Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery experienced notable improvements in disease-free survival (DFS, the time a patient lives without signs of cancer) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) when compared with patients who underwent observation after a 45-month follow-up, study findings have shown.
Findings from the phase 3 AMBASSADOR trial were presented during the 2024 ESMO Annual Congress by Dr. Andrea B, Apolo, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.
Urothelial carcinoma, as defined by the National Cancer Institute, begins in the urothelial cells lining the urethra, bladder, ureters, renal pelvis and other organs, and almost all bladder cancers are urothelial carcinomas.
“In this setting, [Keytruda] doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm,” Apolo said during a presentation of the data in the intention-to-treat population that was published in The New England Journal of Medicine.
A total of 702 enrolled patients were randomly assigned to receive 200 milligrams of Keytruda every three weeks (354 patients) versus observation (348 patients) with dual primary end points of DFS and overall survival (OS, the time a patient lives regardless of disease status). Across both cohorts, the median age was 68 years, and the majority of patients were men (74.6%).
In the Keytruda arm, 57.3% of patients were PD-L1 positive compared with 57.8% of patients in the observation arm. In the Keytruda arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%) and urethra (1.7%) compared with the observation arm: 75.6%, 21% and 3.4%, respectively.
When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. “The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant [Keytruda],” Apolo added.
Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, “so it is hard to draw conclusions from these cohorts,” Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status (if the cancer has spread to the lymph nodes), upper tract neoadjuvant therapy, ECOG performance status (evaluating a patient’s ability to perform daily tasks) and histologic variants.
In all patients with N0 stage disease (cancer has not spread to the lymph nodes, with higher numbers indicating increasing spread to the lymph nodes), the hazard ratio (HR) for DFS was 0.53, meaning there was a 47% likelihood the disease would return compared with the observation group. In N1, the HR was 0.81, and for patients with N2/N3 stage disease, the HR was 0.71. “This was prognostic, but adjuvant Keytruda benefited all groups including N0 and N1, and N2 and N3,” she continued.
Evaluation of lymph node stage by lower tract versus upper tract demonstrated that “patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant [Keytruda], regardless of N0 or N-plus status,” Apolo said. “Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive,” Apolo continued.
The investigators reported that the most common sites of metastatic disease occurrence (702 patients) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%) and liver (18%). Apolo noted that these recurrence sites were “interesting and hypothesis-generating.”
In the primary analysis of the AMBASSADOR study, Keytruda showed a significant improvement in DFS versus observation after a 22-month follow-up.
The trial closed early due to the FDA approval of Opdivo (nivolumab) in high-risk MIUC after surgery. At that point, 34% of patients in the observation arm and 20% of patients in the Keytruda arm had received a non-protocol checkpoint inhibitor or withdrew consent. “The interim OS had been presented, although the final analysis of OS had not been performed because only 8% of events had been reached,” Apolo said.
Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with Keytruda versus observation regardless of PD-L1 expression and lymph node status.
“Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant [Keytruda] as a therapeutic option in patients with high-risk MIUC,” Apolo said.
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