What is the evidence to support the use of adjuvant immunotherapy with checkpoint inhibitors, such as pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in patients with high-risk upper tract urothelial cancer post nephroureterectomy?

Adjuvant Immunotherapy for Upper Tract Urothelial Cancer Post-Nephroureterectomy

Adjuvant immunotherapy with checkpoint inhibitors is NOT recommended as first-line therapy for upper tract urothelial carcinoma (UTUC) following nephroureterectomy, as the key trials supporting immunotherapy in urothelial carcinoma—CheckMate-274 (nivolumab) and the pembrolizumab adjuvant trial—both showed no benefit in UTUC subgroup analyses despite overall trial success. 1, 2, 3

Key Trial Evidence: CheckMate-274

The primary trial examining adjuvant immunotherapy for UTUC is CheckMate-274 (NCT02632409), a randomized, double-blind, placebo-controlled phase 3 study that included patients with high-risk urothelial carcinoma (pT3-pT4a or pN+ disease) after radical resection. 3

Trial Design and Population

• 351 patients received nivolumab 240 mg IV every 2 weeks versus 348 patients receiving placebo for up to 1 year 3
• 21% of the total population had upper tract UC (149 patients), with the majority having bladder cancer 3
• Median treatment duration was 8.8 months (range: 0 to 12.5 months) 3

Overall Trial Results (All Urothelial Carcinoma)

• Disease-free survival (DFS) improved significantly in the overall population: 20.8 months versus 10.8 months (HR not specified in overall population) 1
• DFS benefit was particularly strong in PD-L1 ≥1% subgroup 1, 3

Critical UTUC Subgroup Analysis

In exploratory subgroup analyses of patients with upper tract UC (n=149), no improvement in DFS was observed with nivolumab compared to placebo. The unstratified DFS hazard ratio was 1.15 (95% CI: 0.74,1.80), indicating numerically worse outcomes with immunotherapy. 3

• Overall survival data in UTUC subpopulation: 37 deaths occurred (20 in nivolumab arm, 17 in placebo arm), showing no survival benefit 3
• EMA approval was granted for nivolumab as adjuvant monotherapy for muscle-invasive UC with PD-L1 >1% who decline or are unfit for chemotherapy, but this was primarily based on bladder cancer data 1, 4

Pembrolizumab Trial Evidence

A second major trial randomized 702 patients with UC (including 25% with UTUC) to adjuvant pembrolizumab versus observation after radical surgery. 1

• Overall population showed improved DFS: 29.6 months versus 14.2 months 1
• UTUC subgroup analysis revealed no benefit from adjuvant pembrolizumab, mirroring the CheckMate-274 findings 1, 2

Comparative Efficacy: Chemotherapy Superior to Immunotherapy

Network meta-analysis demonstrates that adjuvant platinum-based chemotherapy yields superior oncological benefit over immune checkpoint inhibitors in UTUC patients treated with radical surgery. 1, 2

The POUT trial (phase 3 RCT) established adjuvant platinum-based chemotherapy as the standard of care, showing significant disease-free survival benefit in pT2-T4 and/or pN+ UTUC that likely translates to overall survival improvement. 2, 5

Current Guideline Recommendations

European Association of Urology (2025)

The EAU recommends adjuvant platinum-based chemotherapy over neoadjuvant treatment for high-risk UTUC (pT2-T4 and/or pN+ disease) after radical nephroureterectomy, based on level I evidence. 2

Adjuvant immunotherapy should only be considered for cisplatin-ineligible patients with PD-L1 >1% who decline or cannot receive chemotherapy, acknowledging the limited UTUC-specific benefit. 2, 4

Real-World Evidence Confirms Lack of Benefit

Recent real-world data from the ROBUUST 2.0 collaborative group (2025) examined 75 patients receiving adjuvant immunotherapy (including nivolumab, pembrolizumab, atezolizumab) matched to 68 patients without adjuvant therapy. 6

• Multivariable analysis revealed adjuvant immunotherapy was not associated with improved urothelial recurrence-free survival, non-urothelial recurrence-free survival, or overall survival 6
• Pathologic nodal involvement (HR 7.52, p < 0.001) was the only independent predictor of worse OS, not immunotherapy receipt 6

A single-institution Japanese study (2025) of 11 UTUC patients receiving adjuvant nivolumab showed modest outcomes with 2-year disease-free survival of only 40.9%, though overall survival was 79.5%. 7

Clinical Decision Algorithm

Step 1: Confirm High-Risk Pathology

• Obtain final pathology showing pT2-T4 and/or pN+ and/or lymphovascular invasion (LVI+) 2, 5

Step 2: Assess Cisplatin Eligibility

• Evaluate renal function immediately post-nephroureterectomy as it declines rapidly, creating a narrow window for cisplatin eligibility 2, 4
• Cisplatin-eligible criteria: GFR ≥60 mL/min, adequate hearing, no significant neuropathy, ECOG 0-1 2

Step 3: First-Line Recommendation

• If cisplatin-eligible: offer adjuvant platinum-based chemotherapy (gemcitabine + cisplatin regimen) 2, 5, 4
• Do NOT offer adjuvant immunotherapy as first-line therapy given lack of UTUC-specific benefit 1, 2, 3

Step 4: Second-Line Consideration (Cisplatin-Ineligible Only)

• If cisplatin-ineligible AND PD-L1 ≥1%: consider adjuvant nivolumab or pembrolizumab only after patient counseling about limited UTUC-specific evidence 2, 4, 3
• If cisplatin-ineligible AND PD-L1 <1%: observation is reasonable given lack of proven benefit 3

Critical Pitfalls to Avoid

Do not extrapolate bladder cancer immunotherapy data directly to UTUC. Despite representing 21-25% of trial populations, UTUC subgroups consistently showed no benefit in both CheckMate-274 and the pembrolizumab trial. 1, 2, 3

Do not delay chemotherapy assessment. Renal function deteriorates rapidly post-nephroureterectomy, and waiting to assess immunotherapy response may eliminate the cisplatin window entirely. 2

Do not use carboplatin-based regimens. POUT trial subgroup analysis showed insufficient evidence for carboplatin efficacy in UTUC. 5

Do not offer immunotherapy to node-positive patients as first-line. For clinically node-positive (cN+) disease at presentation, induction chemotherapy followed by nephroureterectomy provides superior overall survival (HR = 0.58; 95% CI = 0.38–0.89; p = 0.01) compared to surgery plus adjuvant chemotherapy. 1, 2

Safety Profile from CheckMate-274

In the nivolumab arm, serious adverse reactions occurred in 30% of patients, with treatment discontinuation in 18% and treatment delays in 33%. 3

• Most common adverse reactions (≥20%): rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain, and urinary tract infection 3
• Fatal adverse reactions occurred in 1%, including pneumonitis (0.6%) 3
• Treatment-related deaths: 0.6% in the immunotherapy arm 3