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First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid
James J Harding1,2, Christiane Jungels3, Jean-Pascal Machiels4
1Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. Hardinj1@mskcc.org.
Targeted Oncology
|February 14, 2023
Summary
The FGFR4 inhibitor INCB062079 showed manageable safety and target inhibition in advanced solid tumors. Study termination prevented establishing a maximum tolerated dose due to slow patient accrual.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Dysregulation of the Fibroblast Growth Factor Receptor (FGFR)-4/FGF19 pathway is linked to various solid tumors, including hepatobiliary cancers.
- INCB062079 is an orally available, selective inhibitor targeting FGFR4, demonstrating preclinical efficacy in FGF19/FGFR4-driven liver cancer models.
Purpose of the Study:
- To evaluate the safety, tolerability, and maximum tolerated dose (MTD) of INCB062079 in patients with advanced solid tumors.
- To assess the pharmacokinetics, pharmacodynamics (including plasma FGF19 and bile acid levels), and preliminary efficacy of INCB062079.
Main Methods:
- A two-part, Phase I clinical trial (NCT03144661) involving dose escalation (3+3 design) of INCB062079 in previously treated patients.
- Pharmacokinetic and pharmacodynamic assessments, including measurements of plasma FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) levels, were conducted.
- Protocol amendments were implemented to manage dose-limiting toxicities related to C4 concentrations and bile acid levels.
Main Results:
- Twenty-three patients were enrolled, with the most common toxicity being diarrhea (60.9%).
- Dose-limiting toxicities (grade 3 diarrhea, transaminitis) were observed at 15 mg twice daily, leading to a protocol amendment regarding C4 levels and bile acid sequestrant use.
- One partial response in ovarian cancer and two instances of stable disease were recorded; INCB062079 exposure was dose-proportional, with increased FGF19 and bile acid/C4 levels.
Conclusions:
- INCB062079 demonstrated a manageable safety profile and target inhibition when C4 levels and bile acid sequestrant use were managed.
- The study was terminated early due to slow patient accrual and the rarity of FGF19/FGFR4 alterations, preventing the establishment of an MTD.
- These findings suggest potential for FGFR4 inhibition but highlight challenges in patient selection and trial design for targeted therapies.
