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The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin ( mTOR ) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase  II  clinical study of metastatic renal cell carcinoma ( RCC ). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical  RCC  models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human  RCC  xenograft mouse models (A‐498, Caki‐1, and Caki‐2). In particular, the combination led to tumor regression in the A‐498 and Caki‐1 models. In the A‐498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti‐angiogenic effects. The anti‐angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki‐1 xenografts, in which fibroblast growth factor ( FGF )‐driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor ( VEGF )‐activated, and synergistic activity against  FGF ‐activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed  mTOR ‐S6K‐S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic  KP ‐1 xenografts overexpressing  VEGF  or  FGF . Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both  VEGF  and  FGF  signaling pathways by the combination underlies its superior anti‐angiogenic activity in human  RCC  xenograft models.

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus