Gunagratinib, a highly selective irreversible FGFR inhibitor, in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR pathway alterations: A phase IIa dose-expansion study.

Abstract

572 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]

Targeting FGFR for cancer therapy

“…ICP-192, a newly developed covalent inhibitor targeting pan-FGFR, has shown promising results in Phase I clinical trials [ 152 ]. A phase IIa dose extension studied the efficacy of ICP-192 in previously treated patients with FGFR2-altered CCA, resulting in an ORR of 52.9% (9/17), an mPFS of 6.93 months, and a discontinuation rate of 0% due to TRAEs, suggesting that ICP-192 had a favorable response rate and was well tolerated [ 153 ]. Simultaneously, several Phase II clinical trials are being conducted for the subject (NCT04565275, NCT04492293, NCT05678270, NCT05372120).…”

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments

“…In the phase II study, 17 included CCA with FGFR2 fusion/rearrangement, and the ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17), and the median PFS was 6.93 months [53]. Thus, more powerful TKIs have been developed such as futibatinib (TAS-120), an irreversible tyrosine kinase inhibitor targeting FGFR1-4, approved by the FDA in September 2022 based on preliminary results of the FOENIX-CCA2 study, recently confirmed after an extended follow-up [39,50].…”

“…In the phase II study, 17 included CCA with FGFR2 fusion/rearrangement, and the ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17), and the median PFS was 6.93 months [ 53 ].…”

Current progress in cancer treatment by targeting FGFR signaling

“…Based on this finding, gunagratinib was granted an orphan drug designation in 2021 by the FDA for CCA. The latest updated data showed that the ORR was 52.9% (9/17) and the mPFS was 6.93 months 19 .…”