Intravesical Immunotherapy in the Management of NMIBC

By David Ambinder, MD - Last Updated: October 24, 2022

Does intravesical immunotherapy have a role in the management of non-muscle-invasive bladder cancer (NMIBC)? According to a recent study, there is much to be excited about regarding use of immunotherapy when patients do not respond to bacillus Calmette-Guérin (BCG). Researchers in Chicago evaluated the safety and potential efficacy of intravesical pembrolizumab when administered in conjunction with intravesical BCG.1

Currently, management for NMIBC revolves around optimal endoscopic resection and subsequent administration of intravesical BCG and, in certain situations, intravesical chemotherapy (eg, mitomycin-C). Unfortunately, many patients will not respond to BCG, and many recent studies have investigated the treatment of these patients. In 2021, intravenous pembrolizumab—a checkpoint immunotherapeutic agent that targets programmed death 1—was shown to be effective and was approved for use in BCG-unresponsive NMIBC, based on a study showing a response.2

The authors commented that “although the 3-month response was 41% (39/96), the median duration of a complete response (CR) was 16 months with 19% (18/96) complete response at 12 months. While pembrolizumab was well tolerated, 66% of patients reported an adverse event (AE), with a total of 11 serious AEs in 8 patients.” The authors noted that even though a response was seen, >80% of patients did not respond, and 2 of 3 experienced an AE.

This is what led the researchers to evaluate whether changing the route of administration would reduce the rate and severity of AEs while maintaining antitumor activity. To that point, a recent preclinical study published in the Journal of Urology using mouse models showed an increase in lymphocytic activity after the administration of intravesical immunotherapy.3 This was the backbone for this study, namely to conduct a phase 1 dose-escalation trial using increasing doses of intravesical pembrolizumab with BCG in patients unresponsive to BCG and to “report safety, toxicity, and clinical response from the first in-human clinical trial of intravesical administration of an immune checkpoint inhibitor.”

Examining Intravesical Pembrolizumab With BCG

The study was conducted at a single institution. It included patients with high-grade NMIBC who had previously been treated with 5 induction courses and 2 maintenance courses of BCG or had undergone ≥3 doses of a salvage alternative (gemcitabine and/or docetaxel). Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. The authors describe the induction course for patients in the study as a single dose of intravesical pembrolizumab at a specified dose level of 1 to 2 mg/kg at the second week before induction. This was followed by BCG 50 mg BCG from weeks 0 to 5 and intravesical pembrolizumab at weeks 0, 2, and 4. The maintenance regimen consisted only of pembrolizumab every 2 weeks until the 17th week of treatment and then every 4 weeks for the remainder of the year.

The study included 9 patients (3 treated with a starting dose of 1 mg/kg and 6 treated with a starting dose of 2 mg/kg) who were enrolled from 2016 to 2020 and followed until May 2021. The trial was closed prematurely due to the COVID-19 pandemic. Patients were evaluated at each visit and underwent endoscopic evaluation with biopsy if indicated at week 17 and then every 8 weeks from then until the end of the trial at 1 year. Recurrence was evaluated by cystoscopy with bladder biopsy, if indicated, and urine cytology. The finding of high-grade recurrence ended the treatment. After the end of the trial year, patients were followed every 3 months for 2 years.

All patients experienced a grade 1-2 AE. In total, 21 grade 1-2 AEs due to BCG and/or pembrolizumab were reported, with the most common being gross hematuria (55.6%), followed by diarrhea, fatigue, and urinary tract infection (each 22%). One patient had a grade 2 doselimiting toxicity of prolonged diarrhea. The only reported grade ≥3 or higher event reported was 1 patient who had died due to treatment-related myasthenia gravis. The authors describe the timing of symptoms as well as the management of this patient. This patient had a very high number of CD45+ cells (highest in the cohort) in the urine before treatment initiation, and the count increased over the course of the treatment.

A total of 5 patients were alive at the end of the study; the median follow-up time for those patients was 35 months. All patients ultimately experienced a recurrence, with recurrence-free survival (RFS) rates of 100%, 67%, and 22% at 3, 6, and 12 months, respectively. Median RFS was approximately 6 months. Additionally, there were 5 patients who had progression of disease. Median progression-free survival (PFS) was 36 months, and the PFS rates at 6 and 12 months were 100% and 56%, respectively. Development of locally advanced disease was seen in 4 of 9 patients, and 6 of 9 patients developed recurrence outside of the bladder. Two patients underwent radical cystectomy, 1 patient underwent nephroureterectomy, and 1 underwent a partial cystectomy with a distal ureterectomy. A total of 4 patients died during the study period.

To evaluate whether intravesical pembrolizumab remained in the urinary tract, or had systemic absorption urine and plasma pembrolizumab levels, were checked. No detectable levels of pembrolizumab were found in the bloodstream of any patient, whereas detectable pembrolizumab levels were found in the urine after week 4.

Study Results

The researchers found that when comparing the local immune environment 2 weeks before and 2 weeks after treatment with a single dose of intravesical pembrolizumab, there was a significant decrease in granulocytes and a significant increase in CD4+ and CD8+ T cells. They concluded that this “reflects at least transient changes to the microenvironment.” Urinary cytokine profiling showed levels of BCG-regulated inflammatory chemokines, including macrophage inflammatory protein-1β and monocyte chemoattractant protein-1, and cytokines, including tumor necrosis factor-Ơ and interleukin-8 increased over the course of BCG induction.

When comparing urinary immune profiles between patients with early versus late recurrence, the researchers found that there was a difference in the immune profile between the time points when patients were being administered intravesical pembrolizumab plus BCG versus BCG alone, and that in the patients with late recurrence (4 patients with a median recurrence of 12 months) compared to early recurrence (5 patients with a median recurrence of 5.3 months), there was a lower fraction of granulocytes and higher fraction of lymphocytes, including a higher count of CD4+ and CD8+ T cells.

The researchers also looked at complex spatial transcriptomic analysis and found that the “differences in clinical endpoints of BCG unresponsive tumor may be secondary to distinct pathways of the tumor or tumor microenvironment (TME), with responsive tumors showing greater T-cell infiltration with less exhaustion, while resistant tumors have increased neutrophils and a stroma-rich microenvironment.”

Although closed prematurely, this trial aimed to evaluate if intravesical BCG potentially avoiding systemic toxic and serum and plasma pembrolizumab was undetected. The authors noted that there still were significant AEs seen in 2 patients and it remains unclear if lowering the dose would reduce the risk of AEs. The patient who developed myasthenia gravis had the highest number of CD45+ cells in the urine, and the number continued to increase over the treatment period. The authors note that although this patient had a late recurrence, this enhanced immune activation may have contributed to the development of myasthenia gravis. The association of the development of BCG in older patients has been described,4 but only a handful of case reports describe the development of myasthenia gravis in patients being treated with intravenous immunotherapy.5 The study was limited by its small sample size.

Nevertheless, intravesical delivery of pembrolizumab may be a safe and viable treatment option for patients with BCG-unresponsive NMIBC, and further research should include validation in a large cohort and investigation of the correct dosage and patient selection.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

 

References

  1. Meghani K, Cooley LF, Choy B, et al. First-in-human intravesical delivery of pembrolizumab identifies immune activation in bladder cancer unresponsive to bacillus Calmette-Guérin. Eur Urol. 2022. Online ahead of print. doi: 10.1016/j.eururo.2022.08.004.
  2. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study [published correction appears in Lancet Oncol. 2021;22(8):e347]. Lancet Oncol. 2021;22:919-930. Doi: 10.1016/S1470- 2045(21)00147-9.
  3. Kirschner AN, Wang J, Rajkumar-Calkins A, Neuzil KE, Chang SS. Intravesical anti-PD-1 immune checkpoint inhibition treats urothelial bladder cancer in a mouse model. J Urol. 2021;205:1336-1343. doi: 10.1097/JU.0000000000001576.
  4. Takizawa T, Kojima M, Suzuki S, et al. New onset of myasthenia gravis after intravesical bacillus Calmette-Guérin: a case report and literature review. Medicine (Baltimore). 2017;96: e8757. doi: 10.1097/MD.0000000000008757
  5. Becquart O, Lacotte J, Malissart P, et al. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother. 2019;42:309-312. doi: 10.1097/CJI.0000000000000278
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