TY - JOUR
T1 - A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma
AU - Ahn, Daniel H.
AU - Uson Junior, Pedro Luiz Serrano
AU - Masci, Peter
AU - Kosiorek, Heidi
AU - Halfdanarson, Thorvardur R.
AU - Mody, Kabir
AU - Babiker, Hani
AU - DeLeon, Thomas
AU - Sonbol, Mohamad Bassam
AU - Gores, Gregory
AU - Smoot, Rory
AU - Bekaii-Saab, Tanios
AU - Mahipal, Amit
AU - Mansfield, Aaron
AU - Tran, Nguyen H.
AU - Hubbard, Joleen M.
AU - Borad, Mitesh J.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - Bile duct cancers
KW - Cholangiocarcinoma
KW - FGFR
KW - Next generation sequencing
KW - Ponatinib
KW - Targetable mutations
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U2 - 10.1007/s10637-021-01170-x
DO - 10.1007/s10637-021-01170-x
M3 - Article
C2 - 34463891
AN - SCOPUS:85113999935
SN - 0167-6997
VL - 40
SP - 134
EP - 141
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -