First in Human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in BCG-Unresponsive Bladder Cancer

BACKGROUND. Intravenous immune checkpoint inhibition is an effective anti-cancer strategy for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) but may be associated with greater systemic toxicity compared to localized therapies. OBJECTIVE: We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG. DESIGN, SETTING AND PARTICIPANTS: A 3+3 phase I trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143). INTERVENTION: Pembrolizumab was given intravesically (1–5 mg/kg for 2 hours) beginning 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and spatial transcriptomic profiling of pre- and post- treatment tumors was conducted to identify biomarkers that correlated with response. OUTCOMES AND STATISTICAL ANALYSIS: Safety, tolerability with Kaplan-Meier survival analysis. RESULTS AND LIMITATIONS: Nine patients completed therapy. Median follow-up was 35 months for 5 patients still alive at the end of the trial. The trial was closed due to the Covid19 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-month and 1-year recurrence-free rates were 67% (95% 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 post-treatment, and transcriptomic analysis identified decreased expression of T-cell exhaustion markers in late recurrences. CONCLUSION: We demonstrate that intravesical pembrolizumab is safe, feasible and capable of eliciting strong immune responses in a clinical setting and should be investigated further PATIENT SUMMARY: Direct application of pembrolizumab to the bladder is a promising alternative for BCG-unresponsive NMIBC and should be investigated further.