Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma

April 8, 2021

In the April 8, 2021 edition of the NEJM, investigators report on the CLEAR trial. The CLEAR trial is a phase 3 randomized clinical trial, in patients with advanced renal cell carcinoma, with no prior systemic therapy, where patients were randomized in a 1:1:1 fashion to lenvatinib plus pembrolizumab versus lenvatinib plus everolimus or sunitinib.  Dosing and frequency were 20 mg orally once daily for the lenvatinib, pembrolizumab 200 mg intravenously every 3 weeks, versus lenvatinib 18 mg orally once daily plus everolimus 5 mg orally once daily, or sunitinib 50 mg once daily for 4 weeks on a 6-week cycle.  The primary endpoint was progression free survival.  Overall survival and safety were also analyzed. 

1,069 patients were randomly assigned to receive 1 of the 3 treatment arms.  Lenvatinib plus pembrolizumab involved 355 patients, while lenvatinib plus everolimus included 357 patients and sunitinib monotherapy included 357 patients. Progression free survival was longer with a combination of pembrolizumab and lenvatinib versus sunitinib, median 23.9 versus 9.2 months, hazard ratio for disease progression or death, 0.39, 95% confidence interval, 0.32–0.49, p<0.001 and was longer with lenvatinib plus everolimus versus sunitinib, median 14.7 versus 9.2 months, hazard ratio, 0.65, 95% confidence interval, 0.53–0.80, p<0.001.  The overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib, hazard ratio for death 0.66, 95% confidence interval, 0.49–0.80 P = 0.005.  It was longer with lenvatinib plus everolimus and with sunitinib, hazard ratio 1.15, 95% confidence interval, 0.88–1.50 P = 0.30.  With regards to adverse events, grade 3 or higher adverse events were seen in 82.4% of patients who were on treatment with lenvatinib plus pembrolizumab, 83.1% of patients who were treated with lenvatinib plus everolimus, and 71.8% of those who received met monotherapy with sunitinib.  Grade 3 or 4 adverse events occurred in at least 10% of patients.

The authors concluded “lenvatinib plus pembrolizumab was associated with significantly longer progression free survival and overall survival then sunitinib“


Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma