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SAN FRANCISCO -- The use of adjuvant pembrolizumab (Keytruda) more than doubled disease-free survival (DFS) in high-risk muscle-invasive urothelial carcinoma (MIUC) after radical surgery, according to the AMBASSADOR trial.

At a median follow-up of 22.3 months, median DFS was 29.0 months (95% 21.8-not evaluable [NE]) with pembrolizumab compared with 14.0 months (95% CI 9.7-20.20) for patients who underwent observation -- an improvement of 15 months, and translating into a 31% reduced risk of disease recurrence or death (HR 0.69, 95% CI 0.54-0.87, P=0.001), reported Andrea B. Apolo, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland.

"These results support adjuvant pembrolizumab as a new therapeutic option for patients with MIUC with high risk for recurrence," Apolo said at the Genitourinary Cancers Symposium. The agent was FDA approved in for locally advanced or metastatic UC after disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.

While met the DFS endpoint, it failed to meet the second primary endpoint of overall survival (OS) in this interim analysis.

At a median follow-up of 36.9 months, the median OS was 50.9 months (95% CI 43.9‒NE) with pembrolizumab and 55.8 months (95% CI 53.3‒NE) with observation (HR 0.98, 95% CI 0.76–1.26, P=0.88).

When asked about the difference in the DFS and OS benefit seen in the trial, Apolo emphasized that the OS data are not final and that more events are needed to come to a conclusion.

In addition, "there were a lot of issues in terms of censoring," she pointed out. Specifically, more patients in the observation arm dropped out of the study versus the pembrolizumab arm (27.2% vs 17.4%).

She also noted that 22% of patients in the observation arm received a checkpoint inhibitor post-DFS event, while 5% received one pre-DFS, suggesting OS "may have been impacted by the high number of patients on the observation arm receiving a checkpoint inhibitor."

And for high-risk urothelial carcinoma in 2021 "affected the AMBASSADOR study significantly," Apolo said, adding that many of the patients in the observation arm went on get get nivolumab.

"We have data on some of the patients that did that, but not data on all of them because some of the withdrew consent," she said. "I think that's going to affect the overall outcome in terms of overall survival, even with the longer follow-up in the final analysis."

Co-investigator Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York City, noted that the 36-month OS follow-up "is a pretty early time point to be thinking about OS."

"It's not clear that it's ever going to become positive, but it is a relatively short time to really say there is no difference," he added. "We shouldn't rush to judgment quite yet, and with the methodologic problems that were induced by the nivolumab approval, I think it's an open question what we'll see as the long-term outcome."

AMBASSADOR is an open-label, randomized, phase III trial that included patients with invasive muscle disease in the bladder, urethra, renal pelvis, or ureter who had undergone radical surgery in the past 4 to 16 weeks.

The trial enrolled 702 patients who were randomized to receive pembrolizumab (200 mg IV every 3 weeks for up to 18 cycles) or undergo observation. The median age was 68 in the pembrolizumab and 69 in the observation arm, most patients were white male, and 75% had invasive bladder disease, while about 20% upper tract disease. About tw0-thirds of patients received neoadjuvant chemotherapy.

Apolo reported that a DFS benefit was seen with adjuvant pembrolizumab regardless of PD-L1 status. Patients who were PD-L1-positive had a median DFS of 32.8 months in the pembrolizumab arm versus 20.7 months in the observation arm, while those who were PD-L1 negative had a median DFS of 22.1 months and 9.1 months, respectively.

There were no new safety signals seen in in the group. Grade ≥3 adverse events occurred in 48.4% of patients receiving pembrolizumab versus 31.8% in the observation arm.

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