Intravesical Delivery of Anti–PD-1 Antibodies Explored in NIMBC

Targeted Therapies in OncologyJanuary 2022
Volume 11
Issue 1
Pages: 43

Investigation of intravesical checkpoint-targeted therapy may warrant further investigation in patients with BCG-unresponsive bladder cancer.

Using intravesical checkpoint-targeted therapy was shown to be safe and resulted in clinical responses in a phase 1 trial (NCT02808143) that evaluated pembrolizumab (Keytruda) and BCG in patients who were unresponsive to BCG with non–muscle invasive bladder cancer (NMIBC). Joshua J. Meeks, MD, PhD, an associate professor at Northwestern University Feinberg School of Medicine, discussed the maximum tolerated dose (MTD) that resulted in dose-limiting toxicities (DLTs) during a poster presentation of the data at the 22nd Annual Meeting of the Society of Urologic Oncology.1

After a median follow-up of 33.4 months, the MTD was not reached, but 1 case of grade 2 diarrhea was reported, which lasted for 21 days, and required expansion of the second dose level. Investigators said the patient reached 52 weeks without recurrence.

The use of anti–PD-1 therapy is approved for the treatment of BCG-unresponsive NMIBC. Although intravesical administration of anti–PD-1 antibodies has not been tested, like systemic function it could provide similar or improved antitumor activity with less toxicity. However, to date no study has investigated the safety and efficacy of intravesical checkpoint immunotherapy.

The trial followed a 3 + 3 dose-escalation design which evaluated pembrolizumab at 1-, 2-, 5-, and 10-mg/kg. Nine patients received a single dose of pembrolizumab at week –2 for safety, and DLT was monitored during induction therapy when BCG was also administered between August 2017 and November 2019. Cohort 1 (n = 3) received pembrolizumab at 1 mg/kg and 50 mg BCG. Cohort 2 (n = 6) received 2 mg/kg and 50 mg BCG.

During the maintenance phase, beginning 2 weeks after the last dose of BCG, patients received pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then received pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

To be included in the trial, patients had to have a histologically documented recurrence of NMIBC, have persistent high-grade disease or be BCG refractory, have an ECOG performance status of 0 to 2, and have received 1 course of induction treatment with BCG.

The trial was stopped due to COVID-19.

Overall, 41 of 42 adverse events (AEs) were grade 1 to 3 and 15 were related to pembrolizumab (all grade 1). Six severe serious AEs occurred, with one at grade 5. All 9 patients recurred, with 6-month and 1-year recurrence-free rates of 66% and 33%. Progression occurred in 56% of patients, including 4 with extravesical disease (ie, 1 pelvis, 2 with upper tract urothelial cancer, 1 prostate). Three patients died, 2 from bladder cancer and 1 from myasthenia gravis. No serum levels of pembrolizumab were detected.

Intravesical pembrolizumab was well tolerated and, although not a primary objective, the investigators found reasonable rates of recurrence in this high-risk population. Despite intravesical delivery and no detection of systemic pembrolizumab, 1 patient had a grade 2 DLT and 1 had a grade 5 severe AE.

Investigation of intravesical checkpoint-targeted therapy may warrant further investigation in patients with BCG-unresponsive bladder cancer, the investigators wrote.


Meeks JJ, Cooley LF, Choy B, et al. Safety and efficacy of first-in-human phase I study of intravesical pembrolizumab and BCG in BCG-unresponsive non–muscle invasive bladder cancer. Poster presented at: 22nd Annual Meeting of the Society of Urologic Oncology; December 1-3, 2021; Orlando, FL. Accessed December 15, 2021. https://bit. ly/33lxzqz

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