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Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer

Fabrice André1, Thomas Bachelot, Mario Campone

  • 1Department of Medical Oncology, INSERM Unit U981, Paris Sud University, Institut Gustave-Roussy, Villejuif, France. fabrice.andre@igr.fr

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 10, 2013
PubMed
Abstract

Insights

Dovitinib demonstrated antitumor effects in preclinical models and showed activity in patients with fibroblast growth factor receptor (FGFR)-amplified breast cancer. This suggests potential for FGF pathway-targeted therapies in specific breast cancer subtypes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Fibroblast growth factor receptor (FGFR) amplifications in FGFR1 and FGFR2 occur in about 10% of breast cancers, correlating with poor prognosis.
  • Targeting FGFR signaling presents a potential therapeutic strategy for these aggressive breast cancer subtypes.

Purpose of the Study:

  • To evaluate the antitumor activity of dovitinib, an FGFR1, FGFR2, and FGFR3 inhibitor, in breast cancers with FGFR amplifications.
  • To assess the predictive value of FGFR1, FGFR2, and FGF3 amplifications in a phase II clinical trial.

Main Methods:

  • Preclinical assessment of dovitinib in breast cancer cell lines and an FGFR1-amplified xenograft model.
  • Phase II clinical trial in 81 patients with HER2-negative metastatic breast cancer, stratified by FGFR1 amplification and hormone receptor (HR) status.
  • Assessment of FGFR amplifications using silver in situ hybridization and quantitative PCR (qPCR).

Main Results:

  • Dovitinib inhibited proliferation in FGFR1/FGFR2-amplified cell lines and tumor growth in FGFR1-amplified xenografts.
  • In the phase II trial, 25% of patients with FGFR1-amplified/HR-positive breast cancer achieved unconfirmed response or stable disease >6 months.
  • Grouping qPCR-identified FGFR1, FGFR2, or FGF3 amplifications showed a 21.1% mean reduction in target lesions in HR-positive patients with FGF pathway-amplified breast cancer.

Conclusions:

  • Dovitinib exhibits antitumor activity in preclinical models of FGFR-amplified breast cancer.
  • The drug demonstrated potential activity in breast cancers with FGF pathway amplification, warranting further investigation.

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