Five-year KEYNOTE-564 data support adjuvant pembrolizumab as an established option after complete resection for selected patients with high-risk clear-cell RCC. The update shows durable disease-free and overall-survival advantages, while underscoring that toxicity, patient selection, and newer adjuvant options still require individualized discussion.

Why It Matters To Your Practice

• At a median follow-up of 69.5 months, pembrolizumab vs placebo was associated with an HR of 0.71 for recurrence or death and 0.66 for death in KEYNOTE-564.

• Estimated five-year disease-free survival was 60.9% with pembrolizumab vs 52.2% with placebo, and estimated five-year overall survival was 87.7% vs 82.3%. The 5.4-point overall-survival difference is a trial-level estimate, not an individual prediction of benefit.

Clinical Implications

• The trial population was specific: RCC with a clear-cell component and trial-defined intermediate-high risk, high risk, or completely resected M1 NED disease. These findings should not be extended to lower-risk localized disease or purely non-clear-cell RCC.

• No new severe treatment-related adverse events were reported in the five-year update, but long-term immune toxicity remains clinically important in a potentially curative setting. Hypothyroidism, adrenal or pituitary dysfunction, type 1 diabetes, nephritis, pneumonitis, colitis, hepatitis, and inflammatory arthritis may persist or require ongoing management after treatment stops. Nephritis may be especially consequential after nephrectomy because renal reserve is reduced.

Insights

• Developing an immune-related adverse event has not been shown in KEYNOTE-564 to confer better disease-free or overall survival. Patients should not interpret toxicity as evidence that treatment is working.

• No blood, tissue, genetic, microbiome, PD-L1, or postoperative ctDNA biomarker is sufficiently validated to predict severe immune-related adverse events or guide selection for adjuvant pembrolizumab in clear-cell RCC. Baseline labs and clinical assessment are more useful for recognizing toxicity early than for predicting who will develop it, and normal results do not exclude severe irAEs. Exploratory ctDNA work in KEYNOTE-564 also did not support using ctDNA to withhold adjuvant therapy because detectable ctDNA was uncommon and assay sensitivity for subsequent events was low.

The Bottom Line

• Pembrolizumab monotherapy remains a well-supported adjuvant choice for appropriately selected patients with resected high-risk clear-cell RCC based on persistent five-year KEYNOTE-564 benefit.

• Treatment decisions should weigh recurrence risk, comorbidities, renal function after nephrectomy, and the possibility of lasting immune toxicity. Newer options such as belzutifan plus pembrolizumab may expand choices, but the added disease-free-survival benefit must be balanced against higher grade 3 or greater adverse-event rates and immature overall-survival data.

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