The efficacy of immunotherapy in high risk MIUC patients: findings from the AMBASSADOR trial

Dr Marco Gizzi, a medical oncologist at the Grand Hôpital de Charleroi and the Cliniques Universitaires Saint Luc, will present the findings of the AMBASSADOR trial at ASCO GU2024.

This randomized phase 3 trial investigated the efficacy of adjuvant pembrolizumab for one year compared to observation in patients with high-risk MIUC affecting the bladder or upper urinary tract. Eligibility criteria included ineligibility for neoadjuvant chemotherapy or persistent cancer post-neoadjuvant chemotherapy and surgery, with PT3/4 positive lymph nodes or positive surgical margins. The trial’s primary endpoints were DFS and OS, with patient stratification based on receipt of neoadjuvant chemotherapy, pathological stage, and PD-L1 status.

Pembrolizumab demonstrated a significant improvement in DFS (HR: 0.69) but did not show a positive signal in interim OS analysis (HR: 0.98). Interestingly, the benefit of pembrolizumab was consistent regardless of PD-L1 status, with PD-L1 negative patients showing the most significant improvement in DFS, contrary to current expectations.

Subgroup analysis indicated that upper urinary tract tumours derived less benefit from pembrolizumab in the adjuvant setting, aligning with observations from previous studies. Given evidence from the POUT trial demonstrating increased DFS with chemotherapy in this population, it suggests limited efficacy of immunotherapy in this subgroup.

The AMBASSADOR trial contributes to the growing body of evidence supporting the efficacy of immunotherapy in urothelial cancer by improving DFS, despite the absence of a significant OS benefit. Several factors may explain the negative OS signal, including trial design and patient withdrawals from the observation arm. Additionally, the FDA approval of nivolumab for the same indication prompted the trial’s premature termination after enrolling 96% of patients.

Currently, pembrolizumab is approved for second-line metastatic urothelial cancer and FDA-approved for non-invasive non-muscle bladder cancer that is non-responsive to BCG therapy. Positive data also support its combination with enfortumab vedotin in the first-line metastatic setting.

In conclusion, the AMBASSADOR trial underscores the efficacy of pembrolizumab in improving DFS in the adjuvant setting for high-risk MIUC, reinforcing findings from previous studies with nivolumab. Further investigations are warranted to elucidate the impact on OS outcomes.

References:

Apolo AB et al, 2024, AMBASSADOR Alliance A031501: Phase III Randomized Adjuvant Study of Pembrolizumab in Muscle-Invasive and Locally Advanced Urothelial Carcinoma Versus Observation. ASCO GU 2024 #LBA531

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