Skip to main content
SpringerLink
Log in

A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor.

Objective

The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455.

Patients and Methods

This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC). Part A: 36 patients in 11 dose cohorts ranging from 2 to 24 mg twice daily (BID). RP2D was 16 mg BID. Part B: GC cohort, 29 patients, NSCLC cohort, 27 patients, all treated at the RP2D.

Results

LY2874455 was slowly absorbed and generally showed linear PK. The effective half-life was ∼12 h. PD properties of LY2874455 occurred at doses ≥10 mg by increases in serum phosphorus. Phosphate binders were administered to control serum phosphorus. LY2874455 was generally well tolerated; most toxicities were grade 1 or 2; most frequent were hyperphosphatemia, diarrhea, and stomatitis. Efficacy: part A: 24 patients evaluable: 1 patient in the 14-mg BID cohort with GC had a partial response (PR); 14 patients had stable disease (SD); part B: NSCLC cohort: 11 of 12 evaluable patients had SD; GC cohort: 15 patients evaluable: 1 patient with PR; 12 patients with SD.

Conclusions

LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107).

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

Similar content being viewed by others

References

  1. Katoh M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (review). Int J Mol Med. 2016;38:3–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16:139–49.

    Article  CAS  PubMed  Google Scholar 

  3. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4:215–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kelleher FC, O’Sullivan H, Smyth E, et al. Fibroblast growth factor receptors, developmental corruption and malignant disease. Carcinogenesis. 2013;34:2198–205.

    Article  CAS  PubMed  Google Scholar 

  5. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

    Article  CAS  PubMed  Google Scholar 

  6. Zhao G, Li WY, Chen D, et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther. 2011;10:2200–10.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Y, Gao W, Xu J, et al. The role of FGFR1 Gene amplification as a poor prognostic factor in squamous cell lung cancer: a meta-analysis of published data. Biomed Res Int. 2015;2015:763080.

    PubMed  PubMed Central  Google Scholar 

  8. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2:62ra93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cihoric N, Savic S, Schneider S, et al. Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer. Br J Cancer. 2014;110:2914–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gadgeel SM, Chen W, Cote ML, et al. Fibroblast growth factor receptor 1 amplification in non-small cell lung cancer by quantitative real-time PCR. PLoS One. 2013;8:e79820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim Y, Hammerman PS, Kim J, et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in east Asian patients. J Clin Oncol. 2014;32:121–8.

    Article  CAS  PubMed  Google Scholar 

  12. Seo JS, Ju YS, lee WC, et al: the transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109–2119, 2012.

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

  14. Huang HP, Feng H, Qiao HB, et al. The prognostic significance of fibroblast growth factor receptor 4 in non-small-cell lung cancer. Onco Targets Ther. 2015;8:1157–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Seo AN, Jin Y, Lee HJ, et al. FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer. Virchows Arch. 2014;465:547–58.

    Article  CAS  PubMed  Google Scholar 

  16. Holbrook JD, Parker JS, Gallagher KT, et al. Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine. J Transl Med. 2011;9:119.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Deng N, Goh LK, Wang H, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hattori Y, Itoh H, Uchino S, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clin Cancer Res. 1996;2:1373–81.

    CAS  PubMed  Google Scholar 

  19. Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 2001;61:3541–3.

    CAS  PubMed  Google Scholar 

  20. Shoji H, Yamada Y, Okita N, et al. Amplification of FGFR2 Gene in patients with advanced gastric cancer receiving chemotherapy: prevalence and prognostic significance. Anticancer Res. 2015;35:5055–61.

    CAS  PubMed  Google Scholar 

  21. Su X, Zhan P, Gavine PR, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014;110:967–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35:157–65.

    Article  PubMed  Google Scholar 

  23. Papadopoulos K, Tolcher A, Patnaik A, et al: Phase 1, first-in-human study of ARQ 087, an oral pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol 2015;33 (suppl; abstr 2545).

  24. Tabernero J, Bahleda R, Dienstmann R, et al. Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2015;33:3401–8.

    Article  CAS  PubMed  Google Scholar 

  25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  26. Schildhaus HU, Heukamp LC, Merkelbach-Bruse S, et al. Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol. 2012;25:1473–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yanochko GM, Vitsky A, Heyen JR, et al. Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction. Toxicol Sci. 2013;135:451–64.

    Article  CAS  PubMed  Google Scholar 

  29. Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res. 2012;318:1040–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tran TN, Selinger CI, Kohonen-Corish MR, et al. Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. Lung Cancer. 2013;81:462–7.

    Article  PubMed  Google Scholar 

  31. Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259–67.

    Article  CAS  PubMed  Google Scholar 

  32. Matsumoto K, Arao T, Hamaguchi T, et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer. 2012;106:727–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nagatsuma AK, Aizawa M, Kuwata T, et al. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer. 2015;18:227–38.

    Article  CAS  PubMed  Google Scholar 

  34. Chang J, Wang S, Zhang Z, et al. Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer. Oncotarget. 2015;6:2009–22.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer Medicine, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia

    Michael Michael & Jeanne Tie

  2. Seoul National University College of Medicine, Seoul, South Korea

    Yung-Jue Bang

  3. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, South Korea

    Young Suk Park

  4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Yoon-Koo Kang

  5. Seoul National University Hospital, Seoul, South Korea

    Tae Min Kim

  6. Eli Lilly and Company, Indianapolis, IN, USA

    Oday Hamid, Donald Thornton & Eyas Raddad

  7. Eli Lilly and Company, Basingstoke, Hampshire, UK

    Sonya C. Tate

  8. Royal Melbourne Hospital, Melbourne, Australia

    Jeanne Tie

Authors
  1. Michael Michael
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yung-Jue Bang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young Suk Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoon-Koo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tae Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Oday Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Donald Thornton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sonya C. Tate
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eyas Raddad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jeanne Tie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Michael.

Ethics declarations

Funding

This study was funded by Eli Lilly and Company. William Wargin of Nuventra Inc. assisted in pharmacokinetic data analysis, and Nancy Sheridan of INC Research Inc. provided editorial assistance, supported by Eli Lilly and Company.

Conflicts of Interest

Yoon-Koo Kang has received research grants from Daehwa Pharmaceutical Co., LSK BioPharma, Bayer, Novartis, and Roche, and consulting fees or honorarium from Daehwa Pharmaceutical Co., LSK BioPharma, Ono, Taiho, Novartis, and Roche. Yung-Jue Bang has received grants from Eli Lilly and Company for clinical trials (to the institution), and consulting fees or honorarium from Eli Lilly and Company for participating in advisory board meetings. Donald Thornton, Oday Hamid, Eyas Raddad, and Sonya Tate are employees and hold stock/stock options of Eli Lilly and Company. The other authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Michael, M., Bang, YJ., Park, Y.S. et al. A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer. Targ Oncol 12, 463–474 (2017). https://doi.org/10.1007/s11523-017-0502-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-017-0502-9

Search

Navigation