Dr Park on the Combo of Epacadostat and Chemoradiation in Advanced Rectal Cancer

Haeseong Park, MD, MPH, medical oncologist, Gastrointestinal Cancer Treatment Center, Dana-Farber Cancer Institute, discusses the rationale for combining epacadostat with preoperative chemoradiation in patients with locally advanced rectal cancer in a phase 1/2 translational trial (NCT03516708). Data from the phase 1 portion of the trial were presented at the 2024 AACR Annual Meeting.

The rationale behind combining epacadostat with preoperative chemoradiation in locally advanced rectal cancer stems from epacadostat’s ability to inhibit the enzyme IDO1, which plays a crucial role in tryptophan metabolism, a process significant in both inflammatory bowel disease and gastrointestinal tumors, Park begins. Preclinical research revealed that after radiation therapy, colorectal tumors overexpress IDO1. Inhibiting IDO1 can sensitize tumor cells to radiation by reducing immune suppression and enhancing the tumor-killing effects of radiation, she says. Additionally, it was observed that inhibiting IDO1 also protects normal epithelial cells, further supporting the drug’s potential therapeutic role in cancer management, Park explains.

Simultaneously, the phase 3 RAPIDO trial (NCT01558921) established short-course radiation followed by chemotherapy as a viable neoadjuvant treatment option for rectal cancers, she continues. This trial provided an ideal opportunity to combine the benefits of short-course radiation, which theoretically induces a greater immune response, with the IDO1 inhibitor and chemotherapy, Park states. By merging these approaches, researchers aimed to validate their preclinical hypothesis in patients with locally advanced rectal cancer, potentially offering a more effective treatment strategy, she elucidates.

The phase 1/2 study primarily enrolled patients with locally advanced rectal cancer who were suitable for short-course radiation-based neoadjuvant therapy, Park expands. Exclusion criteria included active inflammatory bowel disease, although the other eligibility criteria were relatively lenient for a phase 1 clinical trial, she notes. This enrollment approach allowed for a diverse patient population to participate, facilitating a comprehensive evaluation of epacadostat’s safety and efficacy in combination with preoperative chemoradiation, Park concludes.