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

  • Cancer Discov. 2019 Dec;9(12):1696-1707. doi: 10.1158/2159-8290.CD-19-0555.
Richard D Kim  1 ,  Debashis Sarker  2 ,  Tim Meyer  3 ,  Thomas Yau  4 ,  Teresa Macarulla  5 ,  Joong-Won Park  6 ,  Su Pin Choo  7 ,  Antoine Hollebecque  8 ,  Max W Sung  9 ,  Ho-Yeong Lim  10 ,  Vincenzo Mazzaferro  11 ,  Joerg Trojan  12 ,  Andrew X Zhu  13 ,  Jung-Hwan Yoon  14 ,  Sunil Sharma  15 ,  Zhong-Zhe Lin  16 ,  Stephen L Chan  17 ,  Sandrine Faivre  18 ,  Lynn G Feun  19 ,  Chia-Jui Yen  20 ,  Jean-Francois Dufour  21 ,  Daniel H Palmer  22 ,  Josep M Llovet  9  23 ,  Melissa Manoogian  24 ,  Meera Tugnait  25 ,  Nicolas Stransky  25 ,  Margit Hagel  25 ,  Nancy E Kohl  25 ,  Christoph Lengauer  25 ,  Cori Ann Sherwin  25 ,  Oleg Schmidt-Kittler  25 ,  Klaus P Hoeflich  25 ,  Hongliang Shi  25 ,  Beni B Wolf  25 ,  Yoon-Koo Kang  26
Affiliations
  • 1. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 2. King's College London, London, United Kingdom.
  • 3. University College London, London, United Kingdom.
  • 4. Queen Mary Hospital, Hong Kong, China.
  • 5. Vall d'Hebron University Hospital and Vall d'Hebrón Institute of Oncology (VHIO), Barcelona, Spain.
  • 6. National Cancer Center Korea, Goyang, South Korea.
  • 7. National Cancer Centre Singapore, Singapore.
  • 8. Institute Gustav Roussy, Villejuif, France.
  • 9. Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 10. Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
  • 11. University of Milan, Department of Oncology and Instituto Nazionale Tumori, IRCCS Foundation, Department of Surgery, HPB Surgery and Liver Transplantation, Milan, Italy.
  • 12. Universitätsklinikum Frankfurt, Frankfurt, Germany.
  • 13. Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 14. Seoul National University Hospital, Seoul, South Korea.
  • 15. Huntsman Cancer Institute, Salt Lake City, Utah.
  • 16. National Taiwan University Hospital, Taipei, Taiwan.
  • 17. State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China.
  • 18. Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France.
  • 19. University of Miami, Miami, Florida.
  • 20. National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 21. University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
  • 22. Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom.
  • 23. Translational Research in Hepatic Oncology Group, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain.
  • 24. Roche Tissue Diagnostics, Tucson, Arizona.
  • 25. Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • 26. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. [email protected].
PMID: 31575541 DOI: 10.1158/2159-8290.CD-19-0555
Abstract

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.