What is the role of adjuvant pembrolizumab (programmed death receptor-1 inhibitor) in patients with resected T3N0M0 renal cell carcinoma (kidney cancer)?

Adjuvant Pembrolizumab for Resected T3N0M0 Renal Cell Carcinoma

Adjuvant pembrolizumab is strongly recommended for patients with resected T3N0M0 clear cell renal cell carcinoma, as this population meets the intermediate-high risk criteria defined in KEYNOTE-564 and has demonstrated significant overall survival benefit. 1

Evidence for Survival Benefit

The updated KEYNOTE-564 trial data with 57.2 months median follow-up provides the strongest evidence supporting this recommendation:

• Overall survival benefit: 38% reduction in risk of death (HR 0.62; 95% CI 0.44-0.87; p=0.005) 1, 2
• Disease-free survival benefit: Significant improvement versus placebo (HR 0.68; 95% CI 0.53-0.87; p=0.002) 3, 4
• Quality of life: No deterioration in QoL according to evaluable evidence 1

This represents the only adjuvant therapy for RCC demonstrating both DFS and OS benefits, distinguishing it from failed trials with tyrosine kinase inhibitors and other immune checkpoint inhibitor combinations. 5, 3

Why T3N0M0 Qualifies for Treatment

Your patient with T3N0M0 disease specifically meets the intermediate-high risk criteria from KEYNOTE-564:

• pT3, any grade, N0, M0 is explicitly included in the trial definition of intermediate-high risk 1, 2
• This staging category has demonstrated benefit from adjuvant pembrolizumab in the trial population 1, 2
• The European Association of Urology 2025 guidelines upgraded their recommendation from weak to strong based on mature OS data for this exact risk category 1

Treatment Regimen

• Dose: Pembrolizumab 200 mg IV every 3 weeks 2
• Duration: 17 cycles (approximately 1 year of treatment) 1, 2
• Timing: Initiate after nephrectomy with negative surgical margins 2

Critical Requirement: Clear Cell Histology

Pembrolizumab should only be used in clear cell RCC—there is no evidence of benefit for other histological subtypes. 1, 2 Confirm clear cell histology before initiating treatment, as this was a specific inclusion criterion in KEYNOTE-564. 1, 2

Toxicity Considerations That Must Be Discussed

While the survival benefit is significant, a substantial proportion of patients experience serious adverse events:

• Grade 3-4 treatment-related adverse events occur in a meaningful percentage of patients 1
• Life-changing or serious side effects must be explicitly discussed with every patient before treatment initiation 1
• The discontinuation rate due to toxicity is considerable, though specific rates should be reviewed with patients 2

The EAU guidelines emphasize that despite the strong recommendation, these toxicity risks require thorough informed consent discussions. 1

Contrasting Evidence and Failed Trials

It's important to recognize that other adjuvant immunotherapy trials have been negative:

• CheckMate 914 (nivolumab + ipilimumab): Failed to meet primary DFS endpoint 1, 5
• IMmotion010 (atezolizumab): Failed to meet primary DFS endpoint 1, 5
• PROSPER (perioperative nivolumab): Failed to demonstrate benefit 1, 5

This makes pembrolizumab unique as the only immune checkpoint inhibitor with proven efficacy in the adjuvant RCC setting. 5, 3 The consistency of benefit across the KEYNOTE-564 trial, including the East Asian subgroup analysis (HR for DFS 0.70; HR for OS 0.47), strengthens confidence in this recommendation. 6

Common Pitfalls to Avoid

• Do not use pembrolizumab in non-clear cell histological subtypes—benefit is only established for clear cell RCC 2
• If recurrence occurs during or shortly after adjuvant pembrolizumab, do not rechallenge with PD-1/PD-L1 inhibitors as monotherapy or combination therapy—the EAU issues a weak recommendation against this approach 1, 2
• Do not extrapolate to low-risk disease—only intermediate-high and high-risk patients as defined by KEYNOTE-564 criteria should receive treatment 2

Practical Implementation

For your T3N0M0 patient, the decision algorithm is straightforward:

1. Confirm clear cell histology from surgical pathology 2
2. Verify negative surgical margins from nephrectomy 2
3. Discuss survival benefits (38% reduction in death risk) and toxicity profile in detail 1, 2
4. If patient accepts treatment, initiate pembrolizumab 200 mg IV every 3 weeks for 17 cycles 2
5. Monitor for immune-related adverse events throughout treatment course 1

The strength of the OS benefit (HR 0.62) combined with the specific inclusion of pT3N0M0 disease in the trial makes this a clear indication for adjuvant pembrolizumab. 1, 2