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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.

KEY POINTS

  • 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 nejm.org.

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®.
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