Lucitanib (S80881, formerly E-3810) is a novel tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor (VEGF) receptors 1-3 (VEGFR1-3) and fibroblast growth factor (FGF) receptor 1-2 (FGFR1-2). It exhibits a unique pharmacological profile and demonstrates potent antitumor activity in xenograft models derived from multiple oncology indications. The on-going phase I/II clinical study of lucitanib has demonstrated objective RECIST responses in breast cancer patients with FGF-aberrant (FGFR1 and/or FGF3/4/19 gene amplified) tumors and in oncology indications anticipated to benefit from antiangiogenic agents (e.g. renal cell and thyroid cancer patients).

In an attempt to further elucidate the mechanism of action of lucitanib, we evaluated the in vitro and in vivo activity of lucitanib in lung cell lines with FGFR1 amplification. The FGFR1 gene is frequently amplified in lung cancer tumors and FGFR1 copy number may provide a patient selection marker for clinical trials of FGFR inhibitors. Lucitanib cytotoxic activity was evaluated and compared to other FGFR inhibitors (Dovitinib, AZD4547 and PD173074) in a panel of 11 lung cancer cell lines characterized for FGFR1/2 gene copy number and FGFR1, FGFR2 and FGF2 mRNA expression level. Lucitanib IC50 values ranged from 0.14 to 23 μM; interestingly the two most sensitive cells lines (NCI-H1581 and DMS114) harbored FGFR1 amplification, while cell lines with lower FGFR1 gene copy number (≤2) displayed a higher drug IC50 value. In order to understand the involvement of FGFR1 inhibition in the antitumor activity of lucitanib, nude mice bearing FGFR1 amplified NCI-H1581 cell xenografts were treated with escalating doses of lucitanib (2.5, 5, 10 and 20mg/kg/day PO) continuously for 30 days. The antitumor activity of lucitanib at the dose of 2.5mg/kg was marginal (tumor volume of treated / control (T/C%) = 46), while at 5, 10 and 20mg/kg the drug was equally very active (T/C% = 24, 21 and 16, respectively). Pharmacodynamic and pharmacokinetic assessments were undertaken at the same drug doses employed for the xenograft efficacy experiments in NCI-H1581 tumor bearing mice treated for 12 continuous days. Tumor concentrations of lucitanib, measured by LC-MS/MS, were related to the administered dose and ranged from 0.31-3.68 μM and from 0.26-2.52 μM at 4 and 24hrs, respectively. Lucitanib drug concentrations were higher in the tumor than in the plasma, with tumor/plasma ratios at 4 and 24 hrs of 2.0±0.22 and 20.5±6, respectively. In conclusion, these preclinical data indicate that lucitanib demonstrates in vitro efficacy in lung cancer cell lines with FGFR1 gene amplification and has a favorable drug distribution profile in tumor models.

Citation Format: Ezia Bello, Rosaria Chilà, Federica Guffanti, Monique Zangarini, Laura Ceriani, Massimo Zucchetti, Saba Chaudi, Marie-Jeanne Pierrat, Anne Jacquet-Bescond, Giovanna L.M. Damia. Exploring the in vitro and in vivo activity of lucitanib in FGFR1-amplified lung cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2670. doi:10.1158/1538-7445.AM2014-2670