AMBASSADOR Sets the Stage for Adjuvant Pembrolizumab in MIUC

In the Oral Abstract Session focusing on urothelial cancer at this year’s ASCO Genitourinary Cancer Symposium held Friday January 26, 2024, in San Francisco, Dr. Andrea Apolo presented results of the AMBASSADOR Alliance A031501 trial evaluating the role of adjuvant pembrolizumab following surgical resection for muscle-invasive and locally advanced urothelial carcinoma.

Patients with high-risk muscle invasive bladder cancer (MIBC), while curable, have a generally poor prognosis. Current standard of care is based on neoadjuvant chemotherapy (NAC) followed by radical cystectomy. In spite of this intense therapy, mortality from metastatic disease is significant. Additionally, a large proportion of patients are ineligible for neoadjuvant chemotherapy. Thus, there is an unmet need for further treatment approaches. Adjuvant nivolumab has been shown to improve disease-free survival in this space. Pembrolizumab, a PD-1 inhibitor, has shown survival benefits in patients with advanced urothelial carcinoma.

The AMBASSADOR trial (NCT03244384) is an open-label randomized trial evaluating the role of adjuvant pembrolizumab. The authors enrolled patients with muscle-invasive urothelial carcinoma of the bladder, upper tract, or urethra who either received NAC followed by surgery had were found to have ≥ pT2, pN+, or positive surgical margins at the time of surgery or who had not received NAC, had ≥ pT3, pN+, or positive surgical margins at the time of surgery, and were either cisplatin-ineligible or refused adjuvant cisplatin-based therapy and. On the basis of the primary tumor location, patients could have undergone either radical cystectomy, nephrectomy, or ureterectomy.

Four to 16 weeks after surgery, patients were randomized to receive either pembrolizumab 240 mg every 3 weeks for 1 year, or observation, with stratification according to pathologic stage, central PD-L1 status, and receipt of prior NAC. The authors then followed patients to assess two primary objectives: disease-free survival (DFS) and overall survival (OS). There were a number of additional secondary objectives including DFS and OS in PD-L1-positive and -negative patients and safety with additional correlative objectives including health-related quality of life.

Based on the dual primary endpoints, the target sample size was 739 patients and 387 DFS and 320 OS events were required for final statistical analysis. While data are so far somewhat immature, Dr. Apolo presented interim results at today’s meeting.

The authors enrolled 702 patients between September 2017 and August 2021. At that time, nivolumab was approved as adjuvant therapy for these patients forcing early closure of the trial. Among the 702 patients, 354 were randomized to pembrolizumab and 348 were randomized to observation. Among these, 13% of those randomized to pembrolizumab and 22% of those randomized to observation withdrew prior to experiencing an event. Importantly, 74 patients, representing 21% of the observation arm, actually received an immune checkpoint inhibitor.

Over a median follow-up of 22.3 months for DFS, the authors observed 319 events allowing for efficacy analysis. The median DFS was 29 months (95% CI 22 – not evaluable) among those receiving pembrolizumab and 14 months (95% CI 10-20) for those receiving observation, resulting in a 31% improvement in disease free survival (hazard ratio (HR) 0.69, 95% CI 0.55–0.87; p=0.0013).

Over a median follow-up of 36.9 months for overall survival, 257 events were observed allowing for interim analysis. In patients receiving pembrolizumab, median OS was 51 months (95% CI 44 – no evaluable) while it was 56 months (95% CI 53 – not evaluable) among those who received observation (HR 0.98, 95% CI 0.76–1.26; p=0.88).

Overall, treatment with pembrolizumab was well tolerated with grade 3 or greater adverse events noted among 48% of patients receiving pembrolizumab and 32% of those in the observation arm.

Thus, Dr. Apolo concludes that, in patients with high-risk resected urothelial carcinoma, the use of adjuvant pembrolizumab was associated with statistically significant and clinically meaningful improvement in disease free survival. At this interim analysis, there was no evidence of overall survival benefit, though this may have been affected by relatively high use of immune checkpoint inhibition in the observation arm. Ongoing follow-up will provide more mature data for both DFS and OS, as well as secondary analyses including PD-L1-based subgroups and ctDNA analyses.