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Adjuvant pembrolizumab more than doubled disease-free survival (DFS) after radical surgery in patients with high-risk muscle-invasive urothelial cancer, according to new findings from the phase 3 AMBASSADOR trial.

Interim results from the randomized, open-label trial showed median DFS of 29 months for patients randomized to the pembrolizumab arm vs 14 months for patients in the observation arm, according to findings reported at the 2024 American Association of Clinical Oncology Genitourinary Cancer Symposium.

However, based on the interim findings, adjuvant pembrolizumab did not extend overall survival in this patient population.

Still, "these results support adjuvant pembrolizumab as a new therapeutic option for patients with muscle-invasive urothelial cancer at high risk of recurrence," said Andrea B. Apolo, MD, chief of the Bladder Cancer Section, Genitourinary Malignancies Branch at the Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland.

Pembrolizumab is currently approved as monotherapy and in combination with enfortumab vedotin in patients with metastatic urothelial carcinoma and Bacillus Calmette-Guérin–unresponsive high-risk muscle-invasive bladder cancer.

Standard of care for high-risk muscle-invasive urothelial cancer has been neoadjuvant platinum-based chemotherapy in those eligible for cisplatin. However, many patients are not eligible for cisplatin or have persistent muscle-invasive disease after platinum-based chemotherapy and surgery, Apolo noted.

AMBASSADOR assessed the use of pembrolizumab in the adjuvant setting among patients with high-risk muscle-invasive urothelial cancer. Patients were enrolled between September 2017 and August 2021 at multiple centers across the United States, but enrollment was closed after the US Food and Drug Administration approved nivolumab in August 2021 for the same indication.

Like pembrolizumab, nivolumab is a checkpoint inhibitor that targets and blocks programmed cell death protein 1 (PD-1) on the surface of T cells. Nivolumab was the first drug approved in this setting after demonstrating dramatically improved DFS vs placebo in high-risk muscle-invasive urothelial cancer.

The AMBASSADOR trial enrolled patients with histologically confirmed muscle-invasive disease of the bladder, upper tract, or urethra. More than 60% of patients overall had received neoadjuvant therapy, and nearly 60% had a positive programmed death-ligand 1 (PD-L1) status.

Overall, 354 patients were randomized to adjuvant pembrolizumab at a dose of 200 mg every 3 weeks for 1 year, and 348 were randomized to the observation arm. Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior neoadjuvant platinum-based chemotherapy. Median follow-up was 22.3 months for DFS and 36.9 months for overall survival.

Although patients receiving adjuvant pembrolizumab had twofold higher DFS (hazard ratio [HR], 0.69), these patients did not demonstrate an overall survival benefit at the 36.9-month follow-up. At the follow-up, overall survival was 50.9 months in the treatment group vs 55.8 months in the observation group (HR, 0.98; 95% CI, 0.76-1.26; P = .88).

The lack of overall survival benefit may be explained by the fact that more than 20% of patients in the observation arm received a checkpoint inhibitor, Apolo said.

Findings for both DFS and overall survival were consistent across patient subgroups.

Patients positive for PD-L1 had longer overall DFS following pembrolizumab — 32.8 months vs 20.7 months — but the PD-L1 status did not predict response to therapy. Patients negative for PD-L1 who received pembrolizumab also had notably higher DFS than those in the observation arm — 22.1 months vs 9.1 months.

Grade 3 or higher adverse events were observed in 48% of patients receiving pembrolizumab vs 32% of those in the observation arms. The most common treatment-related adverse events in the pembrolizumab arm were fatigue, pruritus, diarrhea, hypothyroidism, and rash.

The final analysis will include updated DFS and overall survival findings as well as circulating tumor DNA analyses to assess potential markers for better patient selection, Apolo said.

Invited discussant Max Kates, MD, called the AMBASSADOR study a "disruptor" and "tiebreaker" study because it is practice-changing and the second trial to show a DFS benefit with adjuvant immune checkpoint inhibition in this patient population. Another previous study — IMvigor010 — showed no DFS benefit with the PD-1 inhibitor atezolizumab (Tecentriq, Genentech) as adjuvant therapy in the same setting, explained Kates, an assistant professor of urology and director of the Bladder Cancer Program at Johns Hopkins University, Baltimore, Maryland.

Unanswered questions about the use of adjuvant pembrolizumab in high-risk muscle-invasive urothelial cancer remain, Kates said. For instance, do all patients with high-risk features need adjuvant therapy? Which adjuvant therapy is best and in which patients? How long should patients receive either pembrolizumab or nivolumab?

Kates pointed to the need for predictive biomarkers to help answer these questions and guide treatment decisions.

The AMBASSADOR trial is supported by the NCI and led and conducted by the Alliance for Clinical Trials in Oncology and the National Clinical Trials Network as part of a collaboration between Merck and the NCI. Apolo reported no disclosures. Kate reported honoraria from Astellas Pharma and consulting or advisory roles for Astellas Pharma, Genesis Biotechnology Group, Merck, Nanology, Pacific Edge, and Photocure.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.