Skip to main content

Advertisement

SpringerLink
Log in

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All data and materials are available for verification as needed.

Code availability

Not applicable.

References

  1. 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

    Article  Google Scholar 

  2. 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

    Article  Google Scholar 

  3. 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

    Article  CAS  Google Scholar 

  4. 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

    Article  CAS  Google Scholar 

  5. 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

    Article  CAS  Google Scholar 

  6. 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

    Article  CAS  Google Scholar 

  7. Bridgewater J, Palmer D, Cunningham D et al (2013) Outcome of second-line chemotherapy for biliary tract cancer. Eur J Cancer 49:1511

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

  9. 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

    Article  Google Scholar 

  10. 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

    CAS  PubMed  Google Scholar 

  11. Belov AA, Mohammadi M (2013) Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol 5

  12. Churi CR, Shroff R, Wang Y et al (2014) Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One 9:e115383

  13. Javle M, Bekaii-Saab T, Jain A et al (2016) Biliary cancer: Utility of next-generation sequencing for clinical management. Cancer 122:3838–3847

    Article  CAS  Google Scholar 

  14. 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

  15. 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

    Article  CAS  Google Scholar 

  16. 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

    Article  CAS  Google Scholar 

  17. 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

    Article  CAS  Google Scholar 

  18. Wu YM, Su F, Kalyana-Sundaram S et al (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3:636–647

    Article  CAS  Google Scholar 

  19. Graham RP, Barr Fritcher EG, Pestova E et al (2014) Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 45:1630–1638

    Article  CAS  Google Scholar 

  20. 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

    Article  CAS  Google Scholar 

  21. 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

    Article  CAS  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. 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

    Article  Google Scholar 

  24. 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

    Article  CAS  Google Scholar 

  25. 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

    Article  CAS  Google Scholar 

  26. 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

    Article  CAS  Google Scholar 

  27. Common Terminology Criteria for Adverse Events (CTCAE) (2021). In: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed on July 2021

  28. 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

    Article  CAS  Google Scholar 

  29. 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

    Article  CAS  Google Scholar 

  30. 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

    Article  CAS  Google Scholar 

  31. 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

    Article  Google Scholar 

  32. 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

    Article  CAS  Google Scholar 

  33. Uson Junior PLS, Bogenberger J, Borad MJ (2020) Advances in the treatment of biliary tract cancers. Curr opinion gastroenterol 36(2):85–89

    Google Scholar 

  34. 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

  35. 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

    Article  Google Scholar 

  36. 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

  37. 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

  38. 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

    Article  CAS  Google Scholar 

  39. 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

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, USA

    Daniel H. Ahn, Pedro Luiz Serrano Uson Junior, Peter Masci, Thomas DeLeon, Mohamad Bassam Sonbol, Tanios Bekaii-Saab & Mitesh J. Borad

  2. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Pedro Luiz Serrano Uson Junior

  3. Division of Biostatistics and Informatics, Mayo Clinic, Phoenix, AZ, USA

    Heidi Kosiorek

  4. Department of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

    Thorvardur R. Halfdanarson, Rory Smoot, Amit Mahipal, Aaron Mansfield, Nguyen H. Tran & Joleen M. Hubbard

  5. Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA

    Kabir Mody & Hani Babiker

  6. Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA

    Gregory Gores

  7. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    Mitesh J. Borad

  8. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    Mitesh J. Borad

  9. Mayo Clinic Cancer Center, Phoenix, AZ, USA

    Mitesh J. Borad

Authors
  1. Daniel H. Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pedro Luiz Serrano Uson Junior
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Masci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heidi Kosiorek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thorvardur R. Halfdanarson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kabir Mody
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hani Babiker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas DeLeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohamad Bassam Sonbol
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gregory Gores
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rory Smoot
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tanios Bekaii-Saab
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Amit Mahipal
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Aaron Mansfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nguyen H. Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Joleen M. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Mitesh J. Borad
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Mitesh J. Borad.

Ethics declarations

Ethics approval

The study was approved by the Mayo Clinic Institutional Review Board (IRB).

Consent to participate

All participants provided informed consent as outlined in the manuscript.

Consent for publication

All authors approved the final version of this manuscript.

Conflicts of interest

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 884 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-021-01170-x

Keywords

Search

Navigation