@article{005da06e21c644f68ef3982a9056d43f,
title = "First-in-human phase i study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma",
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.",
author = "Kim, {Richard D.} and Debashis Sarker and Tim Meyer and Thomas Yau and Teresa Macarulla and Park, {Joong Won} and Choo, {Su Pin} and Antoine Hollebecque and Sung, {Max W.} and Lim, {Ho Yeong} and Vincenzo Mazzaferro and Joerg Trojan and Zhu, {Andrew X.} and Yoon, {Jung Hwan} and Sunil Sharma and Lin, {Zhong Zhe} and Chan, {Stephen L.} and Sandrine Faivre and Feun, {Lynn G.} and Yen, {Chia Jui} and Dufour, {Jean Francois} and Palmer, {Daniel H.} and Llovet, {Josep M.} and Melissa Manoogian and Meera Tugnait and Nicolas Stransky and Margit Hagel and Kohl, {Nancy E.} and Christoph Lengauer and Sherwin, {Cori Ann} and Oleg Schmidt-Kittler and Hoeflich, {Klaus P.} and Hongliang Shi and Wolf, {Beni B.} and Kang, {Yoon Koo}",
note = "Funding Information: The authors thank Maryann Obiorah, PhD, and Allison Cherry, PhD, for medical writing support sponsored by Blueprint Medicines. Kinome illustrations were reproduced courtesy of CSTI (www. cellsignal.com). The foregoing website is maintained by CSTI, and Blueprint Medicines is not responsible for its content. T. Meyer acknowledges support from the UCL Experimental Cancer Medicine Centre and the NIHR UCLH Clinical Research Facility and Biomedical Research Centre. This study was funded by Blueprint Medicines. Funding Information: R.D. Kim has received honoraria from the speakers bureaus of Lilly and Taiho, and is an unpaid consultant/advisory board member for Bayer, BMS, and Exelixis. D. Sarker is a consultant at Novartis, Ipsen, and Eisai and has received honoraria from the speakers bureaus of MSD, Pfizer, Ipsen, Bayer, and Eisai. T. Macarulla reports receiving commercial research support from Celgene, AstraZeneca, and Bei-Gene, has received honoraria from the speakers bureaus of Celgene, Raffo, Serviere, Incyte, and Sanofi, and is an unpaid consultant/advisory board member for Celgene, Serviere, Incyte, Amgen, and Astra-Zeneca. J.-W. Park is an advisor at Roche-Genentech, Bayer, Ono, Eisai, and Midatech and has received honoraria from the speakers bureaus of Bayer, Ono, and Eisai. S.P. Choo has received honoraria from the speakers bureaus of Lilly Oncology and Bristol-Myers Squibb. J. Trojan is an advisor at BMS, Celgene, Eisai, and Ipsen and has received honoraria from the speakers bureaus of BMS, Lilly, Merck Serono, MSD, Ipsen, and Eisai. A.X. Zhu is a consultant at Bayer, Lilly, Eisai, Merck, Sanofi-Aventis, and Roche-Genentech. J.-H. Yoon reports receiving commercial research grants from AstraZeneca, Bayer HealthCare Pharmaceuticals, Daewoong Pharmaceuticals, and Bukwang Pharmaceuticals. S. Sharma is on the advisory board of Barricade Therapeutics, Exelixis, Dracen Pharmaceuticals, Tarveda Therapeutics, Hengrui Therapeutics, Loxo Oncology, and Natera, Inc., reports receiving a commercial research grant from Salarius Pharmaceuticals, reports receiving other commercial research support from Novartis, GSK, Toray Industries, Celgene, Hengrui Therapeutics, OncoMed, Tesaro, AADi, Merck, Inhibrx Inc., AMAL Therapeutics, Syndax, Millennium, Johnson & Johnson, Gilead Sciences, Plexxikon, Onyx, Blueprint Medicines, XuanZhu, and Incyte, has ownership interest (including patents) in Iterion Therapeutics, Salarius Pharmaceuticals, Proterus Therapeutics, ConverGene, and LSK BioPharma, and is an unpaid consultant/advisory board member for Novartis, Arrien Pharmaceuticals, and Array BioPharma. S. Faivre has received honoraria from the speakers bureaus of Blueprint Medicines, Bristol-Myers Squibb, Bayer, Eli Lilly, Ipsen, Merck Serono, MSD, and Novartis. D.H. Palmer is a speaker and advisor for Bayer, Eisai, BMS, and AstraZeneca, and reports receiving commercial research grants from BMS, AstraZeneca, Sirtex, and BTG. J.M. Llovet is a consultant for Eli Lilly, Bayer Healthcare Pharmaceuticals, Navigant, Leerink Swann LLC, Midatech Ltd., Fortress Biotech Inc., Springbank Pharmaceuticals, Nucleix, Can-Fite, Bristol-Myers Squibb, Eisai Inc., Celsion Corporation, Exelixis, Merck, Blueprint, Ipsen, and Glycotest, and reports receiving commercial research grants from Bayer Healthcare Pharmaceuticals, Eisai Inc., Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen. M. Manoog-ian is a scientist at Roche Tissue Diagnostics. M. Tugnait is Senior Director, Clinical Pharmacology, at Blueprint Medicines and has stock options with Blueprint Medicines. N. Stransky is Senior Director at Celsius Therapeutics, and has ownership interest (including patents) in Blueprint Medicines and Celsius Therapeutics. M. Hagel has ownership interest (including patents) in ISO. C. Lengauer is Executive Vice President at Blueprint Medicines, is a partner at Third Rock Ventures, is a director at Hookipa, is a scientific advisory board member for Mersana, and has ownership interest (including patents) in Blueprint Medicines, Third Rock Ventures, Hookipa, and Mer-sana. C.A. Sherwin is a senior clinical program manager at Blueprint Medicines Corporation. O. Schmidt-Kittler is a principal investigator at Blueprint Medicines and has an ownership interest (including patents) in the same. K.P. Hoeflich is Vice President, Biology, at Blueprint Medicines and has ownership interest (including patents) in the same. H. Shi is Senior Director, Biostatistics and Data Management, at Blueprint Medicines Inc. B.B. Wolf is Senior Vice President, Clinical Development, at Blueprint Medicines and has ownership interest (including patents) in the same. Y.-K. Kang is an unpaid consultant/ advisory board member for Blueprint and BMS. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
month = dec,
doi = "10.1158/2159-8290.CD-19-0555",
language = "English",
volume = "9",
pages = "1696--1707",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}