Efficacy and Safety Assessment of Frontline Lenvatinib Plus Pembrolizumab Underway for nccRCC

The frontline combination of lenvatinib and pembrolizumab is under investigation as a treatment option for patients with non-clear cell renal cell carcinoma in the recently launched phase 2 KEYNOTE-B61 trial.

The frontline combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) is under investigation as a treatment option for patients with non-clear cell renal cell carcinoma (nccRCC) in the recently launched phase 2 KEYNOTE-B61 trial, according to a presented during the 2021 International Kidney Cancer Symposium: North America.

The purpose of the study is to evaluate the objective response rate (ORR) per RECIST v1.1, by blinded independent central review (BICR) in the study.

Non-clear cell histology is observed less commonly than clear-cell RCC (ccRCC) and therefore, therapies are less effective and lead to worse survival outcomes in patients. No standard of care treatment exists for nccRCC, and guidelines recommend enrolling these patients into clinical trials.

Several recent studies indicate that the combination of lenvatinib and pembrolizumab may be beneficial for patients with nccRCC in the first-line setting, including a phase 2 study of pembrolizumab monotherapy (KEYNOTE-427; NCT02853344) and the phase 3 KEYNOTE-581/CLEAR (NCT02811861) study of lenvatinib plus pembrolizumab, which was conducted in patients with ccRCC but signaled benefit for those with non-clear cell disease.

In the phase 2 single-arm, open-label KEYNOTE-427 study, 165 patients were enrolled and received pembrolizumab 200 mg intravenously once every 3 weeks for up to 24 months. In the overall patient population, the ORR was 26.7% with a 29.0 median duration of response (DOR). Notably, in 59.7% of patients, responses lasted for 12 months or more. The median overall survival observed with pembrolizumab monotherapy was 28.9 months (95% CI, 24.3 to not reached).2

The safety of pembrolizumab in KEYNOTE-427 was similar to what has been observed in other tumor types. Treatment-related adverse events (TRAEs) occurred in 69.7% of patients. The most common TRAEs were pruritus (20.0%) and hypothyroidism (14.5%). Death occurred in 2 patients.

The combination of lenvatinib and pembrolizumab as seen in the multicenter, open-label, randomized, phase 3 KEYNOTE-581/CLEAR achieved significantly longer progression-free survival (PFS) and OS compared with sunitinib (Sutent) in patients with ccRCC. A total of 1069 patients were randomized 1:1 to receive with lenvatinib/pembrolizumab or sunitinib.3

The median PFS observed was 23.9 with lenvatinib plus pembrolizumab compared with 9.2 months in the sunitinib arm (HR, 0.39; 95% CI, 0.32 to 0.49; P <.001). The median OS was also improved with lenvatinib and pembrolizumab (HR, 0.66; 95% CI, 0.49 to 0.88; =.005).

High-grade AEs occurred in 82.4% of patients treated with the combination and lenvatinib a pembrolizumab, compared with 71.8% of those who received sunitinib. The most common grade 3 or higher AEs in any treatment arm were hypertension, diarrhea, and elevated lipase levels.

Both studies support the exploration of lenvatinib plus pembrolizumab in the single-arm, open-label, phase 2 trial KEYNOTE-B61.1

Approximately 152 patients will be enrolled to the study. Per the study’s protocol, all patients included must have histologically confirmed nccRCC, locally advanced or metastatic disease who have not previously received systemic treatment and have a Karnofsky Performance Score of ≥ 70%. In addition to the key outcomes, the study will investigate the secondary end points of DOR, PFS, OS, clinical benefit rate (CBR), disease control rate (DCR), and safety/tolerability.

Patients enrolled in the study will receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) plus lenvatinib 20 mg orally once daily. Treatment with pembrolizumab will be administered for up to 18 doses until or until progressive disease (PD), unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib can continue beyond 2 years until a discontinuation criterion is met.

Select patients may be eligible to receive 9 additional cycles of pembrolizumab after experiencing PD including those who have SD or better, or those who have received pembrolizumab for 24 weeks or more with a best response of CR and stop pembrolizumab. Continued lenvatinib is also allowed at the same dose and frequency that they were receiving when PD occurred. In the event that a patient discontinues pembrolizumab due to toxicity, single-agent lenvatinib can be administered at the physician's discretion.

To evaluate efficacy in the study, imaging will occur at 12 weeks from enrollment followed by Q6W through week 54, and Q12W thereafter. Twelve weeks after patients restart treatment, the second course of tumor imaging will be conducted, and the subsequent imaging will be conducted Q12W. The study’s protocol requires that imaging be performed on patients until disease progression, the start of a new anticancer treatment, withdrawal of consent, death, completion of second-course treatment equivalent to 9 cycles, or notification by the sponsor.

The Common Terminology Criteria for Adverse Events version 5.0 will be utilized to assess AEs during the study. Data from laboratory parameters, vital signs, and electrocardiographic measurements will also be included in the safety/tolerability assessment.

KEYNOTE-B61 is actively enrolling patients across Asia, Australia, Europe, and North America.


1. Lee CH, Li C, Perini R, et al. KEYNOTE-B61: An open-label phase 2 study of first-line pembrolizumab with lenvatinib for non–clear cell renal cell carcinoma. Presented at the International Kidney Cancer Symposium: North America. November 5-6, 2021; Austin, TX.

2. McDermott DF, Lee JL, Ziobro M, et al. Open-label, single-Arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non–clear cell renal cell carcinoma. J Clin Oncol. 2021;39(9):1029-1039. doi: 10.1200/JCO.20.02365

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