First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 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 FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and...

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Bibliographic Details
Published in:	Cancer discovery 2019-12, Vol.9 (12), p.1696-1707
Main Authors:	Kim, Richard D, Sarker, Debashis, Meyer, Tim, Yau, Thomas, Macarulla, Teresa, Park, Joong-Won, Choo, Su Pin, Hollebecque, Antoine, Sung, Max W, Lim, Ho-Yeong, Mazzaferro, Vincenzo, Trojan, Joerg, Zhu, Andrew X, Yoon, Jung-Hwan, Sharma, Sunil, Lin, Zhong-Zhe, Chan, Stephen L, Faivre, Sandrine, Feun, Lynn G, Yen, Chia-Jui, Dufour, Jean-Francois, Palmer, Daniel H, Llovet, Josep M, Manoogian, Melissa, Tugnait, Meera, Stransky, Nicolas, Hagel, Margit, Kohl, Nancy E, Lengauer, Christoph, Sherwin, Cori Ann, Schmidt-Kittler, Oleg, Hoeflich, Klaus P, Shi, Hongliang, Wolf, Beni B, Kang, Yoon-Koo
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Biomarkers, Tumor - metabolism Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Cell Line, Tumor Cell Proliferation - drug effects Drug Administration Schedule Female Fibroblast Growth Factors - metabolism Humans Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Male Middle Aged Pyrans - administration & dosage Pyrans - adverse effects Quinazolines - administration & dosage Quinazolines - adverse effects Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors Signal Transduction - drug effects Treatment Outcome Young Adult
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Summary:	Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as 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 FGF19 expression measured by IHC 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. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection. . .
ISSN:	2159-8274 2159-8290