Adjuvant pembrolizumab holds promise in bladder cancer

The phase III AMBASSADOR Alliance A031501 trial showed a statistically significant and clinically meaningful improvement in disease-free survival (DFS) with adjuvant pembrolizumab compared with observation in patients with high-risk locally advanced muscle-invasive urothelial carcinoma (MIUC) after radical surgery regardless of PD-L1 status.

“The trial met the primary efficacy endpoint of DFS and is a positive trial,” said Dr Andrea Apolo from the National Institutes of Health Clinical Center, Bethesda, Maryland, US, at ASCO GU 2024.

Pembrolizumab doubled the DFS seen in the observation arm (median 29 vs 14 months; hazard ratio [HR], 0.69; p=0.001) after a median follow-up of 22 months. “The curves separated early and remained separated at the tail-end,” noted Apolo.

Apart from the upper tract subgroup, all subgroups benefited from adjuvant pembrolizumab. According to Apolo, the upper tract subgroup needs further investigation as the magnitude of benefit is unclear. [ASCO GU 2024, abstract LBA53]

“PD-L1 status was not predictive for benefit with adjuvant pembrolizumab, but it does seem to be prognostic. PD-L1-high patients had a better prognosis in terms of DFS,” Apolo noted.

Of note was the greater benefit seen in PD-L1-negative patients in the pembrolizumab arm, Apolo noted. Nonetheless, both subgroups had a DFS benefit from adjuvant pembrolizumab regardless of PD-L1 status (median 22.1 vs 9.1 months; HR, 0.61; p=0.002 [negative] and 32.8 vs 20.7 months; HR, 0.77; p=0.091 [positive]).

OS analysis

The study did not meet the overall survival (OS) endpoint after a median follow-up of 36.9 months (median 50.9 vs 55.8 months [pembrolizumab vs observation]; HR, 0.98; p=0.88). There were also no major differences between subgroups. According to Apolo, this may have been influenced by the high number of patients in the observation arm who were receiving a checkpoint inhibitor.

OS outcomes based on PD-L1 status mirrored the effect seen in DFS, noted Apolo. “Again, PD-L1 did not discriminate patients who would benefit from adjuvant pembrolizumab in terms of OS, but it is prognostic. PD-L1-high patients had a better OS than those who were PD-L1 low.”

In the PD-L1-positive subgroup, median OS in the respective pembrolizumab and observation arms was not reached and 56.1 months. In the PD-L1-negative subgroup, the corresponding values were 43.8 and 36.7 months, respectively.

“The [OS] data continues to mature. Additional events are needed for the final analysis,” Apolo said.

A new treatment alternative

MIUC is an aggressive disease with high relapse rates. The standard of care is radical surgery with cisplatin-based neoadjuvant chemotherapy. However, many patients are cisplatin-ineligible or have persistent disease even after receiving neoadjuvant chemo, Apolo explained.

A total of 702 patients (median age 68 years, 75 percent male) were registered ≥4–16 weeks post-radical surgery. They were randomized 1:1 to pembrolizumab 200 mg Q3W for a year or observation. Most participants had muscle-invasive disease in the bladder (75 percent), followed by the upper tract (renal pelvis and ureter; 22 percent) and urethra (3 percent). About two-thirds received neoadjuvant therapy.

Overall, DFS events were over 40 percent – 41.5 percent in the pembrolizumab arm and 49.4 percent in the observation arm. For OS events, the corresponding rates were 37.0 percent and 36.2 percent, respectively.

Almost half of pembrolizumab recipients reported a grade ≥3 adverse event (AE) as opposed to only a third in the observation arm. The most common any-grade treatment-related AEs were fatigue, pruritus, diarrhoea, hypothyroidism, and maculopapular rash. Pembrolizumab was tolerable with no new safety signals.

“[Taken together,] the findings support adjuvant pembrolizumab as a new therapeutic option for patients with MIUC at high risk for recurrence,” Apolo concluded.

Apolo also highlighted that although PD-L1 positivity was associated with a better prognosis, it was not predictive for treatment efficacy. “As such, PD-L1 status should not be used to select patients for treatment.”

Additional follow-up is underway for the final DFS/OS, PD-L1 subgroup, and ctDNA analyses, as well as additional correlatives.