The FDA has approved the combination of lenvatinib and everolimus to treat advanced or metastatic renal cell carcinoma. The approval marks the first time that tyrosine kinase and mTOR inhibitors have been combined successfully as second-line treatment for renal cell carcinoma following prior VEGF-targeted therapy.
The FDA approved the combination of lenvatinib (Lenvima; Eisai) and everolimus (Afinitor; Novartis) to treat advanced or metastatic renal cell carcinoma (RCC) in mid-May. The approval marks the first time that a tyrosine kinase inhibitor (TKI) and an mTOR inhibitor have been combined successfully as a second-line treatment for patients with RCC whose tumors advance despite previous VEGF-targeted treatment.
“We have been hoping to treat kidney cancer with this type of vertical blockade for some time, but previous combinations have been unsuccessful due to high toxicity,” says Ana Molina, MD, a medical oncologist at NewYork– Presbyterian Hospital and Weill Cornell Medicine in New York, NY.
Until recently, oncologists had two second-line treatment options: everolimus and the TKI axitinib (Inlyta; Pfizer). New approvals over the past few months have increased that number to five, including the new lenvatinib–everolimus combination; the PD-1 checkpoint inhibitor nivolumab (Opdivo; Bristol-Myers Squibb); and cabozantinib (Cabometyx; Exelixis), another TKI.
Together, lenvatinib and everolimus have a synergistic effect by blocking multiple points along the VEGF and mTOR signaling pathways that are critical to tumor growth, says Molina. In addition, lenvatinib is a strong inhibitor of FGF receptors, which have been implicated as a potential mechanism of resistance to VEGF-targeted treatments.
The approval was based on a phase II trial in which 153 patients with advanced or metastatic RCC whose disease progressed within 9 months of undergoing VEGF-targeted therapy received daily doses of either lenvatinib plus everolimus; lenvatinib alone; or everolimus alone (Lancet Oncol 2015;16:1473–82). The combination significantly prolonged median progression-free survival (PFS) compared with everolimus alone (14.6 vs. 5.5 months)'the current standard of care. Lenvatinib alone also prolonged PFS compared with standard of care (7.4 months).
Despite the combination's promising results, Molina says that the anti–PD-1 drug nivolumab may be even more appealing to many oncologists and patients given its favorable side-effect profile. In addition, FDA approval of nivolumab for advanced RCC was based on more robust phase III data.
“With the approval of lenvatinib plus everolimus, nivolumab, and cabozantinib, we have a number of promising second-line treatment options,” says Molina. “However, we don't yet know what the best sequence should be.” –Janet Colwell
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