Pembrolizumab/Lenvatinib Approved in Europe for Frontline RCC


The European Commission has approved the combination of pembrolizumab and lenvatinib for the treatment of patients with advanced renal cell carcinoma.

Gregory Lubiniecki, MD

Gregory Lubiniecki, MD

The European Commission has approved the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the treatment of patients with advanced renal cell carcinoma (RCC).1

The decision is based on findings from the phase 3 CLEAR (Study 307)/KEYNOTE-581 trial (NCT02811861), which showed that the combination statistically significantly improved progression-free survival (PFS) with a 61% reduction in the risk of disease progression or death vs sunitinib (Sutent).2 The median PFS was 23.9 months vs 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49; P <.0001).

The data also showcased a 34% reduction in the risk of death with pembrolizumab/lenvatinib (HR, 0.66; 95% CI, 0.49-0.88; P = .0049).

“A key focus of our collaboration with Eisai is to advance our clinical development program to evaluate the potential of Keytruda plus Lenvima to improve responses across different types of cancer, including renal cell carcinoma,” Gregory Lubiniecki, MD, vice president of clinical research, Merck Research Laboratories, which develops pembrolizumab, said in a press release. “Today’s approval of Keytruda plus Lenvima brings a new treatment option to patients with advanced renal cell carcinoma in Europe, and further validates our efforts to research this promising combination of an immunotherapy and tyrosine kinase inhibitor for some of the most difficult-to-treat cancers.”

The approval allows for marketing of pembrolizumab plus lenvatinib in all 27 member states of the European Union, plus Iceland, Liechtenstein, Norway, and Northern Ireland.

In the multicenter, randomized CLEAR (Study 307)/KEYNOTE-581 trial, investigators evaluated 1069 patients with advanced clear cell RCC, including those with sarcomatoid and papillary histology, who had not previously received systemic treatment. Patients were enrolled regardless of PD-L1 expression status, but patients could not have active autoimmune disease or a condition that required immunosuppression.

Stratification factors included geographic region (North America vs Western Europe vs rest of world) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable vs intermediate vs poor).

Patients were randomized 1:1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks for up to 2 years plus lenvatinib at 20 mg orally once daily, or lenvatinib at 18 mg orally once daily plus everolimus at 5 mg orally once daily, or sunitinib at 50 mg orally once daily for 4 weeks on treatment, followed by 2 weeks off treatment. Treatment was administered until unacceptable toxicity or investigator- and BICR-assessed disease progression using RECIST v1.1 criteria. Pembrolizumab/lenvatinib treatment could continue beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit.

Pembrolizumab was continued for up to 2 years; however, lenvatinib was able to be continued beyond 24 months. Tumor status was assessed at baseline and then at every 8 weeks. 

The primary end point was PFS via blinded independent central review (BICR) through RECIST v1.1 criterial; key secondary end points were overall survival (OS) and objective response rate (ORR).

Additional results showed that the ORR for pembrolizumab/lenvatinib was 71% (95% CI, 66%-76%) vs 36% (95% CI, 31%-41%) with sunitinib (P <.0001). The complete response and partial response rates were 16% and 55% with pembrolizumab/lenvatinib vs 4% and 32% with sunitinib, respectively.

The PFS benefit was found to be consistent across prespecified subgroups, MSKCC prognostic groups, and PD-L1 expression status.

When lenvatinib/everolimus was compared with sunitinib, the median PFS was 14.7 months vs 9.2 months, respectively (HR, 0.65; 95% CI, 0.53-0.80; P < .001). However, OS was not improved with lenvatinib/everolimus (HR, 1.15; 95% CI, 0.88-1.50; P = .30).

Regarding safety, the combination of pembrolizumab and lenvatinib was assessed in 497 patients with advanced RCC. The most frequently reported adverse effects (AEs) were diarrhea (62%), hypertension (52%), fatigue (47%), hypothyroidism (45%), decreased appetite (42%), nausea (40%), stomatitis (37%), proteinuria (33%), dysphonia (33%) and arthralgia (32%).

“Renal cell carcinoma is the most common type of kidney cancer in both men and women, marking the significance of the European approval for the Keytruda plus Lenvima combination,” said Corina Dutcus, MD, vice president of clinical research, Oncology Business Group at Eisai Inc, which develops lenvatinib. “We remain committed to continuing to explore this combination therapy with the goal of improving care for people living with cancer. The participation of many patients, families and healthcare providers made this approval possible, for which we are very grateful.”

In August 2021, the FDA approved the combination of pembrolizumab and lenvatinib for the frontline RCC indication, also based on the phase 3 CLEAR/KEYNOTE-581 findings.3


  1. European Commission approves Keytruda (pembrolizumab) plus Lenvima (lenvatinib) as first-line treatment for adult patients with advanced renal cell carcinoma. Merck. News release. November 29, 2021. Accessed November 29, 2021.
  2. Motzer RJ, Aleskeev 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
  3. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). Merck. News release. August 11, 2021. Accessed August 11, 2021.
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