What is the indication for adjuvant pembrolizumab (pembrolizumab) in patients with renal cell carcinoma (RCC) who have undergone nephrectomy and are at high risk of disease recurrence?

Adjuvant Pembrolizumab for Renal Cell Carcinoma

Adjuvant pembrolizumab is strongly indicated for patients with clear cell RCC at intermediate-high or high risk of recurrence following nephrectomy, based on proven overall survival benefit. 1

Specific Patient Eligibility Criteria

Pembrolizumab 200 mg IV every 3 weeks for 17 cycles (approximately 1 year) is indicated for the following patient populations 1, 2, 3:

Intermediate-High Risk Patients

• pT2, grade 4 OR sarcomatoid differentiation, N0 M0 1, 2
• pT3, any grade, N0 M0 1, 2

High Risk Patients

• pT4, any grade, N0 M0 1, 2
• Any pT, any grade, N+ M0 1, 2

M1 No Evidence of Disease (M1 NED)

• Complete resection of primary tumor PLUS soft-tissue metastases ≤1 year from nephrectomy 1, 2, 3

Critical Histological Requirement

Only clear cell RCC histology qualifies for adjuvant pembrolizumab—there is no evidence of benefit for non-clear cell subtypes. 2, 4

Evidence Supporting This Indication

The 2025 European Association of Urology guidelines upgraded their recommendation from weak to strong based on mature KEYNOTE-564 data demonstrating 1:

• Overall survival benefit: HR 0.62 (95% CI 0.44-0.87; p=0.005) representing a 38% reduction in risk of death 1, 2
• Disease-free survival benefit: HR 0.68 (95% CI 0.53-0.87; p=0.002) at median follow-up of 57.2 months 1, 5
• No deterioration in quality of life according to evaluable evidence 1

The FDA approved pembrolizumab for adjuvant treatment of RCC patients at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions 3.

Mandatory Pre-Treatment Counseling

Before initiating pembrolizumab, you must discuss with patients that a significant proportion will experience life-changing or serious side effects. 1, 2 This counseling is mandatory despite the strong recommendation for treatment 4.

In real-world data, grade 3 or higher adverse events occurred in 26-29% of patients, with treatment discontinuation rates of 20-30% 6, 7. However, pembrolizumab demonstrates a superior toxicity profile compared to tyrosine kinase inhibitors in the adjuvant setting 7.

Critical Management Pitfalls to Avoid

Do NOT Use Pembrolizumab In:

• Non-clear cell histological subtypes 2, 4
• Low-risk disease 2

If Recurrence Occurs During or After Adjuvant Pembrolizumab:

Do NOT rechallenge with PD-1/PD-L1 inhibitors. 1, 4 Instead, use VEGF-targeted therapy such as cabozantinib, axitinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib 4.

The European Association of Urology issues a weak recommendation NOT to treat patients with recurrence under or after initiating adjuvant pembrolizumab with a subsequent PD-1/PD-L1 ICI 1.

When Pembrolizumab is Unavailable or Contraindicated

Observation is the standard of care. 4 Do not use tyrosine kinase inhibitors (sunitinib, pazopanib, or cabozantinib) in the adjuvant setting, as they have shown no overall survival benefit despite FDA approval 2, 4. Cytokines also provide no benefit 2.

Special Consideration for M1 NED Patients

Real-world data suggests that M1 NED patients demonstrate significantly lower disease-free survival compared to non-metastatic patients (log-rank p=0.025), with recurrence rates remaining high and occurring earlier than in the KEYNOTE-564 trial 6. Despite this, these patients remain eligible for adjuvant pembrolizumab per the approved indication 1, 3.

Comparative Evidence

While other adjuvant ICI trials (CheckMate 914 with nivolumab plus ipilimumab, IMmotion010 with atezolizumab) have reported negative results 1, pembrolizumab remains the only adjuvant therapy for RCC showing survival benefits 5. Network meta-analysis confirms pembrolizumab as the best treatment with regard to both DFS and OS, with the lowest likelihood of adverse events compared to TKIs 7.

Efficacy in East Asian Populations

Subgroup analysis from KEYNOTE-564 demonstrated consistent efficacy in East Asian patients (Japan, South Korea, Taiwan) with HR for DFS of 0.70 (95% CI 0.41-1.20) and HR for OS of 0.47 (95% CI 0.15-1.49), with a safety profile consistent with global results 8.