New Agent Granted Breakthrough Therapy Designation for Advanced RCC

New Agent Granted Breakthrough Therapy Designation for Advanced RCC

August 5, 2015

The US Food and Drug Administration (FDA) on July 29, 2015, granted a breakthrough therapy designation to Eisai's lenvatinib (Lenvima), which is an orally administered, multiple receptor tyrosine kinase (RTK) inhibitor.

Oncologists may soon have a new tool for treating advanced and/or metastatic renal cell carcinoma (RCC) that extends survival. The US Food and Drug Administration (FDA) on July 29, 2015, granted a breakthrough therapy designation to Eisai's lenvatinib (Lenvima), which is an orally administered, multiple receptor tyrosine kinase (RTK) inhibitor. This agent appears to have significant promise for treating advanced and/or metastatic RCC based on the results of a phase II clinical trial (Study 205).1

Preliminary clinical evidence demonstrating the drug may have substantial improvement on at least one clinically significant endpoint over available therapy is required for breakthrough therapy designation. The benefits of this designation include more intensive guidance on an efficient drug development program and submission strategy. This program also allows eligibility for rolling review.

The multicenter, randomized, open-label study involved lenvatinib (18 mg) in combination with everolimus (Afinitor, 5 mg), lenvatinib alone (24 mg), and everolimus alone (10 mg), in 153 patients with advanced or metastatic RCC following one prior VEGF-targeted therapy. Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, FGFR4). It also inhibits in other proangiogenic and oncogenic pathway-related RTKs involved in tumor proliferation. Lenvatinib has been confirmed through X-ray co-crystal structural analysis to demonstrate a new binding mode (Type V) to VEGFR2, according to investigators.

The most recent analysis of the data showed that the combination of lenvatinib plus everolimus extends progression-free survival (PFS) compared to everolimus alone. The median PFS for the lenvatinib plus everolimus group was 14.6 months compared to a median PFS of 5.5 months for the everolimus alone group.  In addition, the median PFS for lenvatinib alone was 7.4 months, demonstrating an extension in PFS compared to everolimus alone (hazard ratio [HR] = 0.61).

The study assessed objective response rate (ORR) and overall survival (OS) as secondary endpoints. The researchers found that the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in ORR compared to the everolimus alone group. The ORR for lenvatinib plus everolimus was 43% compared to 27% for the lenvatinib alone group, and 6% for the everolimus group alone. An updated analysis carried out in December 2014 suggested that lenvatinib plus everolimus extended OS compared to everolimus alone (HR = 0.51).

The most common treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite, and fatigue. The most common TEAEs of grade 3 or higher included diarrhea, hypertension, and fatigue.

Currently, a global phase III study of lenvatinib in hepatocellular carcinoma is underway. There are phase II studies of lenvatinib underway in several other tumor types as well, including endometrial carcinoma and non-small cell lung cancer. Lenvatinib has been granted orphan drug designation by regulatory authorities in the United States, Japan, and Europe for refractory thyroid cancer.

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