Infigratinib

Infigratinib (also known as BGJ398) is a small-molecule, orally bioavailable, ATP-competitive tyrosine kinase inhibitor that selectively targets fibroblast growth factor receptors 1, 2, and 3 (FGFR1-3). It belongs to the class of receptor tyrosine kinase inhibitors and was originally developed as an anticancer agent targeting FGFR-driven malignancies, including cholangiocarcinoma and urothelial carcinoma. Its selectivity for FGFR1-3 over FGFR4 and other kinases distinguishes it from pan-FGFR inhibitors.

The compound achieves oral bioavailability through its optimized molecular structure, which allows sufficient intestinal absorption and systemic exposure. It binds competitively at the ATP-binding site of FGFR kinase domains, blocking receptor phosphorylation and downstream signaling cascades involved in cell proliferation and survival. Because gain-of-function FGFR3 variants drive conditions such as achondroplasia and hypochondroplasia, and because FGFR2 fusions drive a subset of cholangiocarcinomas, infigratinib has been studied across both oncology and rare skeletal dysplasia settings.

Human study: In a phase 3 double-blind placebo-controlled trial in children aged 3–17 years with achondroplasia, once-daily oral infigratinib produced a significantly greater increase in annualized height velocity compared with placebo, with a least-squares mean difference of 1.74 cm per year at week 52. Height z score also improved significantly versus placebo. (PMID 42370681)

Human study: In a phase 2 single-arm study of 108 previously treated adults with FGFR2 fusion-positive advanced cholangiocarcinoma, infigratinib achieved an objective response rate of 23.1%, including one complete response and 24 partial responses. There were no treatment-related deaths. (PMID 34358484)

Human study: A landscape analysis of 82 FGFR2-altered cholangiocarcinoma patients treated with FGFR inhibitors including infigratinib found that 60% developed secondary FGFR2 kinase domain mutations upon acquired resistance, with N550 and V565 mutations being most common. Different FGFR inhibitors showed distinct activity profiles against these resistance mutations in functional studies. (PMID 37843855)

Human study: A review of tumor-induced osteomalacia described BGJ398/infigratinib as a novel medical treatment option for patients in whom tumor resection is not possible, alongside the anti-FGF23 antibody burosumab. This was presented as an emerging therapeutic approach for this rare FGF23-driven paraneoplastic syndrome. (PMID 32504138)

Animal study: In a mouse gastric cancer model with FGFR2 amplified on extrachromosomal DNA, infigratinib alone was insufficient to prevent acquired resistance, but combination with the CHK1 inhibitor BBI-2779 suppressed tumor growth and prevented ecDNA-mediated resistance. The combination resulted in potent and sustained tumor regression in vivo. (PMID 39506153)

Laboratory study: In vitro studies showed that infigratinib potently inhibited FGFR3 phosphorylation associated with hypochondroplasia-causing variants, and in a mouse model of hypochondroplasia (Fgfr3N534K/+), infigratinib produced significant improvement in skeletal growth. In silico modeling also suggested strong binding interactions with hypochondroplasia-associated FGFR3 variants. (PMID 40581757)

Laboratory study: A review of FGFR inhibitor pharmacology classified BGJ398 (infigratinib) as an FGFR1/2/3 inhibitor and noted that FGFR inhibitors exert antitumor effects both directly on cancer cells and indirectly by blocking paracrine signaling within the tumor microenvironment. Inhibition of FGF19-FGFR4 signaling was noted to carry a risk of liver toxicity, while FGF23-FGFR4 activation was associated with cardiac risk. (PMID 27245147)

Human study: Adverse events occurred in 96% of infigratinib-treated patients and 95% of placebo-treated patients in the phase 3 trial; serious adverse events occurred in 5% and 3% respectively, and none were considered by investigators to be related to either treatment. No adverse events led to treatment discontinuation. (PMID 42370681)

Human study: The most common treatment-emergent adverse events in this cholangiocarcinoma phase 2 study were hyperphosphataemia, stomatitis, fatigue, and alopecia; ocular toxicities including central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 17% of patients. The adverse event profile was described as manageable. (PMID 34358484)

Human study: According to the LiverTox database summary, infigratinib is associated with transient and usually mild elevations in serum aminotransferase during therapy but has not been convincingly linked to cases of clinically apparent liver injury. This was based on clinical use data from cholangiocarcinoma treatment. (PMID 36592394)

Limitations:

Human study: A comparative review noted that the overall response rate and median overall survival for infigratinib in cholangiocarcinoma were lower than those reported for futibatinib and pemigatinib in separate studies. The authors also highlighted concerns about acquired resistance driven by the heterogeneous nature of FGFR mutations. (PMID 37954763)

Open questions: Several important questions remain unanswered. Long-term safety of infigratinib in growing children with achondroplasia or hypochondroplasia—including effects on growth plates, bone quality, and fertility—has not yet been established from the available trial data. The optimal duration of therapy and whether treatment benefits persist after discontinuation are unclear. In oncology, while secondary FGFR2 kinase domain mutations are the most common resistance mechanism identified, bypass signaling pathways and epithelial-mesenchymal transition-related mechanisms are not fully characterized, and no validated strategies to overcome the full spectrum of resistance mutations exist.

Whether infigratinib is effective and safe in infants younger than three years, or in adults with skeletal dysplasias, has not been studied. The comparative efficacy of infigratinib versus other FGFR inhibitors in cholangiocarcinoma in a head-to-head setting has not been tested in randomized trials. The relevance of infigratinib for tumor-induced osteomalacia and other rare FGFR-driven conditions also requires further clinical investigation.