Pembrolizumab can be a promising option for MIUC patients after radical surgery
Dr Andrea Apolo – National Cancer Institute, Bethesda, USA
The AMBASSADOR study is a randomised phase III trial of adjuvant pembrolizumab versus observation in patients with muscle-invasive urothelial carcinoma.
What was the study design?
The study design included patients with muscle-invasive urothelial carcinoma. This is a multicentre open-label phase III randomised trial. The key eligibility included patients with muscle-invasive urothelial carcinoma of the bladder, ureter, urethra and renal pelvis. Patients must have had surgery, radical surgery, within 4-16 weeks and they could have persistent muscle-invasive disease if they received neoadjuvant chemotherapy. It must be pT2 or greater, positive lymph nodes or positive surgical margins and if they did not receive neoadjuvant chemotherapy then they had to be at least pT3 or greater, positive margins or positive lymph nodes.
The study stratified by pathologic stage, PD-L1 status and whether the patient received neoadjuvant chemotherapy. The patients were randomised to receive pembrolizumab for one year versus observation and the trial was designed with a dual primary endpoint of disease free survival and overall survival and the secondary endpoint of PD-L1 status and looking at disease free survival and overall survival.
702 patients were randomised to receive pembrolizumab versus observation and the study was well balanced. We had about two-thirds of the patients receive neoadjuvant chemotherapy. Greater than 50% of the patients had lymph node positive disease. There was a small number of patients, about 2.5%, that had positive margins and greater than 50% of the patients were PD-L1 positive by central testing using the combined positive score of 10% or greater. There was a small number of patients, about 15% of patients, that had mixed urothelial histology with variance excluding small cell. We didn’t limit the number of patients with upper tract tumours that could enrol so we had about 20% of patients with upper tract urothelial carcinoma that enrolled.
What were the results?
The study met the primary endpoint of disease free survival with a median disease free survival of 29 months for patients that received pembrolizumab versus 14 months for patients in the observation arm with a hazard ratio of 0.69 and a median follow-up of 22 months. We also looked at the subgroups and we saw that almost all subgroups benefitted with adjuvant pembrolizumab. The subgroup of upper tract urothelial carcinoma was small and the magnitude of benefit is unclear so we think we need to further explore this group.
In terms of the second primary endpoint of overall survival, the data is not yet mature but we did present the interim results and this did not meet the primary endpoint of improvement in overall survival at this point with a hazard ratio of 0.98. But the data continues to mature and more events are needed for the final analysis.
How can these results impact the treatment of urothelial cancer?
The study was positive – adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in disease free survival versus observation in this high-risk patient population of muscle-invasive urothelial carcinoma regardless of PD-L1 status. The overall survival endpoint continues to mature. These results support adjuvant pembrolizumab in this setting, in this adjuvant setting, as the new therapeutic option for patients with muscle-invasive urothelial carcinoma.
Is there anything else you would like to add?
Additional follow-up is ongoing for the disease free survival and the overall survival endpoint and we’re also doing ctDNA analysis using two different platforms – the Signatera and the FoundationOne tracker, along with additional correlatives. So we look forward to presenting the updated data once this data becomes available.