First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin.
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Cited by: 18


Intravenous 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. We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG. A 3 + 3 phase 1 trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143). Pembrolizumab 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. Safety and tolerability of immune checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed. Nine 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. We demonstrate that intravesical pembrolizumab is safe, feasible, and capable of eliciting strong immune responses in a clinical setting and should be investigated further. Direct 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.


Spatial Transcriptomics
Bacillus Calmette-Guérin
Bladder cancer
Clinical trial
Digital spatial profiling
Intravesical pembrolizumab

MeSH terms

Urinary Bladder Neoplasms
Administration, Intravesical
BCG Vaccine
Immune Checkpoint Inhibitors
Neoplasm Recurrence, Local
Neoplasm Invasiveness
Adjuvants, Immunologic


Meghani, Khyati
Cooley, Lauren Folgosa
Choy, Bonnie
Kocherginsky, Masha
Swaminathan, Suchitra
Munir, Sabah S
Svatek, Robert S
Kuzel, Timothy
Meeks, Joshua J