kota Itahashi at the National Cancer Center Japan reported results of a phase 1b/2 trial (NCT05394740) of first-line regorafenib, nivolumab and chemotherapy. The trial enrolled 30 patients with mismatch repair-proficient gastric cancer. The work was published on 4 November 2026 in Science translational medicine. The primary end point was met: 22 of 30 patients had an objective tumor response (73%; 80% confidence interval, 60.3 to 83.8) doi.orgScience translational medicinedoi.orgOpen source ↗. The authors described the treatment as safe.

Trial design and response

Regorafenib is a multikinase inhibitor, and nivolumab is an anti-PD-1 antibody. Earlier studies that combined regorafenib with a PD-1 inhibitor showed promising activity in gastric cancer doi.orgScience translational medicinedoi.orgOpen source ↗. According to the press release, gastric cancer is the fifth most common cancer, and median survival remains 13 to 15 months on average.

The researchers took biopsy samples at baseline, during treatment and at disease progression. They analyzed the samples with single-cell RNA sequencing and T cell receptor sequencing doi.orgScience translational medicinedoi.orgOpen source ↗.

Changes in the tumor microenvironment

During treatment, the number of tumor antigen-reactive CD8+ T cells and M1-like proinflammatory macrophages increased. Immunosuppressive and tumor-promoting populations decreased: activated CCR8+ regulatory T cells, LRRC15+ cancer-associated fibroblasts, RGS5+ pericytes and APLN+ tip cells doi.orgScience translational medicinedoi.orgOpen source ↗.

At progression, LRRC15+ fibroblasts and APLN+ tip cells stayed reduced. Activated CCR8+ regulatory T cells expanded again, and additional treatment-resistant subsets appeared, including APOC1+ lipid-associated macrophages doi.orgScience translational medicinedoi.orgOpen source ↗.

The authors also tested these populations in mouse models of acquired resistance. Antibodies against CCR8 or TREM2 combined with PD-1 blockade restored antitumor immunity in the animals doi.orgScience translational medicinedoi.orgOpen source ↗. This part of the work was done on mice, not in patients.

The authors conclude that the tumor microenvironment is remodeled dynamically during therapy and that the identified cell populations may be potential therapeutic targets. The trial had 30 participants and no comparison group, so the response rate describes this cohort only.