Intravesical pembrolizumab delivers antitumour activity in NMIBC

A recent first-in-human study has shown that directly applying pembrolizumab to the bladder is a safe and effective treatment option for patients with nonmuscle-invasive bladder cancer (NMIBC) who are unresponsive to bacillus Calmette-Guérin (BCG) treatment.

Nine patients completed the pembrolizumab-BCG treatment regimen, of whom five were still alive at the end of the phase I trial. All survivors had a recurrence over a median follow-up of 35 months. The resulting recurrence-free survival (RFS) rates were 100 percent, 67 percent, and 22 percent at 3, 6, and 12 months, respectively, with a median RFS of 6.2 months. [Eur Urol 2022;doi:10.1016/j.eururo.2022.08.004]

Progression likewise occurred in five patients, resulting in a median progression-free survival (PFS) of 36 months. PFS rates at 6 and 12 months were 100 percent and 56 percent, respectively.

Urine analysis showed that directly administering a single dose of pembrolizumab to the bladder led to a significant reduction in granulocytes (median 41-percent decrease, 95 percent confidence interval [CI], 0–60; Wilcoxon signed rank test p=0.023). Concomitantly, treatment increased levels of CD4+ (median, 18 percent, 95 percent CI, 0.2–33; p=0.023) and CD8+ (median, 12 percent, 95 percent CI, 0–14.2; p=0.015).

Comparing those with early (n=5) vs late (n=4) disease recurrence showed that patients in the latter subgroup tended to have more strongly suppressed granulocyte counts, while CD4+ and CD8+ T cells were elevated.

“Collectively, a multiomic urine analysis identified immune recruitment to the bladder following exposure to intravesical BCG and pembrolizumab,” the researchers explained.

“We are encouraged by the broad range of immune responses observed in the urine collected during trial and in the tumour tissue at the end of the trial. Changes in the immune niche are detectable in the urine as early as after one dose of pembrolizumab,” they added.

The efficacy of pembrolizumab remains dependent on tumour characteristics, as shown by the recurrences and deaths among treated patients. Future studies could explore treatment combinations to optimize treatment outcomes.

Treatment toxicities are common

In terms of safety, the researchers documented 21 instances of grade 1–2 adverse events (AE) related to BCG and/or pembrolizumab. One pembrolizumab-related grade 5 AE also arose. The most common toxicities were haematuria, occurring in 55.6 percent. This was followed by diarrhoea, fatigue, renal and urinary disorders, and urinary tract infection, all of which had incidence rates of 22.2 percent.

One patient died of treatment-related myasthenia gravis, while another encountered a dose-limiting toxicity (DLT) of diarrhoea, which lasted for 21 days.

While pembrolizumab was detected in urine samples 2 weeks before and 4 weeks after BCG initiation, the researchers found no such signals in plasma and serum samples, indicating that intravesical administration of pembrolizumab delivered treatment confined to the bladder.

“We attempted to decrease the toxicity of anti-PD1 therapy by intravesical delivery; however, two of nine patients had a DLT or a severe adverse event,” the researchers said. “Overall, intravesical administration of pembrolizumab is a promising therapeutic modality, capable of generating long-lasting antitumour immunity, and should be investigated further.”