Journal
INVESTIGATIONAL NEW DRUGS
Volume 40, Issue 1, Pages 134-141Publisher
SPRINGER
DOI: 10.1007/s10637-021-01170-x
Keywords
Next generation sequencing; Targetable mutations; Bile duct cancers; Cholangiocarcinoma; FGFR; Ponatinib
Categories
Funding
- National Institute of Health (NIH) [CA195764]
- National Cancer Institute (NCI) [CA090628, 5P50CA210964-03]
- Mayo Clinic Center for Individualized Medicine (CIM) Precision Cancer Therapeutics Program
- Mayo Clinic Cancer Center
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Ponatinib as a single agent in treating BTC with FGFR alterations showed limited clinical activity but was tolerable. The study provides valuable information for the further development of ponatinib in BTC treatment.
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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