Editor’s Note: Based on the CheckMate -274 study, nivolumab became the world’s first approved immunotherapy for adjuvant treatment of urothelial carcinoma, while the IMvigor 010 did not achieve positive DFS results, leading to the subsequent focus on ctDNA (MRD) positive patients in the IMvigor 011 study. At the recent 2024 ASCO-GU conference, the results of the pembrolizumab adjuvant therapy AMBASSADOR study were reported. This study uniquely set both DFS and OS as dual endpoints, achieving positive results for DFS, though the control group’s receipt of immunotherapy may impact the OS endpoint. “Oncology Frontier” interviewed the study’s presenter, Professor Andrea B. Apolo from the National Cancer Institute (NCI), at the conference.
Research Introduction
AMBASSADOR Alliance a 031501: A Phase III Study of Adjuvant Pembrolizumab versus Observation in Muscle-Invasive and Locally Advanced Urothelial Carcinoma (MIUC) (Abstract Number: LBA531)
Background: Muscle-Invasive Urothelial Carcinoma (MIUC) is a highly recurrent aggressive disease. Neoadjuvant platinum-based chemotherapy (NAC) is the standard treatment for patients who can tolerate cisplatin. However, many patients are unable to tolerate cisplatin or have persistent muscle-invasive disease post-NAC and surgery. This study evaluated pembrolizumab (Pembro) as adjuvant therapy for high-risk MIUC patients post-surgical resection.
Methods: The AMBASSADOR study is an open-label, randomized, phase III trial including histologically confirmed bladder, upper urinary tract, or urethral MIUC patients who: (1) received NAC and post-surgery pathology showed ≥pT2 and/or pN+ or positive margins; or (2) did not receive NAC, with post-surgery pathology showing pT3 and/or pN+ or positive margins. Participants unable to tolerate cisplatin or who refused cisplatin-based adjuvant therapy were enrolled 4 to 16 weeks post-surgery and randomized 1:1 to receive pembrolizumab (200 mg every 3 weeks for one year) or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The study had dual primary endpoints of Disease-Free Survival (DFS) and Overall Survival (OS), targeting 739 patients with final analyses requiring 387 DFS and 320 OS events. Secondary endpoints included DFS and OS evaluation in PD-L1 positive and negative patients and safety. Here, interim DFS and OS results are reported.
Results: From September 2017 to August 2021, 702 patients were randomized before the study’s early termination due to the US FDA approval of nivolumab for MIUC patients: 354 in the Pembro group and 348 in the observation group; 13.0% and 21.6% respectively withdrew without any events. In the observation group, 74 patients (21%) received checkpoint inhibitor therapy. The median follow-up times for DFS and OS were 22.3 months and 36.9 months, respectively. The DFS endpoint (based on 319 events required for interim analysis) exceeded efficacy boundaries. Median DFS for the Pembro group was 29.0 months (95%CI: 21.8–NE) compared to 14.0 months (95%CI: 9.7–20.20) for the observation group (HR 0.69, 95%CI: 0.55–0.87; P=0.001). In the interim analysis (n = 257 events), median OS for the Pembro group was 50.9 months (95%CI: 43.9–NE), compared to 55.8 months for the observation group (95%CI: 53.3–NE) (HR 0.98, 95%CI: 0.76–1.26; P=0.883). The Pembro group and the observation group experienced grade 3 or higher adverse events at rates of 48.4% and 31.8%, respectively.
Conclusion: For high-risk MIUC patients post-radical surgery, adjuvant therapy with pembrolizumab showed statistically significant and clinically meaningful improvement in DFS compared to observation. The OS endpoint may have been influenced by the use of checkpoint inhibitors in the observation group. Pembrolizumab exhibited no new safety signals. These results support the use of pembrolizumab as a new treatment option for patients at high risk of recurrence in MIUC. Further follow-up for final DFS/OS, PD-L1 subgroup, and ctDNA analysis is ongoing.
Researcher Comments
Oncology Frontier: Postoperative recurrence risk remains high for MIUC patients, with a current lack of standard adjuvant treatment protocols. Can you introduce the background and design of the AMBASSADOR study?
Dr. Andrea B. Apolo: The AMBASSADOR study design specifically addresses the recurrence issues in high-risk patients. It includes patients with muscle-invasive urothelial carcinoma of the bladder, urethra, renal pelvis, or ureter who post-surgery showed high-risk factors such as pN+ or positive margins. The trial involves patients with diverse treatment backgrounds and focuses on those post-radical surgery, assessing them based on pathologic staging, previous neoadjuvant chemotherapy, and PDL1 status. Patients were given adjuvant pembrolizumab or observed, with the study setting dual primary endpoints for DFS and OS, stratified by PD-L1 status.
Oncology Frontier: How do you evaluate the results achieved by the AMBASSADOR study?
Dr. Andrea B. Apolo: The DFS endpoint of the study showed positive results; at a median follow-up of 22 months, the median DFS for patients receiving adjuvant pembrolizumab was 29 months compared to 14 months for the control group, with a hazard ratio of 0.69. This indicates that pembrolizumab is a potential treatment option for patients with persistent disease post-surgery. This aligns with the current FDA-approved indications for nivolumab, suggesting pembrolizumab as another viable option.
Oncology Frontier: What treatment strategies do you think should be chosen in the future to provide better survival for MIUC patients?
Dr. Andrea B. Apolo: Biomarkers are key to selecting the best adjuvant treatment for patients with persistent muscle-invasive disease. Our study focuses on PD-L1 status, a marker used for prognosis but not predictive of treatment response. Therefore, developing effective biomarkers is crucial to avoid overtreatment and optimize prognostic assessments. I am particularly excited about the potential of ctDNA; we have collected ctDNA data and will analyze it in later trials.
