What is the recommended adjuvant therapy for high-risk renal cell carcinoma (RCC) patients to protect against recurrence and improve overall survival?

Adjuvant Therapy for High-Risk Renal Cell Carcinoma

Pembrolizumab is the only adjuvant therapy with proven overall survival benefit and should be strongly recommended for patients with intermediate-high or high-risk clear cell RCC following nephrectomy. 1, 2

Patient Selection Criteria

Risk Categories Eligible for Adjuvant Pembrolizumab

Intermediate-high risk patients (all must be clear cell histology, N0 M0): 1, 2

• pT2 with grade 4 nuclear features OR sarcomatoid differentiation
• pT3, any grade

High-risk patients (clear cell histology): 1, 2

• pT4, any grade, N0 M0
• Any pT stage with N+ (lymph node positive), M0
• M1 disease with no evidence of disease (NED) after complete resection of primary tumor plus soft-tissue metastases ≤1 year from nephrectomy

Critical Histological Requirement

Only clear cell renal cell carcinoma qualifies for pembrolizumab adjuvant therapy—there is no evidence of benefit for other histological subtypes. 2

Treatment Regimen

Pembrolizumab dosing: 1, 2

• 200 mg IV every 3 weeks
• 17 cycles total (approximately 1 year of treatment)
• Must initiate within 12 weeks of surgery 1
• Requires negative surgical margins 2

Evidence Supporting Pembrolizumab

The KEYNOTE-564 trial with 57.2 months median follow-up demonstrates: 1, 2

• Overall survival benefit: 38% reduction in risk of death (HR 0.62,95% CI 0.44-0.87, p=0.005)
• Disease-free survival benefit: HR 0.72 (95% CI 0.59-0.87)
• This represents the first adjuvant therapy with proven survival benefit in operable RCC 1

The 2025 European Association of Urology guidelines upgraded their recommendation from weak to strong based on these mature overall survival data. 1

Critical Safety Considerations

A significant proportion of patients experience severe or life-altering adverse events. 1, 2 You must discuss these risks thoroughly with every patient before initiating treatment, as the toxicity profile is substantial and discontinuation rates are considerable. 2

What NOT to Use

Therapies Without Overall Survival Benefit

Tyrosine kinase inhibitors (TKIs): 2, 3

• Despite FDA approval of sunitinib for adjuvant RCC 4, meta-analysis shows no OS benefit (HR 1.01,95% CI 0.91-1.12) and no DFS benefit (HR 0.92,95% CI 0.86-1.00) with high certainty of evidence 3
• Significantly increases adverse event risk without survival benefit 3

Other immune checkpoint inhibitors: 1

• Atezolizumab showed negative results in adjuvant trials
• Ipilimumab plus nivolumab showed negative results in adjuvant trials

Cytokines (interferon, high-dose IL-2): 1, 2

• No benefit in overall survival or disease-free survival in completed trials

Management After Pembrolizumab Failure

If recurrence occurs during or shortly after adjuvant pembrolizumab, do NOT use: 1, 2

• PD-1/PD-L1 immune checkpoint inhibitor monotherapy
• Combination immune checkpoint inhibitor therapy

There are no prospective trial results supporting ICI rechallenge in this setting. 1 The European Association of Urology issues a weak recommendation against using ICIs for recurrence during or after adjuvant pembrolizumab. 1

Common Clinical Pitfalls

Do not use pembrolizumab in: 2

• Non-clear cell histological subtypes
• Low-risk disease (pT1, low-grade tumors without adverse features)

Do not assume all "high-risk" patients are the same: 2

• Use the specific KEYNOTE-564 criteria for patient selection
• SSIGN score can help: ≥6 = high risk, 3-5 = intermediate risk, 0-2 = low risk

Do not delay treatment initiation: 1

• Must start within 12 weeks of surgery

Alternative for Patients Who Cannot Receive Pembrolizumab

Observation is the standard of care for high-risk patients who cannot receive or decline pembrolizumab. 2 Consider enrollment in clinical trials when available. 1, 2