Three-drug combination remodels immune environment in gastric cancer

A triplet combination therapy can remodel the tumor microenvironment in patients with advanced gastric cancer and shows a promising safety profile, according to results from a new phase 2 clinical trial. The findings provide a detailed breakdown of how the drugs reshape immune cells in the tumor's vicinity, and uncover promising treatment targets for future immunotherapeutic approaches.

Gastric cancer is the fifth most common type of cancer, and the median survival time remains low, at 13 to 15 months on average. In recent years, clinicians have started combining standard chemotherapy with immunotherapies such as anti-PD-1 antibodies, leading to improved survival times. Researchers are also turning to other potential combination strategies, including ones that include the drug regorafenib. This drug targets various enzymes and growth factors that support tumors, and recently displayed promising results in a phase 2 trial. However, more work is needed to understand how regorafenib interacts with other treatments and how it impacts anti-tumor immunity in the tumor milieu. Here, Kota Itahashi and colleagues administered a combination of regorafenib, chemotherapy, and the anti-PD-1 immunotherapy nivolumab to 30 patients with advanced gastric cancer.

They observed that the treatment was safe and that 22 of the patients displayed an objective tumor response, meeting the study's primary endpoint. Using single-cell RNA sequencing on biopsies, the team observed that the treatment augmented anti-tumor CD8+ T cells while suppressing other immune cells that restrain the immune system, including regulatory T cells and cancer-associated fibroblasts. "These findings may shed light on how a multikinase inhibitor, in conjunction with PD-1 blockade and chemotherapy, remodels the [tumor microenvironment] in [advanced gastric cancer] and reveal potential targets for further investigation in rational combination studies," Itahashi et al. write.