A phase 3 randomized clinical trial published in the New England Journal of Medicine on January 2, 2025 has demonstrated a significant disease-free survival benefit for adjuvant pembrolizumab compared to observation in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery.
The AMBASSADOR trial (Alliance A031501) was conducted across 246 sites in the United States and funded by the National Cancer Institute. The study aimed to evaluate the efficacy of one year of pembrolizumab versus observation in patients with high-risk muscle-invasive urothelial carcinoma of the urinary tract who had undergone radical surgery.
A total of 702 patients were enrolled and randomized 1:1 to receive either pembrolizumab 200 mg intravenously every 3 weeks for up to 18 cycles or observation. Eligible patients had confirmed muscle-invasive urothelial carcinoma or lymph node-positive disease and had undergone radical surgery 4-16 weeks prior to trial pre-registration. Those who received neoadjuvant cisplatin-based chemotherapy were required to have pathologic stage ≥ypT2 and/or ypN+ and/or microscopic positive surgical margins. Patients who did not receive neoadjuvant chemotherapy needed pathologic stage ≥pT3 and/or pN+ and/or microscopic positive surgical margins.
The study population had a median age of 68 years, was predominantly male (74.6%) and white (90.2%). The majority of tumors were in the lower urinary tract (78.1%) and 90% were pure urothelial carcinoma. 63.7% of patients had received prior neoadjuvant therapy.
At a median follow-up of 44.8 months, pembrolizumab demonstrated a statistically significant improvement in disease-free survival compared to observation. The median disease-free survival was 29.6 months in the pembrolizumab arm versus 14.2 months in the observation arm (hazard ratio 0.73; 95% CI, 0.59-0.90; p=0.0027). The disease-free survival benefit was observed across subgroups regardless of PD-L1 status, prior neoadjuvant therapy, pathologic stage, or site of disease.
Overall survival data were immature at the time of this analysis, with no significant difference observed between the arms at a median follow-up of 36.9 months. The 3-year survival rate was 60.8% with pembrolizumab versus 61.9% with observation (hazard ratio for death, 0.98; 95% CI, 0.76-1.26).
The safety profile of pembrolizumab was consistent with previous studies. Grade 3 or higher adverse events occurred in 50.7% of patients receiving pembrolizumab compared to 31.6% in the observation arm. The most common treatment-related adverse events with pembrolizumab were fatigue, pruritus, diarrhea, and hypothyroidism. Five treatment-related deaths were reported in the pembrolizumab arm.
The study had some limitations, including early closure after 96% enrollment due to the approval of adjuvant nivolumab in this setting. This may have led to higher rates of censoring and treatment crossover in the observation arm, potentially diluting the overall survival results. Additionally, Black or African American patients were underrepresented in the study population.
The authors concluded that adjuvant pembrolizumab provides a significant disease-free survival benefit compared to observation in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery. This benefit was observed regardless of PD-L1 status, suggesting PD-L1 expression should not be used to select patients for adjuvant pembrolizumab therapy.
These results align with the previously reported CheckMate 274 trial of adjuvant nivolumab, while contrasting with the negative IMvigor010 trial of adjuvant atezolizumab. The findings support the use of adjuvant PD-1 inhibition in this high-risk population.
The potential clinical impact of this study is significant, as it provides further evidence for the role of immunotherapy in the adjuvant setting for urothelial carcinoma. Pembrolizumab may offer an additional treatment option to reduce recurrence risk in patients with high-risk disease after surgery. However, the lack of mature overall survival data and the need for longer follow-up to assess long-term outcomes should be considered when integrating these results into clinical practice.
Future research may focus on identifying biomarkers beyond PD-L1 to better select patients who will derive the most benefit from adjuvant immunotherapy, as well as exploring combination strategies to further improve outcomes in this high-risk population.
References
Apolo AB, Ballman KV, Sonpavde G, et al. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2025;392(1):45-55. doi:10.1056/NEJMoa2401726
