Background: TPST-1495 is a novel oral therapy designed to be a selective dual antagonist of the prostanoid receptors, EP2 and EP4. Through these receptors, PGE2 stimulates tumor growth, suppresses immunity, and supports adaptive resistance to checkpoint inhibitors. In preclinical models, dual EP2/EP4 inhibition with TPST-1495 increased anti-tumor efficacy, reduced immune suppression, and activated immune effector response significantly better than single EP2 or EP4 antagonists and the COX-2 inhibitor celecoxib. Methods: In this Phase 1 study, subjects with advanced solid tumors received TPST-1495 in a modified 3+3 design optimizing dose and schedule as monotherapy and in combination with standard dose pembrolizumab. Study objectives included safety, PK/PD, recommended phase 2 dose (RP2D), anti-tumor activity and exploratory biomarkers. AEs were assessed per CTCAE v5 and efficacy per RECIST v1.1. Results: TPST-1495 monotherapy was dosed BID (n=11), QD (n=22) or QD days 1-5 every 7 days (n=17) and in combination was dosed QD only with pembrolizumab 200 mg IV q3 weeks (n=24). TPST-1495 doses ranged from 15 mg QD to 100 mg BID. Most subjects had CRC (61%) followed by endometrial (5.4%) and pancreatic (5.4%) cancer. Median prior lines of systemic therapy were 4 (2-10) in monotherapy; 3 (1-8) in combination The most common treatment related AEs (TRAEs) were diarrhea (22%), abdominal pain (20%), fatigue, and nausea (18% each) for monotherapy and nausea (29%), fatigue (21%) and diarrhea (17%) for combination therapy. The most common Gr 3 TRAEs were anemia (6.0%) in monotherapy, and ALT/ AST increased and fatigue (4.2% each) in combination. No Gr 4/5 TRAEs were reported. For mono vs combo cohorts, the median time on study was 1.9 mo (0.2 – 10.2) vs 2.7 mo (0.5 – 10.4) and the disease control rate was 43% (19/44) vs 43% (9/21) with 1 PR in a combination subject with MSS CRC. Pharmacodynamic activities included on-treatment increases in urine PGE2 metabolites and drug-dependent TNF-α rescue in an ex-vivo whole blood PGE2 challenge assay. The RP2D is 50 mg QD for mono and in evaluation for combo therapy. In a subject with endometrial cancer with 22% tumor shrinkage and 222+ days on combination therapy paired biopsies showed high COX-2 expression in the TME at baseline and increased CD8+ and CD8+GrB T cell infiltration on treatment. Conclusions: PGE2 is an important target for cancer and immunotherapy but remains ineffectively drugged. TPST-1495 is a novel oral therapy that inhibits signaling only at the tumor promoting EP2/EP4 receptors. In patients with heavily treated solid tumors, primarily MSS CRC, TPST-1495 had pharmacodynamic activity, a manageable safety profile, and a potential signal of activity consistent with the preclinical data and IO combination mechanism. A combination therapy cohort in endometrial cancer is underway. Updated results and biomarker work will be presented. Clinical trial information: NCT04344795.