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

Luke, JJ; Gelmon, K; Siu, LL; Moreno, V; Desai, J; Gomez-Roca, CA; Carlino, MS; Pachynski, RK; Cosman, R; Chu, QS; Damian, S; Curigliano, G; Tam, R; Wang, X; Jeyamohan, C; Wang, L; Zhu, L; Santucci-Pereira, J; Greenawalt, DM; Tabernero, J

Author(s): Luke, JJ; Gelmon, K; Siu, LL; Moreno, V; Desai, J; Gomez-Roca, CA; Carlino, MS; Pachynski, RK; Cosman, R; Chu, QS; Damian, S; Curigliano, G; Tam, R; Wang, X; Jeyamohan, C; Wang, L; Zhu, L; Santucci-Pereira, J; Greenawalt, DM; Tabernero, J;
Details: Publication Year 2025-06-03,Volume 31,Issue #11,Page 2134-2144
Journal Title: Clinical Cancer Research
Publication Type: Research article
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.
Publisher: American Association for Cancer Research
Keywords: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Young Adult; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage; Biomarkers, Tumor; *Hematologic Neoplasms/drug therapy/pathology; *Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors; Ipilimumab/administration & dosage; *Neoplasms/drug therapy/pathology; Nivolumab/administration & dosage; Treatment Outcome
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-24-0439
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-07 06:16:10

Last Modified: 2025-07-31 02:10:28