What is the evidence for using adjuvant nivolumab (Opdivo) in a patient with high-risk urothelial carcinoma of the bladder, specifically ypT2aN1, post radical cystectomy?

Adjuvant Nivolumab for High-Risk Urothelial Carcinoma Post-Cystectomy

For a patient with ypT2aN1 bladder urothelial carcinoma post-radical cystectomy, adjuvant nivolumab is a reasonable option if the tumor demonstrates PD-L1 expression ≥1% and the patient either declined or is unfit for platinum-based adjuvant chemotherapy, though platinum-based chemotherapy remains the preferred first-line adjuvant approach when feasible. 1, 2

Evidence Hierarchy and Primary Recommendation

The FDA has approved nivolumab for adjuvant treatment of urothelial carcinoma in patients at high risk of recurrence after radical resection. 2 The European Medicines Agency specifically approved nivolumab as monotherapy for adjuvant treatment of muscle-invasive UC in patients with tumor-cell PD-L1 expression >1% who are at high risk of recurrence after radical surgery and who decline or are unfit for adjuvant chemotherapy. 1

Your patient with ypT2aN1 disease clearly meets high-risk criteria (node-positive disease). 1, 3

CheckMate 274 Trial: The Pivotal Evidence

The phase III CheckMate 274 trial provides the strongest evidence for adjuvant nivolumab in this setting:

• Disease-free survival benefit: Median DFS was 21.9 months with nivolumab versus 11.0 months with placebo in the intention-to-treat population (HR 0.71,95% CI 0.58-0.86). 4, 3

• PD-L1 ≥1% subgroup: The benefit was substantially greater in patients with PD-L1 ≥1%, with median DFS of 55.5 months versus 8.4 months with placebo (HR 0.58,95% CI 0.42-0.79). 4

• Overall survival benefit: At 5-year follow-up, median OS was 75.0 months with nivolumab versus 50.1 months with placebo (HR 0.83,95% CI 0.67-1.02) in all patients, and HR 0.56 (95% CI 0.36-0.86) in the PD-L1 ≥1% population. 4, 3

• Cure fraction modeling: Mixture cure model analysis estimated cure fractions of 59.1-61.0% with nivolumab versus 35.9-36.4% with placebo in the PD-L1 ≥1% subgroup. 5

Critical Limitation: Bladder vs. Upper Tract Disease

The CheckMate 274 trial predominantly enrolled bladder cancer patients (approximately 75%), with only 25% having upper tract urothelial carcinoma (UTUC). 1

• Subgroup analysis revealed that UTUC patients did not appear to benefit from adjuvant nivolumab, which is a critical finding. 1, 6

• Your patient has bladder primary disease, so this limitation does not apply. The exploratory analysis specifically in muscle-invasive bladder cancer (MIBC) patients showed continued efficacy benefits irrespective of PD-L1 status. 3

Positioning Relative to Platinum-Based Chemotherapy

Platinum-based adjuvant chemotherapy remains the preferred first-line option when feasible:

• NCCN guidelines recommend adjuvant chemotherapy (category 2A) for patients with pT3 or pT4 disease or positive nodes who did not receive neoadjuvant chemotherapy. 1

• Meta-analyses show adjuvant chemotherapy provides a 23% risk reduction for death (HR 0.77,95% CI 0.59-0.99) and improved DFS (HR 0.66,95% CI 0.45-0.91), with node-positive patients deriving even greater benefit. 1

• For UTUC specifically, network meta-analysis suggested that adjuvant platinum-based chemotherapy yields superior oncological benefit over immune checkpoint inhibitors. 1, 6

Clinical Decision Algorithm for Your Patient

Step 1: Assess Platinum-Based Chemotherapy Eligibility

• Evaluate renal function, hearing, neuropathy, and performance status. 1
• If cisplatin-eligible: Offer 3-4 cycles of gemcitabine plus cisplatin or ddMVAC as first-line adjuvant therapy. 1
• Carboplatin should not be substituted for cisplatin in the adjuvant setting. 1

Step 2: If Platinum-Ineligible or Patient Declines Chemotherapy

• Obtain PD-L1 testing on the tumor specimen. 1, 2, 4
• If PD-L1 ≥1%: Offer adjuvant nivolumab 240 mg IV every 2 weeks for up to 1 year. 2, 4
• If PD-L1 <1%: Nivolumab may still be considered given ITT population benefit, but the magnitude of benefit is substantially lower. 4, 3

Step 3: Consider ctDNA Testing (Emerging Strategy)

• Post hoc exploratory analysis from CheckMate 274 showed that baseline ctDNA detection after radical surgery identified patients at highest risk of recurrence. 4
• Patients with detectable ctDNA had median DFS of only 5.0 months versus 52.1 months in those with undetectable ctDNA (HR 0.30,95% CI 0.18-0.48). 4
• In patients with detectable ctDNA, nivolumab showed substantial benefit (HR 0.35,95% CI 0.18-0.66), while those with undetectable ctDNA showed minimal benefit (HR 0.99,95% CI 0.51-1.93). 4
• This suggests ctDNA status may help tailor adjuvant therapy decisions, though this requires further validation. 4

Common Pitfalls to Avoid

Do not extrapolate bladder cancer immunotherapy data to upper tract disease: The 25% UTUC subgroup in CheckMate 274 showed no benefit from adjuvant nivolumab. 1, 6, 7 Your patient has bladder primary disease, so this concern does not apply.

Do not use nivolumab as first-line adjuvant therapy when platinum-based chemotherapy is feasible: The regulatory approval and guidelines position nivolumab for patients who decline or are unfit for chemotherapy. 1, 2

Do not delay initiation of adjuvant therapy: The CheckMate 274 trial required randomization within 120 days of radical surgery. 4 Earlier initiation is preferable to address micrometastatic disease.

Do not assume all high-risk patients benefit equally: PD-L1 expression significantly modifies treatment effect, with substantially greater benefit in PD-L1 ≥1% patients. 4, 3

Safety Profile

The 5-year follow-up data from CheckMate 274 showed no new safety signals beyond the known immune-related adverse event profile of nivolumab. 4, 3 The treatment was generally well-tolerated in the adjuvant setting.

Practical Implementation for Your Patient

Given your patient's ypT2aN1 status (node-positive disease post-neoadjuvant chemotherapy):

1. First, assess current cisplatin eligibility for adjuvant platinum-based chemotherapy, as this patient already received neoadjuvant therapy but has persistent high-risk features. 1

2. If cisplatin-ineligible or patient declines: Obtain PD-L1 testing and strongly consider adjuvant nivolumab if PD-L1 ≥1%. 1, 2, 4

3. Consider ctDNA testing if available, as detectable ctDNA would strengthen the indication for adjuvant systemic therapy. 4

4. Initiate treatment promptly (within 120 days of surgery) with nivolumab 240 mg IV every 2 weeks for up to 1 year. 2, 4