First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin

Abstract

BackgroundIntravenous immune checkpoint inhibition is an effective anticancer strategy for bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) but may be associated with greater systemic toxicity compared with localized therapies. ObjectiveWe assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG. Design, setting, and participantsA 3 + 3 phase 1 trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143). InterventionPembrolizumab was given intravesically (1–5 mg/kg for 2 h) beginning 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and spatial transcriptomic profiling of pre- and post-treatment tumors were conducted to identify biomarkers that correlated with response. Outcome measurements and statistical analysisSafety and tolerability of immune checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed. Results and limitationsNine patients completed therapy. Median follow-up was 35 months for five patients still alive at the end of the trial. The trial was closed due to the COVID-19 pandemic. Grade 1–2 urinary symptoms were common. The maximum tolerated dose was not reached; however, one dose-limiting toxicity was reported (grade 2 diarrhea) in the only patient who reached 52 weeks without recurrence. One death occurred from myasthenia gravis that was deemed potentially related to treatment. The 6-mo and 1-yr recurrence-free rates were 67% (95% confidence interval [CI]: 42–100%) and 22% (95% CI: 6.5–75%), respectively. Pembrolizumab was detected in the urine and not in blood. CD4+ T cells were significantly increased in the urine after treatment, and a transcriptomic analysis identified decreased expression of T-cell exhaustion markers in late recurrences. ConclusionsWe demonstrate that intravesical pembrolizumab is safe, feasible, and capable of eliciting strong immune responses in a clinical setting and should be investigated further. Patient summaryDirect application of pembrolizumab to the bladder is a promising alternative for non–muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin and should be investigated further.