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
Jason J. Luke, Karen A. Gelmon, Lillian L. Siu, Víctor Moreno, Jayesh Desai, Carlos Gomez‐Roca, Matteo S. Carlino, Russell K. Pachynski, Rasha Cosman, Quincy S. Chu, Silvia Damian, Giuseppe Curigliano, Rachel Tam, Xianling Wang, Chandrika Jeyamohan, Lily Wang, Li Zhu, Julia Santucci-Pereira, Danielle Greenawalt, Josep Tabernero
Abstract
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. See related commentary by Zang and Dorff, p. 2077.