In the phase II KEYNOTE-B61 trial reported in The Lancet Oncology, Laurence Albiges, MD, PhD, and colleagues found that first-line pembrolizumab plus lenvatinib produced durable responses in patients with advanced non–clear cell renal cell carcinoma.

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.”

Laurence Albiges, MD, PhD

Study Details

In the trial, 158 patients with stage IV disease enrolled from sites in 14 countries between February 2021 and January 2022 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 confirmed objective response on independent central review.

Responses

At data cutoff in November 2022, median follow-up was 14.9 months (interquartile range = 11.1–17.4 months). Objective response was achieved in 78 (49%, 95% confidence interval [CI] = 41%–57%) of 158 patients, with complete response in 9 (6%). An additional 52 patients (33%) had stable disease, yielding a disease control rate of 82%. Median duration of response was not reached (95% CI = 13.8 months to not reached), with 75% of responses persisting at 12 months.

Median progression-free survival was 18 months (95% CI = 14 months to not reached), with a 12-month rate of 63%. Median overall survival was not reached (95% CI = not reached to not reached); rates at 12 and 18 months were 82% and 72%.

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%. 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.

The investigators concluded, “Pembrolizumab plus lenvatinib has durable antitumor 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.”

Dr. Albiges, of Gustave Roussy, Paris-Saclay University, Villejuif, France, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, and Eisai. For full disclosures of the study authors, visit thelancet.com.