As reported in The Lancet Oncology by Thomas Powles, MD, PhD, and colleagues, the 30-month follow-up of the phase III KEYNOTE-564 trial showed a continued disease-free survival benefit with adjuvant pembrolizumab vs placebo in patients with clear cell renal cell carcinoma who are at increased risk of disease recurrence.
At interim analysis, pembrolizumab was associated with improved disease-free survival (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.53–0.87, P = .0010). These data supported the November 2021 approval of pembrolizumab in this setting. The current analysis represents an additional 6 months of follow-up.
Thomas Powles, MD, PhD
Study Details
In the double-blind trial, 994 patients undergoing nephrectomy were randomly assigned between June 2017 and September 2019 to receive pembrolizumab at 200 mg (n = 496) or placebo (n = 498) every 3 weeks for up to 17 cycles. The primary endpoint was disease-free survival on investigator assessment in the intention-to-treat population.
Updated Efficacy Outcomes
Median follow-up for the current analysis was 30.1 months (interquartile range = 25.7–36.7 months). Disease-free survival remained better with pembrolizumab vs placebo (HR = 0.63, 95% CI = 0.50–0.80). At data cutoff, disease-free survival events had occurred in 23% of patients in the pembrolizumab group vs 34% of the placebo group. At 30 months, the estimated proportions of patients alive without recurrence were 75.2% (95% CI = 70.8%–79.1%) vs 65.5% (95% CI = 60.9%–69.7%).
At 30 months, the cumulative incidence of local recurrence was 3.8% (95% CI = 2.3%–6.0%) in the pembrolizumab group vs 7.6% (95% CI = 5.3%–10.3%) in the placebo group, and distant metastasis–free survival rates were 77.3% (95% CI = 73.0%–81.0%) vs 68.8% (64.4%–72.9%), with a hazard ratio of 0.63 (95% CI = 0.49–0.82).
A total of 14% of patients in the pembrolizumab group and 20% in the placebo group received at least one line of subsequent anticancer drug therapy after disease recurrence. At data cutoff, death had occurred in 5% vs 9% of patients (HR = 0.52, nominal 95% CI = 0.31–0.86). At 30 months, the estimated proportions of patients who were alive were 95.7% (95% CI = 93.3%–97.2%) vs 91.4% (95% CI = 88.3%–93.7%).
KEY POINTS
- Updated results from KEYNOTE-564 show a maintained disease-free survival benefit with adjuvant pembrolizumab.
- Pembrolizumab appeared to be associated with benefits in other efficacy outcome measures.
Adverse Events
The adverse event profile of pembrolizumab was consistent with that reported in the interim analysis, with no new safety signals identified. Treatment-related grade ≥ 3 adverse events occurred in 32% of patients in the pembrolizumab group vs 18% of the placebo group. The most common were hypertension (3%) and increased alanine aminotransferase (2%) in the pembrolizumab group and hypertension (3%) in the placebo group. Treatment-related serious adverse events occurred in 12% of the pembrolizumab group (most commonly, adrenal insufficiency, colitis, and diabetic ketoacidosis in 1% each) vs < 1% of the placebo group. Immune-mediated adverse events irrespective of causal attribution occurred in 36% of the pembrolizumab group (most commonly, hypothyroidism [21%] and hyperthyroidism [13%]) and 7% of the placebo group (most commonly, hypothyroidism [4%]). No treatment-related deaths were reported.
The investigators concluded, “Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.”
Dr. Powles, of Barts Cancer Institute, Queen Mary University of London, St Bartholomew’s Hospital, London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit thelancet.com.
