Lenvatinib for Renal Cell Carcinoma Meets Primary Endpoint in Phase II trial

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Japanese drug maker Eisai announced that the multiple kinase inhibitor lenvatinib, alone and in combination with everolimus, has been shown to prolong progression-free survival (PFS) in patients with unresectable advanced or metastatic renal cell carcinoma (mRCC).

Japanese drug maker Eisai announced  that the multiple kinase inhibitor lenvatinib, alone and in combination with everolimus, has been shown to prolong progression-free survival (PFS) in patients with unresectable advanced or metastatic renal cell carcinoma (mRCC).

The phase 2 clinical trial randomized 153 patients to receive lenvatinib plus everolimus, lenvatinib alone, or everolimus alone. Patients who received the combination showed significantly prolonged PFS compared with those who received everolimus alone.

Through a novel binding mode, lenvatinib inhibits several receptor tyrosine kinases, including VEGFR, FGFR, PDGFRα, KIT, and RET. Metastatic RCC is a highly vascularized tumor type that often involves pro-angiogenic pathways, such as the VEGF pathway. Drug resistance via activation of alternate mitogenic pathways has been problematic for kinase inhibitors and the simultaneous inhibition of FGFR and VEGFR--both involved in angiogenesis and tumor proliferation--is thought to address pathway switching and possibly increase antitumoral effects.

Everolimus was FDA-approved as a second-line treatment for advanced RCC in 2009. It inhibits cell cycle signaling by the mammalian target of rapamycin (mTOR), thereby blocking tumor cell growth and proliferation. VEGF-mediated angiogenesis and mTOR-mediated cell cycle regulation have been shown to be important in the development of RCC. For patients previously treated for RCC, everolimus is the standard recommended treatment, but responses are low and transient for most patients. The combination of agents targeting both VEGF and mTOR pathways may block these two important pathways activated in RCC and potentially overcome resistance to a single-agent therapy.

Late last year the FDA granted lenvatinib Priority Review designation for treatment of progressive radioiodine-refractory differentiated thyroid cancer. Several clinical trials are currently underway to evaluate lenvatinib for oncology indications, including non-small cell lung cancer, ovarian cancer, melanoma, endometrial cancer, and in patients with advanced solid tumors.

 

 

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