• Delia De Lisi, Ugo De Giorgi, Cristian Lolli, Giuseppe Schepisi, Vincenza Conteduca, Cecilia Menna, Giuseppe Tonini, Daniele Santini, and Alberto Farolfi.
• a Medical Oncology Department , Campus Bio-Medico University , Rome , Italy.
• Expert Opin Drug Metab Toxicol. 2018 Apr 1; 14 (4): 461-467.

IntroductionTo date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway. The association of these two drugs was demonstrated to enhance the inhibitory activity against VEGF and FGF-induced angiogenesis by a vertical inhibition of angiogenic signaling pathways, suggesting a synergistic activity. Areas covered: In this review we summarize the lenvatinib pharmacokinetics, pharmacodynamics, characteristics and the main clinical trial that showed lenvatinib activity in advanced RCC. Expert opinion: Lenvatinib plus everolimus showed promising results in a phase II trial, leading to FDA approval of this combination. Their synergic action on inhibiting the VEGF/VEGFR, FGF (a compensatory mechanism to VEGFR inhibition) and mTOR pathway could be a potential mechanism to overcome treatment resistance. Given that the activity of lenvatinib as an immune-regulator in tumor microenvironment has been demonstrated in cell lines, novel combinations, in particular with immune-checkpoint inhibitors, are under development.

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