Abstract Background: Microsatellite stable (MSS) colorectal cancer (CRC) comprises approximately 85% of the total CRC population and outcomes remain poor with five-year survival rates plateauing at roughly 13%. This highlights a significant unmet need, particularly in patients with advanced disease. MSS CRC is characterized by immunologically inactive tumor environments and shows limited response to standard therapies like immune checkpoint inhibitors (ICIs). Clinical activity in MSS CRC was reported in a Phase 2 study (NCT03860272) evaluating the combination of the next-generation CTLA-4 inhibitor botensilimab (bot) with the PD-1 inhibitor balstilimab (bal) in heavily pretreated patients with metastatic disease. The regimen demonstrated a manageable safety profile and durable disease control, particularly among patients without active liver metastases. Approximately 70% of patients achieved stable disease or better, with objective response rates of 17-19%, reductions in tumor burden, and near complete responses in select cases. While these findings represent an improvement over existing standards of care, a large proportion of patients, both with and without liver mets, remain unresponsive to immune therapy. Emerging data suggests that effective responses to adaptive immune therapies depend on successful engagement of innate immune signaling within the tumor microenvironment. In MSS CRC, insufficient innate immune activation contributes to impaired antigen presentation, limited dendritic cell priming, and inadequate T-cell recruitment, further constraining the activity of checkpoint blockade. Innate immune signaling is mediated by the STimulator of INterferon Genes (STING) pathway, which is negatively regulated by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) through hydrolysis of 2′3′-cGAMP. As a direct suppressor of STING signaling, ENPP1 inhibition represents a clinically relevant strategy to enhance innate immune activation. Previously, we reported the development of a clinical candidate, vizenpistat (SR-8541A), a potent, orally bioavailable ENPP1 inhibitor. Here, we report initial findings from the ongoing study of vizenpistat in combination with bot and bal in MSS CRC. Study Design: This Phase 1b/2 study (NCT06589440) is evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of vizenpistat administered orally in combination with bot and bal in patients with refractory metastatic MSS CRC. The primary study objective is to characterize the safety, tolerability, and efficacy of the combination and to define the optimal dose of vizenpistat, which is administered orally twice daily in 28-day treatment cycles. To date, five vizenpistat dose escalation cohorts have been successfully completed. Blood samples are collected for PK analysis, target engagement, and biomarker assessment. Citation Format: Alexis S. Larsen, Mohan R. Kaadige, Trason Thode, Margaux Steinbach, Scott Houston, Jonathan Northrup, Sunil Sharma. A progress report for a Phase 1b/2 study of ENPP1 inhibitor, vizenpistat in combination with botensilimab and balstilimab in subjects with refractory metastatic microsatellite stable colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT221.
Larsen et al. (Fri,) studied this question.