Abstract LB-353: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of cabozantinib.

Abstract

Abstract Introduction: Cabozantinib is an oral, small-molecule inhibitor of MET, VEGFR2, and RET, and it also inhibits AXL, KIT and TIE-2. These targets are known to play important roles in tumor cell proliferation and/or angiogenesis. Cabozantinib is FDA-approved for the treatment of patients with progressive metastatic medullary thyroid cancer. Methods: Cabozantinib was tested against the PPTP's in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. It was tested against the PPTP solid tumor xenografts using a dose of 30 mg/kg administered by the oral route daily for 3 or 4 weeks with a total treatment/observation period of 6 weeks. Results: The median relative IC50 value for the PPTP cell lines was 8.1μM, with a range from 0.034 μM to greater than 10.0 μM and with only 3 cell lines showing IC50 values less than 1 μM. The most sensitive cell line, Kasumi-1, is an AML cell line that is known to have an activating KIT mutation. Cabozantinib was generally well tolerated in vivo, with only a 1.8% toxicity rate in treated animals. Thirty-four of 34 tested xenograft models were considered evaluable for efficacy. Cabozantinib induced significant differences in EFS distribution compared to control in 31 of 34 (91%) of the evaluable solid tumor xenografts. Cabozantinib induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C greater than 2) in 22 of 31 (71%) evaluable solid tumor xenografts. Intermediate activity for the EFS T/C metric was observed across all tumor panels evaluated. Partial responses were observed for two of the solid tumor xenografts, the rhabdoid tumor xenograft BT-29 and the slow-growing ependymoma xenograft BT-41. Tumor growth control was most pronounced for the alveolar rhabdomyosarcoma xenografts (ARMS), with 4 of 5 ARMS lines showing less than 20% increase in tumor volume during the 21 days of treatment. Two of 3 Wilms tumor lines (KT-11 and KT-13) also showed complete tumor growth control at Day 21, as did the medulloblastoma xenograft (BT-28) that was studied. Conclusions: The in vitro and in vivo pattern of activity observed for cabozantinib against the PPTP preclinical models is similar to that of agents previously studied by the PPTP that inhibit angiogenesis (e.g., sunitinib, cediranib, and sorafenib). The absence of in vitro activity for most solid tumor cell lines at concentrations associated with specific kinase inhibition together with widespread in vivo tumor growth inhibition and infrequent tumor regression suggest that for most pediatric cancers the in vivo effects of cabozantinib will primarily result from indirect effects on tumor growth (e.g., inhibition of VEGFR2-mediated angiogenesis). Exceptions would be those pediatric cancers with activating genomic alterations in kinases specifically inhibited by cabozantinib (e.g., medullary thyroid cancer with RET mutations). (Supported by NO1-CM-42216 from the NCI). Citation Format: Malcolm Smith, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Peter Houghton. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of cabozantinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-353. doi:10.1158/1538-7445.AM2013-LB-353