Second-Line Lenvatinib Plus Everolimus Improves Progression-Free Survival vs Everolimus in Metastatic Renal Cell Carcinoma in Phase II Trial


Key Points

  • The combination of lenvatinib and everolimus significantly prolonged progression-free survival vs everolimus alone.
  • A nonsignificant increase was observed for the combination vs lenvatinib alone.

In a phase II trial reported in The Lancet Oncology, Motzer et al found that the combination of the multi–tyrosine kinase inhibitor lenvatinib (Lenvima) plus the mTOR inhibitor everolimus (Afinitor) significantly improved progression-free survival vs everolimus alone in patients with metastatic clear-cell renal cell carcinoma who had received VEGF-targeted therapy. A nonsignificant increase was observed with the combination vs lenvatinib alone.

Study Details

In the open-label trial, 153 patients from 37 sites in five countries were randomly assigned between March 2012 and June 2013 to receive oral lenvatinib at 24 mg/d (n = 52), everolimus at 10 mg/d (n = 50), or the combination at lenvatinib at 18 mg/d and everolimus at 5 mg/d (n = 51) in continuous 28-day cycles until disease progression or unacceptable toxicity.

Patients had to have progressed on or within 9 months of stopping VEGF-targeted therapy. Randomization was stratified for hemoglobin and corrected serum calcium levels. The endpoint was progression-free survival in the intent to treat population.

Patients had a median age of 59 to 64 years, and 69% to 76% were male. Other baseline characteristics were generally balanced across treatment groups, with the exception of proportion of patients with three or more metastases (35% in combination group, 54% in lenvatinib group, 60% in everolimus group) and the proportion who had received sunitinib as VEGF-targeted therapy (71%, 67%, and 56%).

Progression-Free Survival

Median progression-free survival was 14.6 months (95% confidence interval [CI] = 5.9–20.1 months) in the combination group, 7.4 months (95% CI = 5.6–10.2 months) in the lenvatinib group, and 5.5 months (95% CI = 3.5–7.1 months) in the everolimus group. Hazard ratios (HRs) were 0.40 (P = .0005) for the combination vs everolimus, 0.66 (P = .12) for the combination vs lenvatinib, and 0.61 (P = .048) for lenvatinib vs everolimus. Objective response rates were 43%, 27%, and 6%.

Grade 3 or 4 adverse events occurred in 71%, 79%, and 50% of patients, with the most common being diarrhea (20%) in the combination group, proteinuria (19%) in the lenvatinib group, and anemia (12%) in the everolimus group. Treatment-related death occurred in one patient in the combination group (cerebral hemorrhage) and one in the lenvatinib group (myocardial infarction).

The investigators concluded: “Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma.”

Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Lancet Oncology article.

The study was funded by Eisai Inc. For full disclosures of the study authors, visit

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