Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors

Purpose: Taxanesare important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel(XRP6258), a semisynthetic taxanedeveloped to overcome taxaneresistance. Experimental Design: Cabazitaxeleffects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro . Antitumor activity and pharmacokinetics of intravenously administered cabazitaxelwere assessed in tumor-bearing mice. Results: In vitro , cabazitaxelstabilized microtubules as effectively as docetaxelbut was 10-fold more potent than docetaxelin chemotherapy-resistant tumor cells (IC 50 ranges: cabazitaxel, 0.013–0.414 μmol/L; docetaxel, 0.17–4.01 μmol/L). The active concentrations of cabazitaxelin these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxelat 40 mg/kg. Cabazitaxelexhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxelwas active in tumors poorly sensitive or innately resistant to docetaxel(Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxelresistance (melanoma B16/TXT). Conclusions: Cabazitaxelis as active as docetaxelin docetaxel-sensitive tumor models but is more potent than docetaxelin tumor models with innate or acquired resistance to taxanesand other chemotherapies. These studies were the basis for subsequent clinical evaluation. Clin Cancer Res; 19(11); 2973–83. ©2013 AACR .