AMBASSADOR: Adjuvant Pembrolizumab in Muscle-Invasive, Locally Advanced UC

Adjuvant pembrolizumab demonstrates a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus observation for patients with high-risk muscle-invasive and locally advanced urothelial carcinoma (MIUC) after radical surgery, according to results of the AMBASSADOR Alliance A031501 study presented as a late-breaking abstract at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium.

MIUC is associated with high relapse rates, and neoadjuvant platinum-based chemotherapy (NAC) is considered the standard of care in patients who are cisplatin eligible. However, many patients are cisplatin ineligible or have persistent muscle-invasive disease after NAC followed by surgery.

Andrea B. Apolo, MD, and colleagues evaluated pembrolizumab as an adjuvant treatment option in patients with high-risk MIUC following surgical resection (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy). They designed AMBASSADOR as an open-label, randomized, phase 3 trial that enrolled 702 patients with histologically confirmed MIUC of the bladder, upper tract, or urethra. Patients had either:

• ≥pT2 and/or pN+ or positive margins at surgery following NAC
• ≥pT3 and/or pN+ or positive margins at surgery without NAC and were either cisplatin ineligible or declined adjuvant cisplatin-based therapy.

After at least 4 weeks postsurgery, patients were randomized (1:1) to receive pembrolizumab (200 mg every 3 weeks for 1 year) or observation. Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC.

The primary end points were DFS and overall survival (OS), with a target sample size of 739 patients and a requirement of 387 DFS and 320 OS events for final analysis. Researchers also evaluated for DFS and OS in PD-L1-positive and PD-L1-negative patients and assessed safety. The median follow-up was 22.3 months for DFS and 36.9 months for OS.

Dr. Apolo and colleagues reported that the DFS end point—based on 319 events needed for interim analysis—crossed the efficacy boundary; median DFS was 29.0 months (95% CI, 21.8 to not evaluable) with pembrolizumab versus 14.0 months (95% CI, 9.7-20.2) with observation (hazard ratio [HR], 0.69; 95% CI, 0.55-0.87; P=.0013).

At the interim analysis (n=257 events), median OS was 50.9 months (95% CI, 43.9 to not evaluable) versus 55.8 months (95% CI, 53.3 to not evaluable), respectively (HR, 0.98; 95% CI, 0.76-1.26; P=.88). These data may have been impacted by the 21% of patients in the observation arm receiving a checkpoint inhibitor, researchers speculated.

Grade 3 or higher adverse events occurred in 48.4% and 31.8% of patients, respectively, they added.

“Adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in DFS versus observation for high-risk MIUC patients after radical surgery,” they concluded. “These results support adjuvant pembrolizumab as a new therapeutic option for patients with MIUC with high risk for recurrence.”

Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and circulating tumor DNA analyses.