Summary
Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.
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Funding
This work was supported by the National Institute of Health (NIH) through a DP2 Award CA195764 (to MJB); National Cancer Institute (NCI) K12 award CA090628 (to MJB), SPORE Project Award 5P50CA210964-03 (MJB), Mayo Clinic Center for Individualized Medicine (CIM) Precision Cancer Therapeutics Program; and Mayo Clinic Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
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Daniel Ahn has written the manuscript and created the tables, assisted in the design, and final approval of the manuscript. Pedro Uson Junior assisted in writing the manuscript, review, and final approval of the manuscript. Mitesh Borad has assisted in the design, writing, review, and final approval of the manuscript. Peter Masci, Heidi Kosiorek, Thorvardur R. Halfdanarson, Kabir Mody, Hani Babiker, Thomas DeLeon, Mohamad Bassam Sonbol, Gregory Gores, Rory Smoot, Tanios Bekaii-Saab, Amit Mahipal, Aaron Mansfield, Nguyen H Tran, Joleen M Hubbard assisted in the design, review, and final approval of the manuscript.
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MJB has received grant to institution from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Five Prime Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals, consultancy from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, and travel support from Astra Zeneca.
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Ahn, D.H., Uson Junior, P.L.S., Masci, P. et al. A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma. Invest New Drugs 40, 134–141 (2022). https://doi.org/10.1007/s10637-021-01170-x
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DOI: https://doi.org/10.1007/s10637-021-01170-x