Abstract
Abstract Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor-positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive cross-talk between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/ human epidermal growth factor receptor 2 negative (HER2–) breast cancer patients have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy. In preclinical models, resistance to endocrine therapy can be overcome via FGFR1 inhibition. Dovitinib is a potent oral inhibitor of receptor tyrosine kinases, including FGFR, vascular endothelial growth factor receptor (VEGFR), and platelet derived growth factor receptor (PDGFR), that demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and may also inhibit angiogenesis, which plays an essential role in breast cancer development. Dovitinib is studied here in combination with fulvestrant to determine if it can improve outcomes in postmenopausal patients with endocrine resistant HER2−/HR+ breast cancer. Methods: This is a multicenter, randomized, double-blind, placebo-controlled, phase II trial that will enroll postmenopausal HER2–/HR+ locally advanced or metastatic breast cancer patients (N ≈ 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting. Patients prospectively undergo molecular screening to enrich for FGF amplification (FGFR1, FGFR2, or FGF3 amplification by qualitative polymerase chain reaction (qPCR); 45 amplified and 30 nonamplified patients per arm). Patients are randomized 1:1 (stratified by FGF-amplification and presence of visceral disease) to receive fulvestrant intramuscularly (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, death or discontinuation due to any reason (eg, withdrawal). Crossover is not permitted. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, Eastern Cooperative Oncology Group performance status and patient-reported outcome scores over time, and safety. Additionally, the pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-03.
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