IK-175, an Oral Aryl Hydrocarbon Receptor Inhibitor, Alone and with Nivolumab in Patients with Advanced Solid Tumors and Urothelial Carcinoma

PURPOSE: Acquired resistance to anti-PD-1 therapy remains a major barrier to achieving durable responses in patients with solid tumors. The aryl hydrocarbon receptor (AHR) is a downstream mediator of intratumoral immunosuppression. We evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with advanced solid tumors and urothelial carcinoma. PATIENTS AND METHODS: This was a first-in-human, open-label phase 1/1b study. Patients with advanced solid tumors refractory to standard therapies were enrolled in a dose-escalation study of IK-175 monotherapy or IK-175 plus nivolumab. An expansion cohort enrolled patients with advanced urothelial carcinoma previously treated with anti-PD-1 therapies. Primary objectives were safety, tolerability, and determination of recommended phase 2 doses. Secondary objectives included pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. RESULTS: IK-175 was well tolerated, and the recommended phase 2 dose was established. Target engagement was confirmed by ex vivo AHR activation assays and dose-dependent modulation of AHR-regulated genes in tumor biopsies. Clinical responses, including one complete response and durable stable disease, were observed in patients with urothelial carcinoma refractory to prior checkpoint blockade. No new safety signals were identified in combination with nivolumab. CONCLUSIONS: IK-175, alone and with nivolumab, demonstrated a favorable safety profile, evidence of target engagement, and preliminary clinical activity in immune-refractory urothelial carcinoma. These data support continued development of AHR inhibitors to overcome adaptive immune resistance in solid tumors.