한빛사 논문
Richard D. Kim1, Debashis Sarker2, Tim Meyer3, Thomas Yau4, Teresa Macarulla5, Joong-Won Park6, Su Pin Choo7, Antoine Hollebecque8, Max W. Sung9, Ho-Yeong Lim10, Vincenzo Mazzaferro11, Joerg Trojan12, Andrew X. Zhu13, Jung-Hwan Yoon14, Sunil Sharma15, Zhong-Zhe Lin16, Stephen L. Chan17, Sandrine Faivre18, Lynn G. Feun19, Chia-Jui Yen20, Jean-Francois Dufour21, Daniel H. Palmer22, Josep M. Llovet9,23, Melissa Manoogian24, Meera Tugnait25, Nicolas Stransky25, Margit Hagel25, Nancy E. Kohl25, Christoph Lengauer25, Cori Ann Sherwin25, Oleg Schmidt-Kittler25, Klaus P. Hoeflich25, Hongliang Shi25, Beni B. Wolf25, Yoon-Koo Kang26,*
1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States;
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, NY, United States;
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, MA, United States;
14 Seoul National University Hospital, Seoul, South Korea;
15 Huntsman Cancer Institute, Salt Lake City, UT, United States;
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, FL, United States;
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, AZ, United States;
25 Blueprint Medicines Corporation, Cambridge, MA, United States;
26 Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
*Corresponding author: Yoon-Koo Kang, MD, PhD
Asan Medical Center, University of Ulsan College of Medicine Seoul, South Korea
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 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.
Keywords (5 required): hepatocellular carcinoma, FGF19, FGFR4, kinase inhibitor, BLU-554
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