A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.
Adult
Aged
Antineoplastic Agents
/ therapeutic use
Bile Duct Neoplasms
/ drug therapy
Cholangiocarcinoma
/ drug therapy
Female
Humans
Imidazoles
/ administration & dosage
Male
Middle Aged
Pilot Projects
Progression-Free Survival
Pyridazines
/ administration & dosage
Quality of Life
Receptor, Fibroblast Growth Factor, Type 2
/ antagonists & inhibitors
Survival Analysis
Bile duct cancers
Cholangiocarcinoma
FGFR
Next generation sequencing
Ponatinib
Targetable mutations
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
21
07
2021
accepted:
26
08
2021
pubmed:
1
9
2021
medline:
8
3
2022
entrez:
31
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34463891
doi: 10.1007/s10637-021-01170-x
pii: 10.1007/s10637-021-01170-x
doi:
Substances chimiques
Antineoplastic Agents
0
Imidazoles
0
Pyridazines
0
ponatinib
4340891KFS
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
134-141Subventions
Organisme : NCI NIH HHS
ID : P50 CA210964
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Torre LA, Siegel RL, Islami F, Bray F, Jemal A (2018) Worldwide burden of and trends in mortality from gallbladder and other biliary tract cancers. Clin Gastroenterol Hepatol 16(3):427–437
doi: 10.1016/j.cgh.2017.08.017
Jarnagin WR, Ruo L, Little SA et al (2003) Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 98:1689–1700
doi: 10.1002/cncr.11699
Valle J, Wasan H, Palmer DH et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281
doi: 10.1056/NEJMoa0908721
Lamarca A, Palmer DH, Wasan HS et al (2021) Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 22(5):690–701
doi: 10.1016/S1470-2045(21)00027-9
Paule B, Herelle MO, Rage E et al (2007) Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology 72:105–110
doi: 10.1159/000111117
Suzuki E, Ikeda M, Okusaka T et al (2013) A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol 71:1141–1146
doi: 10.1007/s00280-013-2106-0
Bridgewater J, Palmer D, Cunningham D et al (2013) Outcome of second-line chemotherapy for biliary tract cancer. Eur J Cancer 49:1511
doi: 10.1016/j.ejca.2012.11.024
Croitoru A, Gramaticu I, Dinu I et al (2012) Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma - a retrospective study. J Gastrointestin Liver Dis 21:277–284
pubmed: 23012669
Fornaro L, Vivaldi C, Cereda S et al (2015) Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data. J Exp Clin Cancer Res 34:156
doi: 10.1186/s13046-015-0267-x
Sasaki T, Isayama H, Nakai Y et al (2013) A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer. Anticancer Res 33:2619–2622
pubmed: 23749917
Belov AA, Mohammadi M (2013) Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol 5
Churi CR, Shroff R, Wang Y et al (2014) Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One 9:e115383
Javle M, Bekaii-Saab T, Jain A et al (2016) Biliary cancer: Utility of next-generation sequencing for clinical management. Cancer 122:3838–3847
doi: 10.1002/cncr.30254
Borad MJ, Champion MD, Egan JB et al (2014) Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 10:e1004135
Ross JS, Wang K, Gay L et al (2014) New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19:235–242
doi: 10.1634/theoncologist.2013-0352
Sia D, Losic B, Moeini A et al (2015) Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun 6:6087
doi: 10.1038/ncomms7087
Arai Y, Totoki Y, Hosoda F et al (2014) Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59:1427–1434
doi: 10.1002/hep.26890
Wu YM, Su F, Kalyana-Sundaram S et al (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3:636–647
doi: 10.1158/2159-8290.CD-13-0050
Graham RP, Barr Fritcher EG, Pestova E et al (2014) Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 45:1630–1638
doi: 10.1016/j.humpath.2014.03.014
Kouhara H, Hadari YR, Spivak-Kroizman T et al (1997) A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89:693–702
doi: 10.1016/S0092-8674(00)80252-4
Abou-Alfa GK, Sahai V, Hollebecque A et al (2020) Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 21(5):671–684
doi: 10.1016/S1470-2045(20)30109-1
Javle M, Lowery M, Shroff RT et al (2018) Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 36(3):276
doi: 10.1200/JCO.2017.75.5009
Bridgewater J, Meric-Bernstam F, Hollebecque A et al (2020) Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: Subgroup analyses of a phase II study (FOENIX-CCA2). Ann Oncol 31:S261–S262
doi: 10.1016/j.annonc.2020.08.032
Gozgit JM, Wong MJ, Moran L et al (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11:690–699
doi: 10.1158/1535-7163.MCT-11-0450
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
doi: 10.1016/j.ejca.2008.10.026
Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655
doi: 10.1097/00000421-198212000-00014
Common Terminology Criteria for Adverse Events (CTCAE) (2021). In: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm . Accessed on July 2021
Kaupp-Roberts SD, Yadegarfar G, Friend E et al (2016) Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder. Br J Cancer 115:1032–1038
doi: 10.1038/bjc.2016.284
Friend E, Yadegarfar G, Byrne C et al (2011) Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQ-BIL21. Br J Cancer 104:587–592
doi: 10.1038/sj.bjc.6606086
Chren MM, Lasek RJ, Sahay AP, Sands LP (2001) Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Cut Med Surg 5(2):105–110
doi: 10.1177/120347540100500202
Atherton PJ, Halyard MY, Sloan MJ et al (2013) Assessment of patient-reported measures of bowel function before and after pelvic radiotherapy: an ancillary study of the North Central Cancer Treatment Group study N00CA.". Supp Care Cancer 21(4):1193–1199
doi: 10.1007/s00520-012-1648-8
Arora M, Bogenberger JM, Abdelrahman A et al (2020) Evaluation of NUC-1031: A first-in-class ProTide in biliary tract cancer.". Cancer chemother pharmacol 85:1063–1078
doi: 10.1007/s00280-020-04079-z
Uson Junior PLS, Bogenberger J, Borad MJ (2020) Advances in the treatment of biliary tract cancers. Curr opinion gastroenterol 36(2):85–89
Cleary JM, Iyer G, Oh DH et al (2020) Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion. J Clin Oncol 3603–3603
Valle JW, Bibeau K, Cho Y et al (2021) Longitudinal evaluation of quality of life (QoL) in patients (Pts) with FGFR2-driven cholangiocarcinoma (CCA) treated with pemigatinib. J Clin Oncol 39:276–276
doi: 10.1200/JCO.2021.39.3_suppl.276
Bekaii-Saab TS, Valle JW, Van Cutsem E et al (2020) FIGHT-302: Phase III study of first-line (1L) pemigatinib (PEM) versus gemcitabine (GEM) plus cisplatin (CIS) for cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements. J Clin Oncol 38: abstr TPS592
Javle MM, Borbath I, Clarke SJ et al (2019) Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial. J Clin Oncol 37.15 suppl
Goyal L, Saha SK, Liu LY et al (2017) Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. Cancer Discov 7:252–263
doi: 10.1158/2159-8290.CD-16-1000
Goyal L, Shi L, Liu LY et al (2019) TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 Fusion-Positive intrahepatic cholangiocarcinoma. Cancer Disc 9(8):1064–1079
doi: 10.1158/2159-8290.CD-19-0182