Background
Phase 3 multicenter double-blind RCT; N=709 completely resected (R0) high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis); pT3/pT4/pN+ after declining/ineligible for adjuvant cisplatin, or ypT2–ypT4/pN+ after neoadjuvant cisplatin.
Interventions and follow up
Arm A: Nivolumab 240 mg IV q2wk up to 1 year
Arm B: Placebo
Primary endpoint: Disease-free survival (DFS) in ITT and in PD-L1 ≥1% subgroup
mFollow up: ~20.9 mo
Arm B: Placebo
Primary endpoint: Disease-free survival (DFS) in ITT and in PD-L1 ≥1% subgroup
mFollow up: ~20.9 mo
Results
mDFS ITT: 20.8 mo vs 10.8 mo, HR 0.70, 98.22% CI 0.55–0.90, P<.001.
6mo DFS ITT: 74.9% vs 60.3%.
mDFS PD-L1 ≥1%: NR, HR 0.55, 98.72% CI 0.35–0.85, P<.001.
6mo DFS PD-L1 ≥1%: 74.5% vs 55.7%.
mRFS (outside urothelial tract): 22.9 mo vs 13.7 mo, HR 0.72, 95% CI 0.59–0.89.
6mo RFS: 77.0% vs 62.7%.
mRFS PD-L1 ≥1%: NR, HR 0.55, 95% CI 0.39–0.79.
Subgroup: less benefit for upper-tract origin (renal pelvis n=96, HR 1.23, 95% CI 0.67–2.23; ureter n=53, HR 1.56, 95% CI 0.70–3.48) and patients without prior neoadjuvant therapy.
6mo DFS ITT: 74.9% vs 60.3%.
mDFS PD-L1 ≥1%: NR, HR 0.55, 98.72% CI 0.35–0.85, P<.001.
6mo DFS PD-L1 ≥1%: 74.5% vs 55.7%.
mRFS (outside urothelial tract): 22.9 mo vs 13.7 mo, HR 0.72, 95% CI 0.59–0.89.
6mo RFS: 77.0% vs 62.7%.
mRFS PD-L1 ≥1%: NR, HR 0.55, 95% CI 0.39–0.79.
Subgroup: less benefit for upper-tract origin (renal pelvis n=96, HR 1.23, 95% CI 0.67–2.23; ureter n=53, HR 1.56, 95% CI 0.70–3.48) and patients without prior neoadjuvant therapy.
Adverse events
Treatment-related G3+: 17.9% vs 7.2% (A vs B).
Discontinuation (treatment-related): 12.8% vs 2.0%.
Treatment-related deaths: 3 in nivolumab arm (2 pneumonitis, 1 bowel perforation).
Discontinuation (treatment-related): 12.8% vs 2.0%.
Treatment-related deaths: 3 in nivolumab arm (2 pneumonitis, 1 bowel perforation).
Conclusions
Adjuvant nivolumab significantly improved DFS and RFS vs placebo in resected high-risk muscle-invasive urothelial carcinoma, with greater benefit in PD-L1 ≥1% tumors.
Key Limitations
DFS surrogate endpoint; OS immature at primary analysis; limited benefit in upper-tract tumors and chemo-naive subgroups; optimal PD-L1 cutoff debated; relatively short follow-up.
Clinical Context
FDA approved adjuvant nivolumab for high-risk muscle-invasive urothelial carcinoma (Aug 2021), regardless of PD-L1; EMA approved for PD-L1 ≥1%. ASCO/ESMO support adjuvant nivolumab for high-risk patients post-cystectomy/nephroureterectomy; it complements neoadjuvant cisplatin-based chemotherapy in the perioperative pathway.