First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin.
Bacillus Calmette-Guérin
Bladder cancer
Clinical trial
Digital spatial profiling
Intravesical pembrolizumab
Journal
European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
02
04
2022
revised:
15
07
2022
accepted:
03
08
2022
pubmed:
26
8
2022
medline:
18
11
2022
entrez:
25
8
2022
Statut:
ppublish
Résumé
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 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.
Sections du résumé
BACKGROUND
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.
OBJECTIVE
We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG.
DESIGN, SETTING, AND PARTICIPANTS
A 3 + 3 phase 1 trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143).
INTERVENTION
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.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Safety and tolerability of immune checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed.
RESULTS AND LIMITATIONS
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
CONCLUSIONS
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 non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin and should be investigated further.
Identifiants
pubmed: 36008193
pii: S0302-2838(22)02553-2
doi: 10.1016/j.eururo.2022.08.004
pmc: PMC9669228
mid: NIHMS1838520
pii:
doi:
Substances chimiques
BCG Vaccine
0
pembrolizumab
DPT0O3T46P
Immune Checkpoint Inhibitors
0
Adjuvants, Immunologic
0
Banques de données
ClinicalTrials.gov
['NCT02808143']
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
602-610Subventions
Organisme : BLRD VA
ID : I01 BX003692
Pays : United States
Organisme : BLRD VA
ID : I01 BX005599
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
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