KEYNOTE-146: Lenvatinib plus Pembrolizumab Tolerable and Effective in Treatment-Naïve and Previously Treated Patients with RCC

Lenvatinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors, fibroblast growth factor receptors, a platelet-derived growth factor receptor, RET, and KIT.1 Lenvatinib is approved for use in combination with the immune checkpoint inhibitor (ICI) pembrolizumab as a first-line agent for patients with metastatic renal-cell carcinoma (RCC).2

In the open-label Study 111/KEYNOTE-146 phase 1b/2 trial, lenvatinib plus pembrolizumab was evaluated in patients with advanced solid tumors and who had an Eastern Cooperative Oncology Group performance status of 0 or 1. Investigator-assessed objective response rate at week 24 was the primary end point.1,3 In a previous interim report of KEYNOTE-146, which included 30 patients with RCC who had not received previous immunotherapy treatment, the phase 2 dose was selected as once-daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks. The objective response rate at week 24 in the 30 patients with ICI-naïve RCC was 63%.3

In the present study, a total of 145 patients were enrolled in the metastatic RCC cohort, of whom 143 had clear-cell RCC and were included in the efficacy analysis. Outcomes were evaluated according to treatment history subgroup: treatment-naïve (N = 22), previously treated but ICI-naïve (N = 17), or ICI pretreated (N = 104).1

Objective response rate at week 24 was 72.7% for treatment-naïve patients, 41.2% for ICI-naïve patients, and 55.8% for ICI-pretreated patients.1 All responses were partial responses. Progressive disease was reported as the best overall response in 1 (5.9%) ICI-naïve patient and 4 (3.8%) ICI-pretreated patients. Among those who responded, the duration of response was 24.2 months for treatment-naïve patients, 9.0 months for ICI-naïve patients, and 12.5 months for ICI-pretreated patients. The time to response ranged from 1.4 to 2.8 months.1

After a median follow-up of 18.9 months, median progression-free survival was 24.1 months for treatment-naïve patients, 11.8 months for ICI-naïve patients, and 12.2 months for ICI-pretreated patients. Median overall survival was not reached for treatment-naïve patients, 30.3 months for ICI-naïve patients, and not reached for ICI-pretreated patients.1

The most frequently reported grade 3 treatment-related adverse events were hypertension (21%), proteinuria (9%), diarrhea (7%), and fatigue (6%). Toxicities occurred at similar rates for ICI-pretreated patients and the overall safety population. A total of 19% of patients discontinued ≥1 agents as a result of adverse events.1

The researchers concluded that combination therapy with lenvatinib plus pembrolizumab is a tolerable and efficacious treatment option, regardless of treatment history.1


  1. Lee C-H, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naïve or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22:946-958.
  2. US Food and Drug Administration. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. Updated August 11, 2021. Accessed November 18, 2021.
  3. Taylor MH, Lee C-H, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38:1154-1163. Erratum in: J Clin Oncol. 2020;38:2702.

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