Fibroblast growth factor receptors, or FGFRs, are tyrosine kinase receptors on the surface of cells that link growth factor signaling with the downstream PI3K/AKT and MAPK pathways to regulate cellular proliferation and survival. The FGFR family has four members, encoded by the FGFR1-4 genes.

Overactivity in the FGFR pathway can be a critical contributor to many forms of cancers, most notably cholangiocarcinoma (cancer of the bile ducts of the liver) and urothelial carcinoma (cancer of the lining of the bladder) [1]. FGFR2 genomic alterations (e.g., fusions, mutations, amplifications) are present in at least 15% of cholangiocarcinomas [2], and FGFR3 genomic alterations are present in approximately 20% of advanced urothelial carcinomas [3], 50% of non-muscle invasive urothelial carcinomas [4], and up to 70% of upper tract urothelial carcinomas [5].

In achondroplasia, activating mutations in FGFR3 suppress proliferation and maturation of growth plate chondrocytes, leading to shortened bones. Complications can be severe, with an increased risk of death during infancy and the potential for altered bone formation that can lead to nerve compression. Achondroplasia affects approximately one out of every 15,000 live births [6].

ABOUT INFIGRATINIB (BGJ398)

Infigratinib (BGJ398) is an orally administered, FGFR1-3-selective tyrosine kinase inhibitor in clinical development for the treatment of patients with FGFR-driven cancers. QED Therapeutics acquired the worldwide rights to infigratinib from Novartis for use in all applications and will conduct clinical trials to evaluate the safety and efficacy of the product for multiple FGFR-driven diseases, including cancers and skeletal dysplasias.

Infigratinib remains investigational and is currently under study in a single arm, open-label Phase 2 trial for the treatment of chemotherapy-refractory cholangiocarcinoma (bile duct cancer) with FGFR2 fusions and other activating genomic alterations [7]. In an interim analysis of 71 patients in the ongoing trial with FGFR2 fusions/translocations, the confirmed overall response rate (cORR) was 27% for all patients with the potential for confirmation (n=67) and an additional 57% experienced stable disease as their best response, resulting in a disease control rate of 84%. For patients who had received one or fewer prior treatment regimens, the cORR was 39% (n=28), whereas patients who had received two or more treatment regimens had a cORR of 18%. Median progression free survival was 6.8 months and median overall survival was 12.5 months. In the interim analysis, the most common treatment-emergent adverse events (all grades) included hyperphosphatemia (73%), fatigue (49%), stomatitis (45%), alopecia (38%) and constipation (35%). Most adverse events were expected based on infigratinib’s mechanism of action. The trial remains open and is currently enrolling.