CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus vs Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma

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As reported in The New England Journal of Medicine by Motzer et al, the phase III CLEAR trial has shown prolonged progression-free survival with lenvatinib in combination with either pembrolizumab or everolimus vs sunitinib and prolonged overall survival with the lenvatinib/pembrolizumab combination in first-line treatment of advanced renal cell carcinoma.

Study Details

In the open-label trial, 1,069 patients with no prior systemic therapy from sites in 20 countries were randomly assigned 1:1:1 between October 2016 and July 2019 to receive lenvatinib at 20 mg once daily plus pembrolizumab at 200 mg once every 3 weeks (n = 355), lenvatinib at 18 mg once daily plus everolimus at 5 mg once daily (n = 357), or sunitinib at 50 mg once daily 4 weeks on/2 weeks off (n = 357). The primary endpoint was progression-free survival assessed by independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population.

Progression-Free Survival

Data cutoff was in August 2020 for the final analysis of progression-free survival, with a median follow-up for overall survival of 26.6 months.


  • Lenvatinib/pembrolizumab and lenvatinib/everolimus improved progression-free survival vs sunitinib.
  • Lenvatinib/pembrolizumab improved overall survival vs sunitinib.

Compared with the sunitinib group (median = 9.2 months, 95% confidence interval [CI] = 6.0–11.0 months), median progression-free survival was significantly prolonged in the lenvatinib/pembrolizumab group (median = 23.9 months, 95% CI = 20.8­–27.7 months; hazard ratio [HR] = 0.39, 95% CI =  0.32-0.49, P < .001) and in the lenvatinib/everolimus group (median = 14.7 months, 95% CI = 11.1–16.7 months; HR  = 0.65, 95% CI = 0.53–0.80, P < .001).

Median overall survival was not reached in any treatment group. Overall survival at 2 years was 79.2% in the lenvatinib/pembrolizumab group, 66.1% in the lenvatinib/everolimus group, and 70.4% in the sunitinib group, with a significant benefit vs sunitinib observed for lenvatinib/pembrolizumab (HR = 0.66, 95% CI = 0.49–0.88, P = .005) but not for lenvatinib/everolimus (HR = 1.15, 95% CI = 0.88­–1.50, P = .30).

Objective response rates were 71.0% with lenvatinib/pembrolizumab (relative risk = 1.97, 95% CI =1.69–2.29 vs sunitinib), 53.5% with lenvatinib/everolimus (relative risk =1.48, 95% CI = 1.26–1.74 vs sunitinib), and 36.1% with sunitinib. Complete response was observed in 16.1%, 9.8%, and 4.2% of the three groups. Median durations of response were 25.8 months (95% CI = 22.1­­–27.9 months), 16.6 months (95% CI = 14.6–20.6 months), and 14.6 months (95% CI = 9.4–16.7 months).

Adverse Events

Grade ≥ 3 adverse events occurred in 82.4% of the lenvatinib/pembrolizumab group (most common = hypertension in 27.6%, diarrhea in 9.7%), 83.1% of the lenvatinib/everolimus group (most common = hypertension in 22.5%, diarrhea in 11.5%), and 71.8% of the sunitinib group (most common = hypertension in 18.8%, diarrhea in 5.3%). Adverse events led to discontinuation of treatment in 37.2% of the lenvatinib/pembrolizumab group (lenvatinib in 25.6%, pembrolizumab in 28.7%, both in 13.4%), 27.0% of the lenvatinib/everolimus group (lenvatinib in 22.0%, everolimus in 24.8%, both in 18.9%), and 14.4% of the sunitinib group.

The investigators concluded:Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib.”

Robert Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Eisai and Merck Sharp and Dohme. For full disclosures of the study authors, visit

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