The combination of pembrolizumab plus lenvatinib was found to prolong survival compared with sunitinib among patients with previously untreated advanced renal cell carcinoma (RCC), according to the results of a study published in the New England Journal of Medicine.

Both pembrolizumab and lenvatinib have been demonstrated to have activity as monotherapies against RCC. The aim of this trial was to evaluate the efficacy and safety of their combination vs sunitinib.

The phase 3 CLEAR trial ( Identifier: NCT02811861) randomly assigned 1069 treatment-naive patients with advanced RCC to receive pembrolizumab plus lenvatinib, lenvatinib plus everolimus, or sunitinib. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate, and safety.

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At baseline, the median age was 62 years and 74.5% of patients were men. The majority of patients had an intermediate (63.8%) or favorable (27.2%) Memorial Sloan Kettering Cancer Center score and intermediate (55.9%) or favorable (32.5%) International Metastatic Renal Cell Carcinoma Database Consortium score.

Both combination regimens prolonged PFS compared with sunitinib. The median PFS with pembrolizumab plus lenvatinib was 23.9 months compared with 9.2 months with sunitinib (hazard ratio [HR], 0.39; 95% CI, 0.32-0.49; P <.001). The median PFS with lenvatinib plus everolimus was 14.7 months (HR, 0.65; 95% CI, 0.53-0.80; P <.001).

All subgroups also favored the combination of pembrolizumab plus lenvatinib for PFS compared with sunitinib, including risk group, performance status, number of organs with metastases, and PD-L1 expression status.

Median OS was not yet reached for all treatment groups, with a 24-month OS of 79.2%, 66.1%, and 70.4% in the pembrolizumab plus lenvatinib, lenvatinib plus everolimus, and sunitinib groups, respectively. However, the HR favored pembrolizumab plus lenvatinib vs sunitinib at 0.66 (95% CI, 0.49-0.88; P =.005), whereas the HR with lenvatinib plus everolimus was 1.15 (95% CI, 0.88-1.50; P =.30).

Objective response rates were highest for pembrolizumab plus lenvatinib at 71%, compared with 53.5% for lenvatinib plus everolimus and 36.1% for sunitinib, and complete response rates were 16.1%, 9.8%, and 4.2%, respectively.

Adverse events (AEs) led to treatment discontinuation of 1 or more agents among 37.2% of patients in the pembrolizumab plus lenvatinib group, 27.0% in the lenvatinib plus everolimus group, and 14.4% in the sunitinib group. The most common treatment-related AEs across treatment groups were diarrhea and hypertension.

The authors concluded that “Our trial showed that combination therapy with lenvatinib plus pembrolizumab provided significantly greater benefits than sunitinib.”

Disclosure: Several study authors declared affiliations with medical institutions. Please see the Appendix in the original reference for a full list of authors’ affiliations.


Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716