Phase II trial of pembrolizumab in combination with odetiglucan for patients with metastatic colorectal adenocarcinoma with liver-predominant disease.

Abstract

TPS3673 Background: Liver metastases are associated with resistance to immune checkpoint inhibitors in patients with mismatch repair proficient (MMRp) metastatic colorectal cancer (mCRC). (Beiter JCO 2025) Odetiglucan is a pathogen associated molecular pattern (PAMP) that modulates the tumor microenvironment and may enhance the activity of immune checkpoint inhibition. In syngeneic colon cancer mouse models, the combination of odetiglucan and PD-1/PD-L1 inhibition was associated with a larger proportion of tumor-free mice than either treatment alone. (Jonas Cancer Res. 2017; Fraser Cancer Res. 2016; Chan Frontiers Oncol. 2020) In a mouse model of pancreatic cancer liver metastases, odetiglucan reprogrammed liver-resident macrophages to stimulate tumor-specific T-cell responses, which was associated with reduced cancer cell proliferation and increased sensitivity to anti-PD-1 therapy. (Thomas Nat Commun. 2023) In a clinical trial of anti-PD-1 therapy plus odetiglucan in patients with triple negative breast cancer, tumor regression was observed in 56% of liver lesions classified as target lesions, with one patient experiencing complete regression of both target liver lesions, which remained undetectable after more than 70 weeks of treatment. (Stopeck J Immun. 2025). Methods: We are performing a single-center, investigator-initiated, single-arm phase II clinical trial with a Simon two-stage mini-max design of the combination of pembrolizumab with odetiglucan in patients with liver-predominant, MMRp mCRC who have experienced disease progression on standard therapies (3L+ setting). Treatment consists of intravenous infusion of odetiglucan (4mg/kg) and pembrolizumab on day 1 of a 21-day cycle. Patients with prior exposure to immunotherapy or odetiglucan, peritoneal metastases, symptomatic lung or bony metastases, autoimmune conditions requiring systemic immunosuppression, or a history of pneumonitis are excluded. The primary endpoint of the study is objective response by RECIST 1.1. The null hypothesis that the true response rate is 6% will be tested against a one-sided alternative. In the first stage of the study, 13 patients will be accrued and if there are no partial or complete responses, then the study will be stopped for futility. Otherwise, 14 additional patients will be accrued to a total of 27 patients. If four or more responses are observed in 27 patients, then the null hypothesis will be rejected. As of 1/2026, four patients have been enrolled and started study treatment. The study includes pre-treatment and on-treatment research biopsies and longitudinal research blood collection for immune pharmacodynamic profiling to investigate mechanisms of treatment response and resistance. Clinical trial information: NCT07082439 .