First-in-Human Phase 1 Study of the Arginase Inhibitor INCB001158 Alone or Combined With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumours

Authors

Aung Naing
Kyriakos P Papadopoulos
Michael J Pishvaian
Osama Rahma
Glenn J Hanna
Elena Garralda
Omar Saavedra
Sven Gogov
Howard Kallender
LuLu Cheng
Michael Smith
Xuejun Chen
Emil Kuriakose
Todd Bauer

Publication Date

1-1-2024

Journal

BMJ Oncology

DOI

10.1136/bmjonc-2023-000249

PMID

39886141

PMCID

PMC11235002

PubMedCentral® Posted Date

5-9-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Objective: The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.

Methods and analysis: In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).

Results: A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50-100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti-PD-1/PD-L1-naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.

Conclusions: INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.

Keywords

Metastatic cancer, Immunotherapy, Adverse effects, Solid tumour, Colorectal cancer

Comments

Trial registration number: NCT02903914.

Published Open-Access

yes

Recommended Citation

Naing, Aung; Papadopoulos, Kyriakos P; Pishvaian, Michael J; et al., "First-in-Human Phase 1 Study of the Arginase Inhibitor INCB001158 Alone or Combined With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumours" (2024). Faculty, Staff and Student Publications. 4865.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4865