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First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.

  • Kim RD H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • Sarker D King's College London, London, United Kingdom.
  • Meyer T University College London, London, United Kingdom.
  • Yau T Queen Mary Hospital, Hong Kong, China.
  • Macarulla T Vall d'Hebron University Hospital and Vall d'Hebrón Institute of Oncology (VHIO), Barcelona, Spain.
  • Park JW National Cancer Center Korea, Goyang, South Korea.
  • Choo SP National Cancer Centre Singapore, Singapore.
  • Hollebecque A Institute Gustav Roussy, Villejuif, France.
  • Sung MW Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Lim HY Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
  • Mazzaferro V University of Milan, Department of Oncology and Instituto Nazionale Tumori, IRCCS Foundation, Department of Surgery, HPB Surgery and Liver Transplantation, Milan, Italy.
  • Trojan J Universitätsklinikum Frankfurt, Frankfurt, Germany.
  • Zhu AX Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Yoon JH Seoul National University Hospital, Seoul, South Korea.
  • Sharma S Huntsman Cancer Institute, Salt Lake City, Utah.
  • Lin ZZ National Taiwan University Hospital, Taipei, Taiwan.
  • Chan SL State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China.
  • Faivre S Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France.
  • Feun LG University of Miami, Miami, Florida.
  • Yen CJ National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Dufour JF University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
  • Palmer DH Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom.
  • Llovet JM Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Manoogian M Roche Tissue Diagnostics, Tucson, Arizona.
  • Tugnait M Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Stransky N Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Hagel M Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Kohl NE Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Lengauer C Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Sherwin CA Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Schmidt-Kittler O Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Hoeflich KP Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Shi H Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Wolf BB Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • Kang YK Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. ykkang@amc.seoul.kr.
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  • 2019-10-03
Published in:
  • Cancer discovery. - 2019
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
Drug Administration Schedule
Female
Fibroblast Growth Factors
Humans
Liver Neoplasms
Male
Middle Aged
Pyrans
Quinazolines
Receptor, Fibroblast Growth Factor, Type 4
Signal Transduction
Treatment Outcome
Young Adult
English 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.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/179009
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