Adjuvant pembrolizumab significantly improves overall survival (OS) in patients with clear cell renal cell carcinoma (ccRCC) who are at increased risk for disease recurrence after nephrectomy. The KEYNOTE-564 study demonstrated a 38% lower risk of death compared to placebo, marking a clinically meaningful advancement in the treatment of this patient population. This benefit was observed after a median follow-up of 57.2 months.
KEYNOTE-564 Study Details
The phase III, double-blind, placebo-controlled KEYNOTE-564 study randomly assigned patients with ccRCC at increased risk of recurrence after surgery to receive either pembrolizumab (200 mg every 3 weeks for up to 17 cycles) or placebo. The primary endpoint was disease-free survival (DFS), while overall survival (OS) was a key secondary endpoint. The study included 496 patients in the pembrolizumab arm and 498 in the placebo arm.
Survival Benefits
The estimated overall survival rate at 48 months was 91.2% in the pembrolizumab group compared to 86.0% in the placebo group (HR for death 0.62; 95% CI, 0.44 to 0.87; p = 0.005). The survival curves began to diverge at 15 months, with the separation continuing beyond 2 years of follow-up. According to Dr. Toni K. Choueiri of the Dana-Farber Cancer Institute, the DFS benefit was consistent with previous analyses (HR for recurrence or death 0.72; 95% CI, 0.59 to 0.87).
Safety Profile
Pembrolizumab was associated with a higher incidence of serious adverse events (20.7% versus 11.5% with placebo) and grade 3 or 4 adverse events (18.6% versus 1.2%). However, no deaths were attributed to pembrolizumab therapy. This suggests that while there are increased risks of adverse events, they are generally manageable.
Implications for Treatment
These results further support the use of adjuvant pembrolizumab as a standard intervention after surgery in patients with ccRCC who are at increased risk for disease recurrence. Prior to this, adjuvant treatment after surgery for localized RCC has been a challenging area with limited success. While sunitinib showed a DFS benefit in one randomized trial, no prolongation in OS has been reported with an adjuvant VEGFR TKI.
Expert Commentary
Dr. Thomas Powles, professor of genitourinary oncology at Queen Mary University of London, noted that patients with high- and intermediate-risk clear-cell renal cancer should discuss the benefits and risks of adjuvant therapy, emphasizing that pembrolizumab is associated with a significant survival advantage.
Future Directions
Ongoing randomized studies are exploring pembrolizumab in combination with a HIF2 inhibitor or a personalized cancer vaccine. Biomarker testing on KEYNOTE-564 samples may help identify patients who benefit most from pembrolizumab, potentially avoiding overtreatment in those for whom surgery alone may be sufficient.
