The AMBASSADOR trial's extended follow-up data, presented at ESMO, reveal that adjuvant pembrolizumab provides a sustained and clinically meaningful improvement in disease-free survival (DFS) for patients with high-risk muscle-invasive urothelial carcinoma. This phase 3 study, evaluating pembrolizumab versus observation, demonstrates a significant advancement in treating this aggressive disease.
Sustained Disease-Free Survival
With a 45-month follow-up, the data showed a median DFS of 29.6 months in the pembrolizumab arm compared to 14.2 months in the observation arm. This represents a near doubling of DFS, underscoring the durable benefit of pembrolizumab in this setting. The study enrolled 702 patients with high-risk muscle-invasive urothelial carcinoma, defined as those who did not receive neoadjuvant cisplatin-based chemotherapy (due to ineligibility or refusal) and had pT3 or higher disease, including lymph node-positive disease, or positive surgical margins. It also included patients who received neoadjuvant cisplatin-based chemotherapy but had persistent muscle-invasive disease, positive lymph nodes, or positive surgical margins.
Impact Across Subgroups
Subgroup analyses demonstrated that the DFS benefit with pembrolizumab was consistent regardless of PD-L1 status or lymph node involvement. Patients with PD-L1 positive tumors (combined positive score ≥10%) experienced improved outcomes with pembrolizumab, but a larger delta in benefit was observed in patients with PD-L1 negative tumors. Similarly, patients with and without lymph node involvement benefited from pembrolizumab, although those without lymph node involvement at baseline experienced the best overall outcomes.
Metastatic Recurrence Patterns
The study also examined common sites of metastatic recurrence. In the observation arm, recurrences were most frequent in lymph nodes (including abdominal, chest, neck, and pelvic lymph nodes), followed by bone, liver, and lung. These findings offer insights into the natural history of urothelial carcinoma recurrence and may inform future surveillance strategies.
Challenges and Future Directions
Notably, the trial faced challenges due to unplanned crossover, with some patients in the observation arm receiving nivolumab after its FDA approval. This crossover, along with patient withdrawals, complicates the overall survival analysis. While overall survival data is not yet mature, it remains a key endpoint of interest. Dr. Apolo noted that the study is a foundation for future perioperative studies and combination therapies. She emphasized the need for biomarkers to identify patients who would benefit most from treatment, aiming to reduce overtreatment while improving outcomes for those at highest risk.
Clinical Implications
The extended follow-up data from the AMBASSADOR trial reinforce the role of adjuvant pembrolizumab as a therapeutic option for patients with high-risk muscle-invasive urothelial carcinoma. The manageable toxicity profile and significant DFS benefit support its use in this setting. As research progresses, ongoing trials are exploring combination therapies and utilizing biomarkers to refine patient selection and optimize treatment strategies in the perioperative setting.
