For the first time, an adjuvant treatment has led to a survival benefit in clear cell renal cell carcinoma (ccRCC). Data from the multicenter phase 3 KEYNOTE-564 study demonstrate that adjuvant pembrolizumab led to a 38% lower risk of death compared with placebo among patients with ccRCC who had a high risk of recurrence after surgery. The findings were presented by Toni K. Choueiri, MD, at the 2024 ASCO Genitourinary Cancers Symposium.
Currently, adjuvant pembrolizumab is approved for use in patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
“Between 1973 and now, 17 randomized controlled trials with over 12,000 patients with kidney cancer were enrolled on adjuvant therapies in RCC, with zero survival improvement,” said Dr Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston. “This is the first study to show a statistically significant and clinically meaningful survival improvement with any adjuvant therapy in kidney cancer.”
He continued, “Through this study, we now understand that pembrolizumab is more than just a measure to delay recurrence in kidney cancer; it is a means to significantly improve overall survival [OS] for patients. Considering that many patients with ccRCC have a high risk of recurrence leading to noncurable distant metastases, this finding is practice changing.”
The KEYNOTE-564 study is a randomized, double-blind trial designed to evaluate the efficacy of pembrolizumab as adjuvant therapy in patients with ccRCC. A total of 994 patients were randomized to receive either pembrolizumab (n=496) or a placebo (n=498). At entry, patients were ≥18 years, had ccRCC with or without sarcomatoid features, were at intermediate-high or high risk of recurrence, received no prior therapy for ccRCC, and underwent surgery ≤12 weeks prior to enrollment. The primary end point of disease-free survival (DFS) was met at the first interim analysis (30.1 months of follow-up) presented in 2021 (hazard ratio [HR], 0.68; P=.0001). At that time, OS data were immature.
At a median follow up of 57.2 months, median OS was not reached in either arm, and the HR of 0.62 for OS favored pembrolizumab and was highly significant (P=.002). At 1 year, OS was 98.6% in the pembrolizumab arm versus 98.0% with placebo, and at 48 months, the estimated OS rate was 91.2% versus 86.0%, respectively. Patients randomized to adjuvant pembrolizumab had a 28% improvement in DFS relative to placebo (HR, 0.72; 95% CI, 0.59-0.87), consistent with the interim analysis. The updated results further support adjuvant pembrolizumab as a standard of care after surgery in ccRCC, said Dr Choueiri.
In the subgroup of patients with M0 disease (intermediate-high risk), who represented 85% of all study participants, “the HR for OS was even lower than the overall HR for the study at 0.59,” he said.
Side effects were predominantly autoimmune in nature, affecting various organs, consistent with what is generally observed with other PD-1 inhibitors. Health-related quality-of-life (HRQoL) data showed more any-grade and grade 3-4 treatment-related adverse events with adjuvant pembrolizumab versus placebo, but no clinically meaningful deterioration of HRQoL was observed. With 27 additional months of follow-up, safety findings did not change substantially, Dr Choueiri said. At the latest follow-up, treatment-related adverse events (TRAEs) occurred in 79.1% of patients in the pembrolizumab arm and 53.0% of patients in the placebo arm, and rates of grade 3-4 TRAEs were 18.6% and 1.2%, respectively. TRAEs resulted in discontinuation of any treatment in 18.2% of pembrolizumab and 0.8% of placebo recipients.
“This is a breakthrough for our patients,” said discussant Pedro C. Barata, MD, MSc, from the University Hospitals Seidman Cancer Center, Cleveland. “It’s the first time to see a checkpoint inhibitor improve OS in a genitourinary tumor, and pembrolizumab is the first PD-1 inhibitor to show both DFS and OS benefit in the pure adjuvant setting across solid tumors.”
The benefit of immunotherapy seems to be enriched in subgroups identified by sarcomatoid features and high PD-L1 expression, he observed.