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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.
Introduction:
Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models.
Methods:
This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination.
Results:
Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations < 40.9 ng/mL and concomitant prophylactic bile acid sequestrant treatment. No additional DLTs were reported at 10 and 15 mg twice daily; higher doses were not assessed. The most common toxicity was diarrhea (60.9%). INCB062079 exposure was dose-proportional; FGF19 and bile acid/C4 concentrations increased with exposure. One partial response was achieved (15 mg twice daily; ovarian cancer; FGF/FGFR status unknown; duration of response, 7.5 months); two patients had stable disease.
Conclusions:
With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD.
Insights
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.
