BACKGROUND: Currently, metastatic renal cell carcinoma is treated with 
sequential single agents targeting VEGF or mTOR. Here, we aimed to assess 
lenvatinib, everolimus, or their combination as second-line treatment in 
patients with metastatic renal cell carcinoma.
METHODS: We did a randomised, phase 2, open-label, multicentre trial at 37 
centres in five countries and enrolled patients with advanced or metastatic, 
clear-cell, renal cell carcinoma. We included patients who had received 
treatment with a VEGF-targeted therapy and progressed on or within 9 months of 
stopping that agent. Patients were randomised via an interactive voice response 
system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 
mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) 
administered orally in continuous 28-day cycles until disease progression or 
unacceptable toxic effects. The randomisation procedure dynamically minimised 
imbalances between treatment groups for the stratification factors haemoglobin 
and corrected serum calcium. The primary objective was progression-free survival 
in the intention-to-treat population. This study is closed to enrolment but 
patients' treatment and follow-up is ongoing. This study is registered with 
ClinicalTrials.gov, number NCT01136733.
FINDINGS: Between March 16, 2012, and June 19, 2013, 153 patients were randomly 
allocated to receive either the combination of lenvatinib plus everolimus 
(n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). 
Lenvatinib plus everolimus significantly prolonged progression-free survival 
compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 
months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not 
compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 
0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged 
progression-free survival compared with everolimus alone (HR 0·61, 95% CI 
0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated 
single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone 
(41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 
4 treatment-emergent adverse event in patients allocated lenvatinib plus 
everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib 
it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it 
was anaemia (six [12%]). Two deaths were deemed related to study drug, one 
cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial 
infarction with single-agent lenvatinib.
INTERPRETATION: 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.
FUNDING: Eisai Inc.