IK-175, an oral AHR inhibitor, as monotherapy and in combination with nivolumab in patients with urothelial carcinoma resistant/refractory to PD-1/L1 inhibitors.

2599 Background: IK-175 is an oral, selective, small molecule Aryl Hydrocarbon Receptor (AHR) inhibitor. AHR is a ligand-activated transcription factor that binds kynurenine causing gene expression that promotes an immunosuppressive tumor microenvironment, possibly driving resistance to PD-1/L1 inhibitors (CPIs). Urothelial carcinoma (UC) demonstrates increased AHR signaling and nuclear protein localization as shown by gene expression analysis and tissue-based immunohistochemistry. Methods: This is a first-in-human, open-label, multicenter, study of IK-175 monotherapy and with nivolumab initially in solid tumors and for expansion in UC. Dose expansion patients received 1200mg QD of IK-175. Nivolumab was given at 480mg q4w in the combination cohorts. Both monotherapy and combination expansion arms utilized Simon 2-stage designs, and enrolled heavily pretreated UC patients who progressed ≤ 12 weeks of last dose of PD-1/L1 inhibitors (CPIs) and were enriched for nuclear AHR+ tumors by IHC. Study objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, MTD, RP2D and antitumor activity (RECIST 1.1) of IK-175 as a monotherapy and in combination with nivolumab. Results: Fifty-seven UC expansion patients were evaluated for safety. Median age was 69 years (range 26-81), 52/57 (91%) patients received ≥2 lines of prior therapy including CPIs. 5/14 monotherapy and 14/43 combo had nuclear AHR+ tumors. The most common treatment-related AEs were nausea, fatigue, and diarrhea. Infrequent immune-related AEs occurred in <9% of patients and included adrenal insufficiency, proteinuria, rash, pneumonitis, and immune-related arthritis. Significant reduction in tumor target lesions (-30% to -100%) was observed in 6/46 (13%) response-evaluable UC patients (both arms). DCR was 46% and 49% for monotherapy and combination. Confirmed partial responses were observed in 1/13 (7.7%) monotherapy (DoR 22.6 months) and 2/33 (6%) in combo (DoR 4.4 and 7.3 months). Two patients in combo were treated beyond progression (for 4 and 10 months) due to investigator-assessed clinical benefit, including tumor shrinkage of target lesions. Conclusions: IK-175 showed a predictable, consistent safety profile as a monotherapy and in combination with nivolumab. Meaningful clinical benefit and objective, durable, prolonged responses were demonstrated in both monotherapy and combination arms in heavily pretreated UC patients with tumors refractory to CPI and supports further development of this asset in solid tumors. Clinical trial information: NCT04200963 .