FDA Approves Lenvatinib in Combination With Everolimus in Advanced Renal Cell Carcinoma


On May 13, 2016, the U.S. Food and Drug Administration (FDA) approved lenvatinib capsules (Lenvima), in combination with everolimus (Afinitor) for the treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. Lenvatinib was first approved in 2015 for the treatment of locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.

Lenvatinib is a multiple kinase inhibitor against the vascular endothelial growth factor receptors VEGFR1, VEGFR2, and VEGFR3.

Study Details

The current approval was based on a randomized, multicenter study in patients with advanced or metastatic renal cell carcinoma who previously received antiangiogenic therapy. The major efficacy outcome measure was investigator-assessed progression-free survival evaluated according to RECIST v1.1.  

The trial randomized 153 patients 1:1:1 to lenvatinib at 18 mg plus everolimus at 5 mg (n = 51), lenvatinib at 24 mg monotherapy (n = 52), or everolimus at 10 mg monotherapy (n = 50). All medications were administered orally once daily. Metastases were present in 95% of patients. Memorial Sloan Kettering Cancer Center favorable-, intermediate-, and poor-risk prognostic categories were seen, respectively, in 24%, 37%, and 39% of patients receiving lenvatinib plus everolimus and were well balanced between arms.


The hazard ratio for the comparison of investigator-assessed progression-free survival between lenvatinib plus everolimus and everolimus was 0.37 (95% confidence interval [CI] = 0.22–0.62). The median progression-free survival was 14.6 (95% CI = 5.9–20.1) months for the lenvatinib-plus-everolimus arm vs 5.5 (95% CI = 3.5–7.1) months for the everolimus arm. 

This treatment effect was supported by a retrospective independent review of radiographs in these two arms with an observed hazard ratio of 0.43 (95% CI = 0.24–0.75). The hazard ratio for a post hoc, updated comparison of overall survival between the lenvatinib-plus-everolimus and everolimus arms was 0.67 (95% CI = 0.42–1.08).

Comparison of investigator-assessed progression-free survival between lenvatinib monotherapy and everolimus monotherapy supported the activity of lenvatinib in renal cell cancer. The combination of lenvatinib plus everolimus demonstrated numerically superior progression-free survival, objective response rate, and overall survival, compared to lenvatinib monotherapy. There was no prespecified plan for multiple comparisons. 

The most common adverse reactions (greater than 30%) with lenvatinib in combination with everolimus were diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, bleeding events, and proteinuria. Diarrhea was increased with the combination of lenvatinib plus everolimus (19% grade 3–4) and was added to the package insert as a new safety warning.  

The recommended dose and schedule is lenvatinib at 18 mg plus everolimus at 5 mg taken by mouth once daily.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.