Combination lenvatinib and pembrolizumab demonstrated antitumor activity in patients with metastatic renal cell carcinoma (RCC) regardless of prior treatment, according to trial results published in The Lancet Oncology.

The phase 1b/2 KEYNOTE-146 trial ( Identifier: NCT02501096) enrolled 145 patients with advanced RCC. There were 2 patients with non-clear cell RCC who were excluded from the efficacy analysis but included in the safety analysis.  

The patients were divided into 3 groups based on previous therapy: patients who received prior immune checkpoint inhibitor (ICI) therapy (n=104), previously treated but ICI-naïve patients (n=17), and treatment-naïve patients (n=22).

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Each group received oral lenvatinib once daily and intravenous pembrolizumab once every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

The median follow-up was 19.8 months. At week 24, the objective response rate was 55.8% among ICI-pretreated patients, 41.2% among previously treated but ICI-naive patients, and 72.7% among treatment-naive patients.  

The median progression-free survival by investigator assessment was 12.2 months for ICI-pretreated patients, 11.8 months for previously treated ICI-naive patients, and 24.1 months for treatment-naive patients.

The median overall survival was 30.3 months for previously treated ICI-naïve patients and was not reached for the other groups.

Of the 145 patients included in the safety analysis, 57% had grade 3 treatment-related adverse events (TRAEs), and 7% had grade 4 TRAEs. Hypertension was the most common grade 3 TRAE (21%). Serious TRAEs were observed in 25% of patients.

There were 3 treatment-related deaths. In the treatment-naïve group, 1 patient had grade 5 pneumonia. In the ICI-pretreated group, 1 patient had a grade 5 upper gastrointestinal hemorrhage, and another experienced sudden death that was not specified.

“Lenvatinib plus pembrolizumab resulted in promising overall objective response rates irrespective of previous treatment regimens,” the study authors wrote. “Lenvatinib plus pembrolizumab might therefore be a future potential standard-of-care treatment for patients with metastatic clear cell RCC after disease progression with ICI therapy.”

Disclosures: This research was supported by Eisai and Merck Sharp & Dohme. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi: 10.1016/S1470-2045(21)00241-2