First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant Fibroblast Growth Factor 19 Signaling as a Driver Event in Hepatocellular Carcinoma

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib ( BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19expression by immunohistochemistry as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum-tolerated dose(600 mg once daily) was expanded in 81 patients. fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients (median duration of response: 5.3 months [95% CI, 3.7-not reached]) and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC.