Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined with Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies

Purpose: To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 inhibitor combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. Patients and Methods: In this phase 1/2 study, patients received once-daily linrodostat [part 1 (escalation), 25–400 mg; part 2 (expansion), 100 or 200 mg] plus nivolumab (480 mg every 4 weeks or 240 mg every 2 weeks) or triplet therapy (part 3, linrodostat 20–100 mg once daily; nivolumab 360 mg every 3 weeks or 480 mg every 4 weeks; ipilimumab 1 mg/kg every 6 weeks or every 8 weeks). Endpoints included safety and efficacy (coprimary; parts 2 and 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Results: A total of 55, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1% to 63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune-related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naïve patients. Kynurenine decreased with linrodostat + nivolumab regardless of response. In contrast, IFN-γ gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase gene expression plus high IFN-γ signature was associated with response. Conclusions: Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported indoleamine 2,3-dioxygenase 1 pathway inhibition but did not correlate with response. A composite biomarker of low tryptophan 2,3-dioxygenase expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.