A phase 2 study of SR-8541A in combination with botensilimab and balstilimab in subjects with refractory metastatic microsatellite stable colorectal cancer (MSS-CRC).

e15602 Background: The five-year survival rate for colorectal cancer (CRC) remains at 14% despite improvements in early detection and the development of novel treatments, underscoring the need for new therapeutic strategies. The immune landscape of CRC is heterogeneous and complex, posing challenges in treatment decision-making. Colorectal tumors presenting with high microsatellite instability (MSI) or mismatch repair deficiency (MMRD) represent 15 - 20% of all CRC cases, are heavily infiltrated by immune cells, and have a better response to immune checkpoint inhibitors (ICIs). Colorectal tumors presenting with microsatellite stable (MSS) or mismatch repair proficiency (MMRP) account for 85% of CRCs, are immune deserts, and respond poorly to ICIs. Recently, a Phase 2 study (NCT03860272) of 2nd generation CTLA-4 (botensilimab/bot) and PD-1 (balstilimab/bal) inhibitors reported clinical activity in pretreated patients with metastatic MSS CRC. The study also reported a manageable safety profile with excellent disease control in patients with no active metastatic disease in the liver. Around 70% of patients had stable disease or better, with a 17-19% objective response rate, a 30% reduction in cancer burden, and near-complete responses in some patients. While these results are an encouraging improvement from the standard of care, a large proportion of MSS CRC patients with and without liver metastases remain immune-resistant. About 85% of CRCs exhibit chromosomal instability, which results in chromosome segregation errors and micronuclei formation. The latter releases dsDNA into the cytosol, stimulating a cGAS-STING-dependent innate immune response. Preclinical studies have shown that activation of STING in the tumor microenvironment leads to induction of an interferon response, activation and maturation of dendritic cells, and stimulation of T-cell responses. ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) is the direct negative regulator of the STING pathway. Therefore, combining our ENPP1 inhibitor, SR-8541A, with bot and bal would be a novel strategy to activate both innate and adaptive immune responses, generating a robust and durable clinical response rate in MSS CRC patients. Methods: The Phase 2 study is evaluating the safety, tolerability, PK, and efficacy of SR-8541A administered in combination with bot and bal in patients with refractory metastatic MSS CRC (NCT06589440). The primary objective of the study is to characterize the safety, tolerability, efficacy, and define the optimal dose of SR-8541A in combination with bot and bal. Secondarily, the study aims to evaluate the PK and preliminary efficacy of SR-8541A in combination with bot and bal. SR-8541A is administered orally twice daily (BID) in 28-day cycles. Blood samples are being collected for PK, target engagement, and biomarker assessment. Clinical trial information: NCT06589440 .