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Blueprint, CStone Enroll First Patient in Phase Ib/II Trial for FGFR4-Driven Liver Cancer

NEW YORK – CStone Pharmaceuticals and Blueprint Medicines said Monday that they dosed their first patient in a Phase Ib/II trial investigating fisogatinib (BLU-554) in combination with CStone's PD-L1 inhibitor CS1001 to treat FGFR4-driven, locally advanced or metastatic hepatocellular carcinoma (HCC). 

The companies aim to enroll approximately 50 patients across multiple sites in China for the trial, which will contain a dose-escalation and a dose-expansion phase. The dose-escalation phase will evaluate two doses of fisogatinib in combination with a fixed dose of CS1001. Researchers will use this to identify the optimal dosage for Phase II.

Investigators will also evaluate drug safety, tolerability, pharmacokinetics, and anti-tumor activity of the combination regimen. Patients' FGF19 expression status, using an immunohistochemistry assay developed by Blueprint, will be determined at a central laboratory. 

In a Phase I trial, Blueprint's investigational FGFR4 inhibitor demonstrated a 17 percent overall response rate in patients whose tumors tested positive for FGF19 expression. 

The trial results indicated that FGF19 overexpression was a driver of the disease. Researchers claimed that overexpression of FGF19 may create an autocrine–paracrine signaling loop in which the ligand binds to receptors such as FGFR4 and KLB to promote cancer proliferation and survival. In preclinical models, targeting FGFR4 with antibodies or small-molecule inhibitors reduced tumor growth. 

Preclinical HCC studies also showed that fisogatinib stimulated T-cell infiltration into the tumor microenvironment, giving researchers the idea to combine fisogatinib with a PD-L1 inhibitor to enhance anti-tumor activity in patients with FGFR4-driven HCC.

Blueprint said that from the promising results in the early Phase I trial so far, fisogatinib has potential to become the first molecular biomarker-driven targeted therapy in HCC. The company estimated that approximately 30 percent of HCC patients have aberrant FGFR4 signaling.