Extended follow-up data from the phase 3 AMBASSADOR trial (A031501) indicates that adjuvant pembrolizumab (Keytruda) continues to demonstrate a significant improvement in disease-free survival (DFS) compared to observation in patients with high-risk muscle-invasive urothelial carcinoma (MIUC). The findings, presented at the 2024 European Society for Medical Oncology (ESMO) Annual Congress and published in the New England Journal of Medicine, reinforce the role of pembrolizumab in this setting.
The AMBASSADOR trial is a phase 3, randomized, open-label, multicenter study evaluating adjuvant pembrolizumab versus observation in patients with high-risk MIUC. Patients were randomized 1:1 to receive pembrolizumab (200 mg q3W for 1 year) or observation. The dual primary endpoints were DFS and overall survival (OS).
Disease-Free Survival Results
After a median follow-up of 44.8 months (range, 0.03-70.1 months), the median DFS in the pembrolizumab arm was 29.6 months (95% CI, 20.0-40.7) compared to 14.2 months in the observation arm (95% CI, 11.0-20.2). The hazard ratio (HR) was 0.73 (95% CI, 0.59-0.90, P = .0027), indicating a statistically significant improvement in DFS with pembrolizumab.
Subgroup analysis showed a DFS benefit with pembrolizumab regardless of PD-L1 expression and lymph node status. In PD-L1-positive patients, median DFS was 36.9 months in the pembrolizumab arm (95% CI, 27.2-not reached) versus 21.0 months in the observation arm (95% CI, 13.6-53.3). In PD-L1-negative patients, median DFS was 22.1 months in the pembrolizumab arm (95% CI, 13.2-32) versus 9.0 months in the observation arm (95% CI, 6.9-15.3).
Overall Survival and Further Observations
The final analysis of the OS data has not yet been performed, as only 80% of the events have been reached, and the efficacy boundary was not crossed at the interim analysis. Notably, 34% of patients in the observation arm and 20% in the pembrolizumab arm received a non-protocol checkpoint inhibitor or withdrew consent.
Baseline characteristics showed that approximately 50% of patients in the pembrolizumab arm had lymph node-positive disease, 57.3% were PD-L1 positive, and 22.9% had upper tract urothelial carcinoma.
Clinical Implications
According to Dr. Andrea B. Apolo, medical oncologist at the National Cancer Institute, the trial supports adjuvant pembrolizumab as a therapeutic option in patients with high-risk muscle-invasive urothelial carcinoma, citing the doubling of the median disease-free survival and manageable toxicity. Common sites of recurrence included lymph nodes, lung, bone, and liver.
