Andrea Apolo, MD, National Cancer Institute, Bethesda, Maryland, discusses the results of the phase 3 AMBASSADOR Alliance AO31501 study, which evaluated adjuvant pembrolizumab among patients with high-risk muscle-invasive urothelial carcinoma after surgical resection, compared with observation.

The results of this study support the use of adjuvant pembrolizumab among patients with muscle-invasive urothelial carcinoma at a high risk for recurrence.

Transcript: 

Hi, my name is Andrea Apolo, I'm a medical oncologist at the National Cancer Institute in Bethesda, Maryland, and I presented this year at GU ASCO 2024 the results of the AMBASSADOR adjuvant study of pembrolizumab in patients with muscle-invasive urothelial carcinoma versus observation. 

The goal of this study was to assess the benefit of adjuvant checkpoint inhibitor with pembrolizumab in patients that have high risk muscle-invasive urothelial carcinoma—and what is the definition of high risk? It's patients that have persistent muscle-invasive urothelial carcinoma after receiving neoadjuvant cisplatinum-based chemotherapy, or that were not eligible to receive cisplatinum-based chemotherapy, and patients have persistent muscle invasive disease, lymph node positive disease.  We also allowed patients with positive surgical margins to enroll, which is very unique to this study. The patients were randomized to receive one year of pembrolizumab versus observation and the study had a dual primary end point of disease-free survival [DFS] and overall survival, and secondary end points of assessing DFS and overall survival [OS] in patients based on PD-L1 status.

So, 702 patients enrolled in the study that were randomized to pembrolizumab versus observation, and about 2/3 of the patients had received neoadjuvant chemotherapy, about 50% of the patients had lymph node positive disease, over 50% of the patients were PD-L1 positive. About 20% of the patients had upward track urothelial carcinoma and the findings were that there was a DFS benefit. The trial met the primary endpoint of DFS with a median DFS of 29 months versus 14 months for the patients receiving observation, with a hazard ratio of 0.69, and a median follow-up of 22 months. 

When we looked at the subgroups of patients to see if there was any increased benefit based on pathologic stage, we saw that really all stages that we enrolled had a benefit. We also looked at whether neoadjuvant chemotherapy made a difference and whether you received neoadjuvant chemotherapy or not, there was a benefit. We also looked at PD-L1 status and this was interesting in that we saw that patients that were PD-L1 high had a benefit, but patients that were PD-L1 low had even a greater benefit, so that was interesting, but regardless of PD-L1  status, adjuvant pembrolizumab had a DFS benefit. The marker was prognostic but not predictive. 

We also looked at other subgroups such as age ECOG performance status and there was a benefit toward adjuvant pembrolizumab for all of these. The upper track subgroup the magnitude of benefit was a little bit unclear compared to the bladder primary, so that's an area I think that we need to further investigate. We also looked at the interim results of the OS, and the trial did not meet the secondary end point of OS, but there were a lot of crossovers. A lot of patients in the observation arm went on to receive a checkpoint inhibitor at progression and even before progression so this could be a confounder in assessing OS but again, these are still interim results. The data continues to mature and additional events are needed for the final analysis. 

The trial met the primary endpoint of DFS. This is statistically significant, and this was regardless of PD-L1 status. The OS endpoint was not met at this interim analysis, but again, the data continues to mature. The PD-L1 status was not predictive of response, but it was prognostic and there was no new safety signals with adjuvant pembrolizumab. The patients did well, tolerated it well, and the safety profile was consistent what has been previously recorded, so I think the results of the adjuvant pembrolizumab study support adjuvant pembrolizumab as a new therapeutic option for patients with muscle-invasive urothelial carcinoma.

Source:

Apolo AB, Ballman KV, Sonpavde GP, et al. AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. Presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California. Abstract LBA 531