At the first prespecified interim analysis of the investigator-initiated phase III Alliance A031501, AMBASSADOR study, treatment with adjuvant pembrolizumab, as compared with observation, was associated with a significant prolongation of disease-free survival (DFS) in patients with high-risk muscle invasive urothelial carcinoma after radical surgery. The median DFS with adjuvant pembrolizumab was double that seen with observation.
A benefit was observed regardless of PD-L1 status, the receipt of neoadjuvant therapy, the pathological stage of the disease, or the site of the disease. Although PD-L1 status was prognostic, it was not predictive of DFS benefit and therefore, PD-L1 status should not be used to select patients for the treatment with adjuvant pembrolizumab according to Dr. Andrea B. Apolo of the Genitourinary Malignancies Branch, US National Cancer Institute (NCI) in Bethesda, MD, US and colleagues, who reported the findings at ESMO Congress 2024 along with a simultaneous publication on 14 September 2024 in The New England Journal of Medicine.
Muscle invasive urothelial carcinoma is aggressive with high rates of relapse. Although neoadjuvant cisplatin-based chemotherapy has been shown to have an overall survival (OS) benefit, many patients are not eligible for treatment or decline therapy. Furthermore, adjuvant cisplatin-based therapy prolongs DFS after radical cystectomy in patients who did not receive neoadjuvant cisplatin-based chemotherapy, but up to one third of patients are not medically fit to receive chemotherapy in the postoperative setting.
Two previous phase III randomised studies had conflicting results regarding the efficacy of adjuvant immune checkpoint inhibitors (ICIs) in patients with high-risk muscle invasive urothelial carcinoma. The IMvigor010 study randomly assigned patients with postoperative muscle invasive urothelial carcinoma to adjuvant atezolizumab or observation and did not show a treatment benefit with respect to the primary endpoint of DFS. However, the CheckMate 274 study compared adjuvant nivolumab with placebo and showed a treatment benefit with respect to the coprimary endpoints of DFS among all the patients - intention-to-treat (ITT) population, and among patients with a tumour PD-L1 expression level of 1% or more.
The OS data from the CheckMate 274 study are immature and have not crossed the prespecified interim efficacy boundaries. The results from the CheckMate 274 study with respect to DFS led to the approval of adjuvant nivolumab in the US for all patients regardless of the PD-L1 status and in EU for patients with a PD-L1 expression of 1% or more.
Pembrolizumab has been approved as monotherapy and in combination with enfortumab vedotin for the treatment of patients with metastatic urothelial carcinoma and as monotherapy for high-risk non–muscle invasive bladder carcinoma that is unresponsive to Bacille Calmette-Guérin. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle invasive urothelial carcinoma after radical surgery is unknown.
The Alliance for Clinical Trials in Oncology (Alliance) A031501, AMBASSADOR is an investigator-initiated phase III study that examined the efficacy of pembrolizumab as compared with observation in patients with high-risk muscle invasive urothelial carcinoma after radical surgery. The study investigators randomly assigned patients in a 1:1 ratio to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomisation was stratified according to pathological stage, centrally tested PD-L1 status, and previous neoadjuvant chemotherapy.
The coprimary endpoints were DFS and OS in the ITT population. The investigators considered the study to be successful if either DFS or OS was significantly longer with pembrolizumab than with observation. A total of 702 patients underwent randomisation; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of 5 July 2024, the median duration of follow-up for DFS was 44.8 months.
The median DFS was 29.6 months (95% confidence interval [CI] 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI 11.0 to 20.2) with observation (hazard ratio for disease progression or death 0.73, 95% CI 0.59 to 0.90; two-sided p = 0.003). Subgroup analyses showed similar estimates for DFS with pembrolizumab as compared with observation regardless of age, pathological stage, previously received neoadjuvant chemotherapy, and PD-L1 status.
Grade 3 or higher adverse events, regardless of attribution, occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. The adverse event profile of pembrolizumab was consistent with what has been reported previously, and no new safety concerns were noted.
In the pembrolizumab group, 26.4% of the patients had a treatment-related adverse event (TRAE). The most common TRAEs of any grade in the pembrolizumab group were fatigue (47.3%), pruritus (22.4%), diarrhoea (20.6%), and hypothyroidism (20.0%). Five grade 5 adverse events were attributed to pembrolizumab: one patient died from respiratory failure, one patient from multiorgan failure, one patient from sepsis, and two from uncertain causes. A total, 15 grade 5 adverse events were noted in the observation group. The most common adverse events of any grade reported in the observation group were fatigue (56.1%), abdominal pain (33.1%), peripheral sensory neuropathy (25.0%) and arthralgia (24.7%).
The final analysis of the OS data has not been performed since only 80% of the deaths needed for the final analysis have occurred and the efficacy boundary was not crossed at the second interim analyses. The authors commented that the approval of adjuvant nivolumab for patients with high-risk muscle invasive urothelial carcinoma led to early closure of the AMBASSADOR study and the OS results may also be diluted by the inclusion of data from patients in the observation group who received an off-protocol ICI. The higher percentage of patients in the observation group than in the pembrolizumab group who withdrew from the study means that the remaining patients in the observation group may no longer be similar to those in the pembrolizumab group.
However, the AMBASSADOR results are in line with those previously reported in the CheckMate 274 study, which showed a DFS benefit of similar magnitude. Ongoing analyses of biomarker correlatives, as well as newly developed clinical trials, are exploring whether further risk stratification can be performed to better identify patients who may benefit from adjuvant therapy.
The study was supported by grants from the NCI of the National Institutes of Health, Merck Sharp and Dohme (a subsidiary of Merck), a grant to Dr. Apolo’s Funded Research Portfolio from the NCI Intramural Program, Center for Cancer Research, and the Cancer Therapy Evaluation Program, and the supporters of the Alliance for Clinical Trials in Oncology and Alliance Foundation Trials programmes.
References
- Apolo AB, Ballman KV, Sonpavde G, et al. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. NEJM; Published online 14 September 2024. DOI: 10.1056/NEJMoa2401726
- Apolo AB, Ballman K, Sonpavde GP, et al. 1964MO Alliance A031501: AMBASSADOR study of adjuvant pembrolizumab (Pembro) in muscle-invasive urothelial carcinoma (MIUC) vs observation (Obs): Extended follow-up disease-free survival (DFS) results and metastatic (met) disease recurrence distribution. Annals of Oncology 2024;35(Suppl 2):S1135-S1136.