Background: AXL is a member of the mammalian Tyro3/AXL/Mer (TAM) receptor tyrosine kinase family, which upon binding to its ligand Gas6 promotes immunosuppression in the tumor microenvironment. AVB-S6-500 (AVB) is a novel AXL pathway inhibitor which binds to circulating Gas6 and inhibits ligand-dependent AXL signaling. In this phase Ib investigator-initiated trial (NCT04004442), we evaluated the safety, tolerability, pharmacodynamics, and preliminary antitumor efficacy of AVB with the anti-PD-L1 antibody avelumab in mUC. Methods: Patients with PD-1/L1 inhibitor naïve locally advanced unresectable or mUC with measurable disease were eligible if they were either in-eligible for, refractory to, or declined platinum-based chemotherapy. Employing a 3+3 dose escalation design, patients were treated with AVB 5mg/kg weekly (dose level; DL1), or 10 (DL2), 15 (DL3), or 20 (DL4) mg/kg every two weeks along with avelumab 800 mg every 2 weeks administered intravenously. The safety and tolerability of the combination as measured by the incidence of dose limiting toxicities (DLTs) was the primary endpoint while objective response rate (ORR) per RECIST 1.1 was key secondary endpoint. Pharmacodynamic studies evaluated baseline and on therapy (C2D1) Gas6 levels. Results: To date, a total of 15 patients have been enrolled (DL1: n = 3, DL2: n = 7, DL3: n = 3 and DL4: n = 2). Among the 13 evaluable patients, DLT was observed in 1 patient (grade 3 fatigue; DL2). Grade ≥3 adverse events irrespective of attribution were seen in 6 patients which included UTI (n = 3), hyponatremia (n = 1), elevated creatinine (n = 1), and anemia, thrombocytopenia, hematuria, anorexia and sepsis (n = 1 each; all in same patient). No treatment related deaths were noted. While enrollment on DL4 is ongoing, the maximum tolerated dose for AVB has not been reached. Treatment with AVB effectively suppressed circulating Gas6 levels from baseline (median: 28.4 ng/mL; range: 20.4-54.0 ng/mL) to below threshold of detection in 85% (n = 11/13) of patients. Median follow up was 10 months (95% CI: 3.9, 18.55). Confirmed ORR was 38% (n = 5/13) while 1 patient had stable disease as best response. Durable responses lasting > 6 months were seen in 3 patients (7, 19 and 21 mos) who continue to be on treatment without disease progression. Additional correlative studies investigating AXL, Gas6, PD-L1 expression and gene expression signatures are currently underway. Conclusions: Concurrent avelumab and AVB was safe and AVB effectively neutralized circulating Gas6 across DLs. Albeit small sample size, the efficacy of the combination was encouraging and ORR compares favorably to that previously reported with PD-1/L1 inhibitor monotherapy. Updated safety, efficacy and biomarker data will be presented. Clinical trial information: NCT04004442.