Background
Phase III, open-label RCT. 702 patients with high-risk muscle-invasive urothelial carcinoma of the bladder (MIBC) following radical cystectomy, with or without prior neoadjuvant chemotherapy. High-risk defined as ypT2–T4a or ypN+ (after neoadjuvant chemo) or pT3–T4a or pN+ (cystectomy-only patients). Tested adjuvant pembrolizumab to reduce recurrence in high-risk post-cystectomy MIBC.
Interventions and follow up
Arm A: Pembrolizumab 200mg IV q3wk × up to 18 cycles (approximately 1 year)
Arm B: Observation
Primary endpoint: Disease-free survival (DFS)
mFollow up: 36.0 mo
Arm B: Observation
Primary endpoint: Disease-free survival (DFS)
mFollow up: 36.0 mo
Results
DFS: Not reached vs 29.6 mo, HR 0.69, P=.0007
OS: Not reached vs not reached, HR 0.82, P=.13 — not significant
DFS (PD-L1 CPS ≥10): HR 0.61
DFS (PD-L1 CPS <10): HR 0.79
OS: Not reached vs not reached, HR 0.82, P=.13 — not significant
DFS (PD-L1 CPS ≥10): HR 0.61
DFS (PD-L1 CPS <10): HR 0.79
Adverse events
Overall grade ≥3: 33.4% (pembrolizumab) vs 16.9% (observation)
Immune-mediated (any grade): 43.0% vs 5.7%
Endocrine: hypothyroidism (any grade) 17.4% vs 2.2%
GI: diarrhea/colitis grade ≥3 5.3% vs 0.4%
Pulmonary: pneumonitis grade ≥3 2.1% vs 0%
Discontinuation due to AEs: 11.5%
Immune-mediated (any grade): 43.0% vs 5.7%
Endocrine: hypothyroidism (any grade) 17.4% vs 2.2%
GI: diarrhea/colitis grade ≥3 5.3% vs 0.4%
Pulmonary: pneumonitis grade ≥3 2.1% vs 0%
Discontinuation due to AEs: 11.5%
Conclusions
Adjuvant pembrolizumab significantly improved DFS after radical cystectomy in high-risk MIBC, with benefit observed across PD-L1 subgroups. OS was not significantly improved at this analysis. AMBASSADOR represents the first positive adjuvant immunotherapy trial in MIBC, offering patients an evidence-based option to reduce recurrence after surgery.
Key Limitations
Key Limitations: OS did not reach statistical significance, limiting the certainty of survival benefit. DFS is a surrogate endpoint whose correlation with OS in MIBC has been debated. AMBASSADOR allowed enrollment regardless of neoadjuvant chemotherapy use, making the population heterogeneous. Some post-cystectomy patients may benefit more from adjuvant chemotherapy (if neoadjuvant-naïve) than immunotherapy — the optimal sequencing remains unsettled. The perioperative pembrolizumab approach (NIAGARA trial) with neoadjuvant + adjuvant dosing may offer different efficacy/safety tradeoffs.
Clinical Context
AMBASSADOR established adjuvant pembrolizumab as an FDA-approved option (2024) for high-risk MIBC after cystectomy. It is distinct from NIAGARA (perioperative durvalumab + neoadjuvant chemo) and the EV-302 landscape (metastatic UC). For post-cystectomy high-risk MIBC patients who received neoadjuvant cisplatin-based chemotherapy, adjuvant pembrolizumab or observation are both options; for those who did not receive neoadjuvant therapy, adjuvant chemotherapy or pembrolizumab can be considered. The comparison between AMBASSADOR and NIAGARA approaches is an ongoing clinical debate.
References
References: Apolo AB et al, NEJM 2024