2. Academic Validation
  3. TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma

  • Cancer Discov. 2019 Aug;9(8):1064-1079. doi: 10.1158/2159-8290.CD-19-0182.
Lipika Goyal  # 1,  Lei Shi  # 1,  Leah Y Liu  # 1,  Ferran Fece de la Cruz  # 1,  Jochen K Lennerz 2,  Srivatsan Raghavan 3 4,  Ignaty Leschiner 4,  Liudmila Elagina 4,  Giulia Siravegna 5 6,  Raymond W S Ng 3 4,  Phuong Vu 1,  Krushna C Patra 1,  Supriya K Saha 1,  Raul N Uppot 7,  Ron Arellano 7,  Stephanie Reyes 1,  Takeshi Sagara 8,  Sachie Otsuki 8,  Brandon Nadres 1,  Heather A Shahzade 1,  Ipsita Dey-Guha 1,  Isobel J Fetter 1,  Islam Baiev 1,  Emily E Van Seventer 1,  Janet E Murphy 1,  Cristina R Ferrone 9,  Kenneth K Tanabe 9,  Vikram Deshpande 2,  James J Harding 10,  Rona Yaeger 10,  Robin K Kelley 11,  Alberto Bardelli 5 6,  A John Iafrate 2,  William C Hahn 3 4,  Cyril H Benes 1,  David T Ting 1,  Hiroshi Hirai 7,  Gad Getz 1 4,  Dejan Juric 1,  Andrew X Zhu 12,  Ryan B Corcoran 12,  Nabeel Bardeesy 12 4
Affiliations

Affiliations

  • 1 Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 2 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 4 Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • 5 Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
  • 6 Department of Oncology, University of Torino, Candiolo, Torino, Italy.
  • 7 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 8 Tsukuba Research Institute, Taiho Pharmaceutical Co., Ltd., Japan.
  • 9 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 10 Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 11 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
  • 12 Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. bardeesy.nabeel@mgh.harvard.edu azhu@partners.org rbcorcoran@partners.org.
  • # Contributed equally.
PMID: 31109923 DOI: 10.1158/2159-8290.CD-19-0182
Abstract

ATP-competitive Fibroblast Growth Factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic Sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR Inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

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