Epacadostat Plus Preoperative Chemoradiation Is Feasible in Locally Advanced Rectal Cancer


Haeseong Park, MD, MPH, discusses findings from a phase 1 study of epacadostat with preoperative chemoradiation in locally advanced rectal cancer.

Haeseong Park, MD, MPH

Haeseong Park, MD, MPH

The investigational IDO1 inhibitor epacadostat combined with preoperative chemoradiation displayed a tolerable safety profile and preliminary efficacy in patients with locally advanced rectal cancer, according to Haeseong Park, MD, MPH.

During the 2024 AACR Annual Meeting, Park and coauthors presented findings from a translational phase 1 study (NCT03516708) evaluating the safety and preliminary efficacy of epacadostat in combination with preoperative chemoradiation in patients with locally advanced rectal cancer. Among patients in the safety population (n = 17), 2 experienced dose-limiting toxicities (DLTs) at the 600 mg dose level; no DLTs were observed at other dose levels. In terms of efficacy, among the 6 patients who underwent surgery the mean neoadjuvant rectal score was 7.46 (standard deviation, 7.11; range, 0-20.4) compared with 17.8 in an institutional 2:1 matched control cohort (P = .03).

“We want to point out that IDO1 research has been stagnant for the past few years, but we’re hoping this is a new avenue, a new indication where IDO1 inhibition can be better looked at,” Park said. “We have a lot more to go, but hopefully this is a good opportunity to try to combine immunotherapy with the current standard radiation and chemotherapy approach for rectal cancer.”

In an interview with OncLive®, Haeseong Park, MD, MPH, a gastrointestinal medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, discussed the design of the phase 1 study as well as the key findings and future research plans.

OncLive: What was the rationale for combining epacadostat with preoperative chemoradiation in locally advanced rectal cancer?

Park: Epacadostat is a drug that inhibits an enzyme called IDO1 that’s involved in tryptophan metabolism, which happens to be important in both inflammatory bowel disease as well as tumors in the gastrointestinal tract. My translational colleague who is an inflammatory bowel disease researcher established these beautiful preclinical data showing that IDO1 can be overexpressed after radiation to colorectal tumors. Then, inhibiting IDO1 sensitizes colorectal tumor cells to radiation by relieving immune suppression and augmenting the tumor killing effect of radiation.

Secondarily, they also showed that it protects normal epithelium. At the same time, those preclinical data were developing there was a [phase 3] trial called RAPIDO [NCT01558921]. That [study] established short-course radiation followed by chemotherapy as one of the new options for neoadjuvant treatment for rectal cancers.

We thought it was a great opportunity to combine both. Short-course radiation compared with long course theoretically can elicit greater immune response. It was a good opportunity to combine the IDO1 inhibitor with radiation and chemotherapy. We wanted to test our preclinical hypothesis and see if it really worked in patients with locally advanced rectal cancer.

What were the key eligibility criteria for this phase 1 study?

We were mainly looking for patients with locally advanced rectal cancer who would be candidates for short-course radiation based neoadjuvant therapy. We did not want to enroll patients who had active inflammatory bowel disease, but otherwise [we had] fairly relaxed eligibility [criteria] for a phase 1 clinical trial.

What were the key findings from the study that you presented during the 2024 AACR Annual Meeting?

We were pleasantly surprised to see that the efficacy is not any worse, and possibly better, than standard, short-course radiation-based therapy. We measured the efficacy by neoadjuvant rectal score, which we calculate based on the pre- and post-treatment tumor staging. Our scores were lower than what’s expected from standard therapy and lower is better, meaning the tumors had better responses. This is a small study, we had 17 patients, but at least based on those patients, it seems to have a fairly good effect.

What was observed in terms of safety?

The most common adverse effect we saw was diarrhea, which is expected for patients who go through radiation and chemotherapy. We also noted that our patients in this study had quite advanced disease. More than half the patients had T4 disease and N2 disease, so it was somewhat expected. We’re still trying to tease out whether epacadostat added to that.

In terms of DLTs, the only two things we saw were one patient who had aspartate aminotransferase and alkaline phosphatase elevation, which we attributed to epacadostat, and grade 3 rash. For most patients, rash was very manageable. There was 1 patient whose rash was more than what we wanted to see. So, that’s how we landed on 400 mg for the recommended phase 2 dose of epacadostat.

What does the future hold for this research?

We’re wrapping up the phase 1 portion and we’re going to complete all those correlative studies. We have a phase 2 study that’s planned to better look at the safety and home in on the efficacy side. The trial will be enrolling both at Washington University in St Louis and at Dana-Farber Cancer Institute.


Park H, Pedersen K, Huang K, et al. Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): results of a translational phase I clinical trial. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT130.

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