First-Line Pembrolizumab Plus Lenvatinib Active in Advanced Non–Clear Cell Renal Cell Carcinoma

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Laurence Albiges, MD, PhD

Laurence Albiges, MD, PhD

In a phase II trial (KEYNOTE-B61) reported in The Lancet Oncology, Laurence Albiges, MD, PhD, of Gustave Roussy, Paris–Saclay University, Villejuif, France, and colleagues found that first-line pembrolizumab plus lenvatinib produced durable responses in patients with advanced non–clear cell renal cell carcinoma.1

As stated by the investigators: “Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterized in non–clear cell renal cell carcinoma.”

Study Details

In the trial, 158 patients with stage IV disease enrolled from sites in 14 countries between February 2021 and January 2022. They received pembrolizumab at 400 mg every 6 weeks for up to 18 cycles (2 years) plus lenvatinib at 20 mg once daily or until disease progression or unacceptable toxicity; lenvatinib could be continued beyond 2 years. The primary endpoint was a confirmed objective response on independent central review.


At data cutoff (in November 2022), the median follow-up was 14.9 months (interquartile range = 11.1–17.4 months). An objective response was achieved in 78 of 158 patients (49%, 95% confidence interval [CI] = 41%–57%), with a complete response in 9 (6%). An additional 52 patients (33%) had stable disease, yielding a disease control rate of 82%. A median duration of response was not reached (95% CI = 13.8 months to not reached), with 75% of responses persisting at 12 months. Among nine patients with a complete response, six (67%) had an ongoing response at data cutoff. Overall, 91 patients (58%) had at least a 30% reduction in target lesion size.

By histologic types, an objective response was observed in 50 of 93 patients (54%, 95% CI = 43%–64%) with papillary histology, with a complete response in 8 (9%); 8 of 29 patients (28%, 95% CI = 13%–47%) with chromophobe histology; 11 of 21 patients (52%, 95% CI = 30%–74%) with unclassified histology; 4 of 6 patients (67%, 95% CI = 22%–96%) with translocation histology; and 5 of 9 patients (56%, 95% CI = 21%–86%) with other histology, with a complete response in 1 (11%). An objective response was observed in 9 of 19 patients (47%, 95% CI = 24%–71%) with and 45 of 96 patients (47%, 95% CI = 37%–57%) without sarcomatoid features. An objective response was observed in 54 of 93 patients (58%, 95% CI = 47%–68%) with a PD-L1 combined positive score (CPS) of at least 1 and in 16 of 50 patients(32%, 95% CI = 20%–47%) with a CPS of up to 1.

Among all patients, the median progression-free survival was 18 months (95% CI = 14 months to not reached), with an estimated 12-month rate of 63% (95% CI = 54%–70%). In a post hoc analysis, median progression-free survival was 17.5 months (95% CI = 15 months to not reached) among patients with papillary histology, with an estimated 12-month rate of 67% (95% CI = 56%–76%), and 12.5 months (95% CI = 3.9 months to not reached) among those with chromophobe histology, with an estimated 12-month rate of 53% (95% CI = 32.4%–70.4%). At data cutoff, death had occurred in 22% of patients; median overall survival was not reached; and the estimated 12-month and 18-month overall survival rates were 82% (95% CI = 75%–88%) and 72% (95% CI = 62%–80%).

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 51% of patients, most commonly hypertension (23%), proteinuria (4%), and stomatitis (4%). Serious treatment-related adverse events occurred in 20% of patients, including acute kidney injury, increased aspartate aminotransferase, asthenia, diarrhea, and hyponatremia in two patients each. Adverse events of any cause led to discontinuation of lenvatinib in 14% of patients, of pembrolizumab in 15%, and of both in 7%. Immune-related adverse events of any grade occurred in 53% of patients, most commonly hypothyroidism (42%), hyperthyroidism (12%), adrenal insufficiency (4%), and pneumonitis (3%). Adverse events led to death in eight patients (5%; consisting of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism), with none considered related to treatment.


  • Pembrolizumab plus lenvatinib produced an objective response in 49% of patients with advanced non–clear cell renal cell carcinoma.
  • Median response duration was not reached.

The investigators concluded: “Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non–clear cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients.” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co and Eisai. Dr. Albiges has received institutional consulting fees from Astellas, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Eisai, and Roche; and travel expenses from Bristol Myers Squibb, MSD, and Ipsen.


1. Albiges L, Gurney H, Atduev V, et al: Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear cell renal cell carcinoma (KEYNOTE-B61): A single-arm, multicentre, phase 2 trial. Lancet Oncol 24:881-891, 2023.