Adjuvant pembrolizumab improves DFS in high-risk muscle-invasive urothelial carcinoma

The phase III AMBASSADOR study evaluates pembrolizumab versus observation as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma (MIUC). Interim results presented at ASCO GU 2024 demonstrated that adjuvant pembrolizumab results in a statistically significant and clinically meaningful improvement in disease-free survival versus observation in patients with high-risk MIUC after radical surgery, regardless of PD-L1 status.

Muscle-invasive urothelial carcinoma (MIUC) is an aggressive tumour with a high recurrence rate. Currently, the standard of care for patients with MIUC is radical surgery with or without neoadjuvant cisplatin-based chemotherapy. However, many patients are cisplatin-eligible or have persistent muscle-invasive disease after surgery and neoadjuvant chemotherapy. Therefore, there is an unmet therapeutic need for these patients. Pembrolizumab is a checkpoint inhibitor that selectively blocks PD-1 and is approved as monotherapy and in combination with enfortumab vedotin for the treatment of patients with metastatic urothelial carcinoma and for patients with BCG-unresponsive, high-risk non-muscle invasive urothelial cancer of the bladder. In the phase III AMBASSADOR study, the efficacy and safety of adjuvant treatment with pembrolizumab versus observation was studied in patients with MIUC.

Methods

AMBASSADOR is a randomised, open-label, phase III study that enrolled patients with a histologically confirmed MIUC of the bladder, urethra, renal pelvis or ureter ≥4 to 16 weeks after radical surgery (cystectomy, nephrectomy, nephroureterectomy or ureterectomy). Eligible patients had: (a) a pathologic stage ≥T2 tumour and/or positive lymph nodes or surgical margins following neoadjuvant platinum-based chemotherapy; or (b) a pathologic stage ≥T3 tumour and/or positive lymph nodes or surgical margins and were cisplatin-ineligible or refused adjuvant cisplatin-based adjuvant therapy. Participants were randomised 1:1 to treatment with pembrolizumab (200 mg every 3 weeks for 1 year) or observation. The co-primary endpoints were disease-free survival (DFS) and overall survival (OS). Key secondary endpoints included DFS and OS in PD-L1-positive and PD-L1-negative patients and safety.

Results

In total, 702 patients were randomised before the study was prematurely closed due to US FDA approval of nivolumab for patients with MIUC. Of them, 354 patients received pembrolizumab and 348 patients were randomised to the observation arm. In total, 403 (57%) had a positive PD-L1-status. Median follow-up was 22.3 months for DFS and 36.9 months for OS.

Median DFS was 29.0 months (95% CI: 21.8-NR) in the pembrolizumab group and 14.0 months (95% CI: 9.7-20.2) in the observation group (HR [95% CI]: 0.69 [0.55-0.87], p= 0.001). In patients with a negative PD-L1-status, PFS was significantly longer in patients treated with pembrolizumab compared with those in the observation arm (median: 22.1 vs. 9.1 months; HR [95% CI]: 0.61 [0.44-0.84], p= 0.002). In patients with a positive PD-L1-status, no significant difference in PFS was found between treatment groups (median: 32.8 vs. 20.7 months; HR [95% CI]: 0.77 [0.57-1.04], p= 0.091).

At the interim analysis, median OS was 50.9 months in the pembrolizumab group and 55.8 months in the observation group (HR [95% CI]: 0.98 [0.76-1.26], p= 0.884). Furthermore, no significant difference in OS was found in both patients with a negative PD-L1-status (median: 43.8 vs. 36.7 months; HR [95% CI]: 0.83 [0.59-1.18], p= 0.297) and patients with a positive PD-L1-status (median: NR vs. 56.1 months; HR [95% CI]: 1.09 [0.77-1.54], p= 0.624).

Grade ≥3 adverse events occurred in 167 (48%) and 109 (32%) patients in the pembrolizumab and observation group, respectively. The most common pembrolizumab-related grade 3 adverse events were: increased lipase levels (3%), diarrhoea (3%), fatigue (2%), maculo-papular rash (2%), anaemia (2%), and increased serum amylase levels (2%).

Conclusions

The phase III AMBASSADOR study shows that adjuvant treatment with pembrolizumab results in a significant and clinically meaningful improvement in DFS versus observation in high-risk patients with MIUC after radical surgery. Treatment with pembrolizumab was tolerable and no new safety signals were observed. According to the researchers, these results support adjuvant pembrolizumab as a new therapeutic option for patients with MIUC and high recurrence risk.

Reference

Apolo AB, et al. AMBASSADOR Alliance A031501: phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. Presented at ASCO GU 2024; Abstract LBA531.