Abstract 697: Stage 1 in vivo evaluation of multi-receptor tyrosine-kinase inhibitor lenvatinib in osteosarcoma patient derived mouse xenograft models
Authors: Zhang Wendong , Roth Michael E. , Gill Jonathan , Piperdi Sajida , Kolb E. Anders , Geller David S. , Hoang Bang , Yang Rui , Gorlick Richard 
Published: July 2017

Background: Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Over the past three decades improvement in outcomes for children with OS have remained stagnant. Novel therapies are needed to improve outcomes for these patients. Lenvatinib is an oral small-molecule tyrosine-kinase inhibitor (TKI), targeting multiple receptors including VEGFR1-3, FGFR 1-4, PDGFRα, RET, and c-kit. Prior studies have shown that PDGFR-VEGF/VEGFR and FGFR3 are overexpressed in human OS cell lines. Lenvatinib is FDA-approved for the treatment of differentiated thyroid cancer, and, in combination with mTOR inhibitor everolimus, for the treatment of renal cell carcinoma. The current study assessed the in vivo efficacy of lenvatinib in osteosarcoma xenograft models.

Materials and Methods: Single agent lenvatinib was tested against 5 well-established osteosarcoma patient derived mouse xenograft models. Lenvatinib was administered using a dose of 7.5mg/kg given by oral route daily (5/7 days) for 6 weeks or until study endpoints were met. Tumor volume and mouse body weight were measured bi-weekly. Tumor volume was compared to baseline tumor volume to calculate the relative tumor volume (RTV). The RTV was compared between the control and experimental groups utilizing the student t-test. P-values &lt;0.05 were considered statistically significant. Additional statistical analyses were conducted as per the Pediatric Preclinical Testing Program analysis plan.

Results: Lenvatinib was generally well tolerated in vivo, without noted toxicity in any of the treated animals. Lenvatinib treatment led to delayed tumor progression in 4/5 models tested. Relative tumor volumes in the treatment group compared to the control group at week 3 in xenografts OS1, OS2, OS17, OS31, and OS33 were 0.77 (p=0.013), 0.88 (p=0.147), 0.49 (p&lt;0.001), 0.66 (p&lt;0.001), and 0.40 (p&lt;0.001), respectively. Despite delayed progression observed in the OS xenografts treated with lenvatinib, all groups experienced progressive disease by the end of the study period.

Conclusions: Single agent lenvatinib demonstrates consistent anti-tumor activity in osteosarcoma patient derived mouse xenograft models. Preclinical studies, as well as clinical trials, have demonstrated the efficacy of tyrosine kinase inhibition in combination with inhibition of mTOR in a variety of malignancies. The current study, along with prior data, suggests that targeting receptor tyrosine kinases, in addition to mTOR, may lead to more effective inhibition of osteosarcoma cell growth. Ongoing studies are assessing the efficacy of lenvatinib, administered in combination with mTOR inhibitor, everolimus, in osteosarcoma patient derived mouse xenografts.

Citation Format: Wendong Zhang, Michael E. Roth, Jonathan Gill, Sajida Piperdi, E. Anders Kolb, David S. Geller, Bang Hoang, Rui Yang, Richard Gorlick. Stage 1 in vivo evaluation of multi-receptor tyrosine-kinase inhibitor lenvatinib in osteosarcoma patient derived mouse xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 697. doi:10.1158/1538-7445.AM2017-697