KEYNOTE-564 5-Year Data: Adjuvant Pembrolizumab Benefits ccRCC

Five-year follow-up results from the phase III KEYNOTE-564 trial (NCT03142334) demonstrate sustained disease-free survival (DFS) and overall survival (OS) improvements with adjuvant pembrolizumab (Keytruda) compared with placebo in patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence.

The findings, published in Annals of Oncology, represent the fourth prespecified interim analysis of the trial with a minimum follow-up of 60 months. Adjuvant pembrolizumab is approved for patients with ccRCC following nephrectomy or following nephrectomy and resection of metastatic lesions.

Efficacy Outcomes and Survival Benefit

The randomized, double-blind, phase III trial enrolled 994 adult patients with ccRCC at increased risk of recurrence following nephrectomy or nephrectomy with metastasectomy. Participants were assigned in a 1:1 ratio to receive either adjuvant pembrolizumab 200 mg intravenously every 3 weeks (n = 496) or placebo every 3 weeks (n = 498). Treatment continued for up to 17 cycles (approximately 1 year), or until disease recurrence, unacceptable toxicity, or withdrawal criteria were met. Investigator-assessed DFS served as the primary endpoint, with OS evaluated as a key secondary endpoint.

At a median time from randomization to data cut-off of 70 months (range, 60–87), pembrolizumab maintained a statistically significant improvement in DFS compared with placebo. The hazard ratio (HR) for DFS was 0.71 (95% CI, 0.59–0.86). Median DFS was not reached in the pembrolizumab arm compared with 68.0 months in the placebo arm. Estimated 5-year DFS rates were 60.9% for patients receiving pembrolizumab versus 52.2% for those receiving placebo.

Adjuvant pembrolizumab yielded a statistically significant OS benefit over placebo, with an HR of 0.66 (95% CI, 0.48–0.90). Median OS was not reached in either study arm. The estimated 5-year OS rate was 87.7% with pembrolizumab compared with 82.3% with placebo. Treatment benefit across both DFS and OS remained consistent across all key prespecified and exploratory subgroups, regardless of tumor grade, disease risk category, geographic region, or presence of sarcomatoid features.

Key Clinical Takeaways for Oncology Nurses: Efficacy Metrics

• Sustained Disease-Free Survival Improvement: Adjuvant pembrolizumab reduces the risk of disease recurrence or death by 29% compared with placebo at 5 years (HR 0.71; 95% CI, 0.59–0.86).
• Long-Term Overall Survival Advantage: Treatment demonstrates a 34% reduction in the risk of death (HR 0.66; 95% CI, 0.48–0.90), establishing an estimated 5-year OS rate of 87.7% versus 82.3%.
• Broad Subgroup Consistency: Clinical benefit applies across all risk categories, tumor grades, geographic regions, and patients with or without sarcomatoid features.
• Extended Treatment Duration: Protocol compliance involves administering pembrolizumab 200 mg every 3 weeks for up to 17 cycles (~1 year), requiring consistent patient engagement.

Secondary and Exploratory Endpoints

Exploratory analysis evaluated time to recurrence (TTR) and distant metastasis-free survival (DMFS). Pembrolizumab prolonged TTR compared with placebo (HR 0.69; 95% CI, 0.57–0.84). Median TTR was not reached in the pembrolizumab group and was 80.9 months (95% CI, 58.8–NR) in the placebo group. Recurrence rates at 5 years were 63.3% for pembrolizumab and 54.5% for placebo. DMFS was significantly longer in the pembrolizumab arm (HR 0.73; 95% CI, 0.60–0.89). Median DMFS was not reached with pembrolizumab versus 80.7 months (95% CI, 64.5–NR) with placebo.

These exploratory findings align with primary DFS and OS outcomes, confirming that adjuvant pembrolizumab delays distant metastatic progression. Patterns of subsequent anticancer therapy remained consistent with previously published trial updates.

Safety Profile and Adverse Event Analysis

The safety profile of adjuvant pembrolizumab remained unchanged with 5 years of follow-up. No new any-cause or treatment-related adverse events (AEs) were collected, as participants completed study therapy more than 3 years prior to this data cut-off.

The median duration of grade ≥3 AEs of any cause was 42 days (Q1–Q3, 10–155) in the pembrolizumab arm compared with 20 days (Q1–Q3, 5–64) in the placebo arm. The most common grade ≥3 AEs recorded during treatment and up to 30 days post-treatment in the pembrolizumab group were hypertension (2.9%), increased alanine aminotransferase (2.3%), and diarrhea (1.8%).

Key Clinical Takeaways for Oncology Nurses: Safety and Patient Care

• No Late Toxicity Signals: Long-term follow-up confirms no unexpected or late-emerging adverse events after completion of 1 year of therapy.
• Common Grade ≥3 Toxicities: Oncology nurses must monitor for hypertension (2.9%), ALT elevations (2.3%), and diarrhea (1.8%) during active treatment and within 30 days post-treatment.
• Adverse Event Resolution Timeline: Grade ≥3 toxicities associated with pembrolizumab required a median duration of 42 days to resolve, requiring extended nursing assessment and intervention.
• Adherence and Surveillance: Maintaining 17 cycles of therapy necessitates structured symptom tracking, routine lab monitoring, and patient counseling regarding recurrence surveillance.

Reference

1. Haas NB, Powles TB, Tomczak P, et al. Adjuvant pembrolizumab for the treatment of clear cell renal cell carcinoma: Five-year results from the phase III KEYNOTE-564 study. Ann Oncol. Published online August 26, 2026. doi:10.1016/j.annonc.2026.08.006