Phase 1 study of KHK2455, a long-acting, potent and selective IDO1 inhibitor, in combination with avelumab in patients with locally advanced or metastatic urothelial carcinoma.

Dual inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1) may alleviate suppression of antitumor immune responses by overcoming redundant immunosuppressive pathways. This study evaluated the combination of KHK2455, a novel and selective, long-lasting, and potent oral IDO1 inhibitor, with avelumab, a PD-L1 inhibitor, in adults with locally advanced or metastatic urothelial carcinoma. This multicenter, open-label Phase 1 study evaluated the safety and tolerability of oral daily KHK2455 (30, 100, and 200 mg) plus intravenous avelumab (800 mg biweekly), the safety of KHK2455 200 mg monotherapy, KHK2455 and avelumab antitumor activity, avelumab antidrug antibodies, and combination therapy pharmacokinetics. 16 subjects were enrolled (n=4, 4, and 8 in the 30, 100 and 200 mg cohorts, respectively). No dose-dependency was observed for KHK2455-only related treatment-emergent adverse events (TEAEs). No TEAEs were considered related to KHK2455 or avelumab. Four subjects had fatal TEAEs considered not related to treatment.One subject in the KHK2455 30 mg cohort achieved a complete response (CR) and one in the KHK2455 200 mg cohort achieved a partial response (PR), both with avelumab.PD-L1 expression was evaluated in the 13 available baseline tumor biopsy samples. All biopsies expressed PD-L1 in at least one compartment; 31% (4/13) were positive on tumor cells and 69.2% (9/13) were positive on tumor-associated immune cells. Over half (53.8%, 7/13) expressed PD-L1 at high levels and within the disease control group consisting of CR (n=1), PR (n=1) and stable disease (n=5), 57.1% (4/7) were PD-L1 high. Baseline expression profiles showed significantly higher immune activation in the subject with CR compared with the subject with PR and those with progressive disease. The subject with CR had the highest baseline Tumor Inflammation Signature (TIS) score (9.06) compared with 4.8 in the subject with PR and lower TIS score values in subjects with progressive disease. Changes in gene expression were observed, including upregulation of CXCL12, CCND2, and MMRN2, and downregulation of HLA-DRB5, CRABP2, and VEGFA in responders versus progressive disease comparisons. The favorable safety profile and preliminary efficacy results of KHK2455 in combination with avelumab, along with the translational biomarker findings, warrant further investigation.