Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Clin Cancer Res. 2013 May 8;

Authors: Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia J, Hurvitz SA, Turner NC, Rugo H, Smith JW, Deudon S, Shi MM, Zhang Y, Kay A, Graus Porta D, Yovine A, Baselga J

Abstract
PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included four groups of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer based on FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative polymerase chain reaction (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified but not in FGFR-normal breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease > 6 months was observed in five (25%) and one (3%) patients with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSIONS: Dovitinib demonstrated antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

PMID: 23658459 [PubMed - as supplied by publisher]

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