A Phase 1-2 clinical program for the teatment of Microsatellite Stable Colorectal Cancer with the combination of SR-8541A, Botensilimab, and Balstilimab

ABSTRACT Metastatic microsatellite stable colorectal cancer (MSS-CRC) accounts for 80% of CRCs with a standard of care that provides a dismal 10% objective response rate (ORR). It is a cancer where immune checkpoint inhibitors (ICIs) work poorly, innate immunity is known to be shut off, and ENPP1 levels are high. Recently, Agenus reported in a Phase 2 study (NCT03860272) of their second-generation, Fc-enhanced CTLA-4 (Botensilimab) and PD-1 (Balstilimab) inhibitors to have clinical activity and durable responses in heavily 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, with a 17- 19% ORR. While these results are an encouraging improvement from the standard of care, many of these patients remain immune-resistant. In recent years, much emphasis has been placed on improving adaptive immune responses to suppress tumor evasion. We propose ENPP1 as a novel dual immunosuppressive checkpoint target that can directly modulate innate and adaptive immune responses through 2′3′-cGAMP and adenosine levels within the tumor microenvironment (TME). To this end, Stingray Therapeutics has used the Direct to Phase II SBIR award (R44 CA278144) and investor funding to advance our ENPP1 inhibitor SR-8541A to human trials. Multiple selectivity studies, cancer cell line panels, normal cells, tolerability in the mouse, rat, and dog, and toxicology in rat and dog show no direct cytotoxic activity or harmful effect. Combination studies of SR-8541A and ICIs, including Botensilimab, showed robust tumor growth inhibition in the CT26 CRC model. Our phase 1 dose escalation study (NCT06063681) to assess SR-8541A safety, tolerability, and pharmacokinetics is ongoing, with no dose-limiting toxicities (DLTs) in the three dose cohorts tested to date. The current objective for our ENPP1 program and the purpose of this Phase IIB Bridge SBIR application is to test the hypothesis that adding an appropriate activator of the innate immune system, such as our ENPP1 inhibitor SR-8541A, will enhance the breadth of response and durability when added to Agenus' adaptive immune modulators. In Aim 1, we will conduct a phase 2 trial to evaluate the safety and efficacy of SR-8541A administered orally with Agenus Botensilimab and Balstilimab for patients with MSS CRC. We received IND clearance for this study (#170805) on July 26, 2024. In Aim 2, we will investigate the participants’ systemic immunity and that of the TME pre- and post-treatment, as well as its association with clinical response as part of the exploratory objective of the phase 2 trial. If successful, SR-8541A could substantially modify the landscape of treatment options for patients with MSS CRC and other solid tumors.