Lenvatinib/Everolimus: Robust Combination in Metastatic Renal Cell Carcinoma

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Robert Motzer, MD

The combination of lenvatinib (Lenvima) plus everolimus (Afinitor) significantly extended progression-free survival compared with everolimus alone in metastatic renal cell carcinoma, according to a randomized phase II trial.1 Median progression-free survival for patients who received the combination was 14.6 months, significantly longer than 5.5 months for everolimus alone (P < .001), which is currently a National Comprehensive Cancer Network–recommended second-line therapy for unresectable or advanced or metastatic renal cell carcinoma.

“The combination of lenvatinib and everolimus was superior to everolimus in previously treated metastatic renal cell carcinoma patients. Progression-free survival was longer—and response rates were higher—with the combination, and study results suggest that the combination will have a survival benefit over everolimus. This speaks to the high level of efficacy for the combination in this study. Further study of the combination of lenvatinib and everolimus is warranted,” said lead author Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

Targeted therapy with a tyrosine kinase inhibitor is the current standard of care for metastatic renal cell carcinoma. Lenvatinib, a new, powerful tyrosine kinase inhibitor, has potent selectivity and a binding mode that differs from that of other tyrosine kinase inhibitors. Lenvatinib simultaneously inhibits vascular endothelial growth factor receptors (VEGFR-1, -2, -3), fibroblast growth factor receptors (FGFR 1-4), RET, KIT, and platelet-derived growth factor receptors (PDGFR), and it is the first tyrosine kinase inhibitor to have these ­properties.

Lenvatinib is currently approved in the United States for the treatment of refractory differentiated thyroid cancer. Currently, no combination therapy has been approved for metastatic renal cell carcinoma anywhere in the world.

Study Details

Between March 2012 and July 2013, the international, prospective, open-label, phase II study randomized 153 patients with metastatic renal cell carcinoma who progressed on one prior VEGF-targeted therapy to receive lenvatinib, everolimus, or the combination of both drugs. Patients were treated until progressive disease or unacceptable toxicity.

All patients had measurable disease and disease progression within 9 months of stopping their prior therapy. No crossover was allowed in the trial.

At the 2015 ASCO Annual Meeting, Dr. Motzer presented an updated overall survival analysis up to December 2014.

“Patients enrolled in the trial were typical metastatic renal cell carcinoma pretreated patients balanced for Memorial Sloan Kettering risk factors. All patients had prior VEGF treatment, most commonly with sunitinib followed by pazopanib [Votrient],” Dr. Motzer said.

Median progression-free survival was 14.6 months with the combination, 7.4 months with lenvatinib alone, and 5.5 months with everolimus alone, representing a 60% reduction in disease progression favoring the combination over everolimus and a 39% reduction in disease progression favoring lenvatinib alone over everolimus.

The highest overall response rates were observed with the combination: 43%, followed by 27% with lenvatinib alone and 6% with everolimus alone. The median duration of response was 13.1 months for the combination therapy arm.

“At the time of data cutoff, a trend was observed favoring the combination for overall survival,” Dr. Motzer said. Median overall survival was 25.5 months for the combination, 18.4 months for lenvatinib alone, and 17.5 months for everolimus alone. The updated overall survival analysis in December 2014 showed a significant difference favoring the combination over everolimus alone (P = .024).

All patients had at least one treatment-emergent adverse event. Adverse events were more frequent in the combination therapy arm but were manageable with dose reduction, Dr. Motzer said.

Lenvatinib was associated with more grade 3 diarrhea, fatigue, nausea, and vomiting. The most common treatment-related grade 3 or higher adverse events were diarrhea, hypertension, and fatigue. Relatively few grade 4 adverse events were reported with the combination treatment. There were two grade 5 events, one in each of the lenvatinib-containing arms. ■

Disclosure: Dr. Motzer is a consultant for Pfizer; has received research funding (institutional) from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer; and travel expenses from Bristol-Myers Squibb and GlaxoSmithKline.


1. Motzer R, et al: 2015 ASCO Annual Meeting. Abstract 4506. Presented June 1, 2015.


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Expert Point of View: Sumanta K. Pal, MD

This combination [lenvatinib and everolimus] is a potential game-changer in metastatic renal cell carcinoma. We’ve studied other combinations to no avail; for example, bevacizumab [Avastin] plus everolimus had no advantage over everolimus alone. Other combinations are too toxic, such as sunitinib...