Pembrolizumab plus belzutifan resulted in higher investigator-assessed disease-free survival than pembrolizumab plus placebo among patients with surgically resected clear-cell renal-cell carcinoma at increased risk for recurrence, according to findings published in The New England Journal of Medicine. Grade 3 or higher adverse events occurred more frequently with the combination regimen, whereas overall survival did not differ significantly at the first interim analysis.
In the randomized, double-blind, multinational phase 3 LITESPARK-022 trial, investigators compared adjuvant pembrolizumab plus belzutifan with pembrolizumab plus placebo among patients with surgically resected clear-cell renal-cell carcinoma at increased risk for recurrence. Eligible patients were aged 18 years or older with histologically confirmed, surgically resected clear-cell renal-cell carcinoma classified as intermediate-to-high risk, high risk, or stage M1 with no evidence of disease following complete resection of metastatic lesions. Patients underwent randomization within 12 weeks after surgery.
A total of 1,841 patients underwent randomization and were assigned to receive a 400 mg dose of intravenous pembrolizumab every 6 weeks plus daily oral belzutifan at a 120 mg dose or placebo for up to 1 year. Among the participants, 921 were assigned to pembrolizumab plus belzutifan and 920 to pembrolizumab plus placebo. The primary end point was investigator-assessed disease-free survival, defined as the time from randomization to first documented local or distant recurrence or death from any cause. Secondary end points included overall survival and safety. Investigators also evaluated disease-free survival using blinded independent central review as part of a sensitivity analysis. Patients were followed for a median of 28.4 months after randomization.
Baseline characteristics were generally balanced between treatment groups. The median age was 59 years in the pembrolizumab-belzutifan group and 60 years in the pembrolizumab-placebo group. Approximately 85% of patients had intermediate-to-high-risk disease, approximately 9% had stage M1 disease with no evidence of disease, and nearly 90% had stage T3 tumors.
Disease recurrence or death occurred in 186 patients receiving pembrolizumab plus belzutifan compared with 246 patients receiving pembrolizumab plus placebo. Estimated disease-free survival was 92% vs 85% at 12 months, 81% vs 74% at 24 months, and 76% vs 69% at 30 months. Investigators also performed a sensitivity analysis using blinded independent central review, in which disease recurrence or death occurred in 205 patients receiving pembrolizumab plus belzutifan and 252 patients receiving pembrolizumab plus placebo.
Overall survival data remained immature at the interim analysis. Death occurred in 38 patients receiving pembrolizumab plus belzutifan and 49 patients receiving pembrolizumab plus placebo. Estimated overall survival at 24 months was 96% in both groups. The investigators noted that only 29% of the planned overall survival events had occurred at the interim analysis. “Additional follow-up is necessary for an informative analysis of overall survival,” wrote lead study author Toni K. Choueiri, MD of the Dana–Farber Cancer Institute and Harvard Medical School in Boston, and colleagues.
Grade 3 or higher adverse events of any cause occurred in 52% of patients receiving pembrolizumab plus belzutifan compared with 30% of those receiving pembrolizumab plus placebo. Serious adverse events occurred in 30% and 20% of patients, respectively. Anemia occurred in 84% of patients receiving pembrolizumab plus belzutifan, including grade 3 or higher anemia in 12%, compared with 11% and less than 1%, respectively, among patients receiving pembrolizumab plus placebo. Hypoxia occurred in 7% of patients receiving pembrolizumab plus belzutifan compared with less than 1% of those receiving pembrolizumab plus placebo. Treatment-related adverse events leading to death occurred in 0.3% of patients in each group.
The investigators concluded that adjuvant pembrolizumab plus belzutifan resulted in higher disease-free survival than pembrolizumab plus placebo among patients with clear-cell renal-cell carcinoma at increased risk for recurrence. The investigators also noted that small subgroup sample sizes and the underrepresentation of Black patients may limit interpretation and generalizability.
The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Toni K. Choueiri, reported additional research support from multiple academic and philanthropic funding sources. Disclosure forms are available with the published article.
