Completed phase 1a dose escalation study of the first oral ENPP1 inhibitor RBS2418 immunotherapy in subjects with metastatic solid tumors.

2577 Background: ENPP1 clears cGAMP and ATP in the tumor microenvironment (TME). Its expression is associated with poor prognosis in cancer and development of metastases. ENPP1 inhibition can protect cGAMP and ATP from hydrolysis and reduce adenosine levels in the TME. These immune modulators are known to activate APCs and increase T-cell infiltration, promoting anticancer immunity. RBS2418 is a potent and selective oral first-in-class inhibitor of ENPP1. In this open-label, multi-site Phase 1a/b study, safety and efficacy of RBS2418 is being evaluated as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors. Methods: The phase 1a dose escalation part comprised 100, 200, 400 and 800 mg BID dose levels of RBS2418 alone or in combination with pembrolizumab (200 mg IV q3w) in patients who have failed all approved treatments including immunotherapy using a 3+3 study design. Study objectives were to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes. Tumor and blood samples were collected to determine PK/PD and immune profiles using LC/MS, IF, IHC, TCR and RNAseq analyses. Results: Dose escalation is complete, andRBS2418 was safe and well tolerated at all dose levels with no DLTs (n = 24). Treatment durations range from 1 to 15 months to date, and no treatment-related grade 3 adverse effects (TRAEs) or serious AEs (SAEs) have been observed. A total of 21 grade 1 or grade 2 TRAEs were reported in 9 (37.5%) subjects; the most common TRAE was grade 1 fatigue. Median plasma concentrations of RBS2418 increased in a dose-proportional manner. Plasma and tumor concentrations of RBS2418 were maintained above the ENPP1 inhibition EC90 level in all patients and at all dose levels tested. Of 19 patients with adequate baseline tissue, pre-treatment ENPP1 and cGAS co-expression (EG+ phenotype, n = 8) in tumors correlated with RBS2418 treatment-associated immune activation and significantly improved progression-free-survival (PFS) as compared to EG- phenotype at baseline (n = 11). A switch from “cold” tumor to “hot” tumor phenotype was consistently observed in EG+ subjects. Disease control rate (DCR) was 75% (6/8) in EG+ and 9% (1/11) in EG- subjects. Conclusions: The Ph1a dose escalation study with oral RBS2418 alone, and with pembrolizumab has been completed. All doses were safe and well tolerated with no grade 3 TRAEs, SAEs or DLTs. RBS2418 plasma concentrations enabling full cGAMP protection was observed in all patients at all dose levels. Immune activation and clinical benefits strongly correlated with EG+ phenotype. RBS2418 achieved Phase 1a goals of safety, PK, PD, and target engagement and showed significant treatment benefits in advanced metastatic cancer patients. The results support further development of RBS2418. Phase 1b dose expansion is in progress and the first Phase 2a study has been initiated for the treatment of mCRC. Clinical trial information: NCT05270213 .