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Bladder Preservation – A New Age of Sparing Bladders That Includes Immunotherapy?

Checkpoint inhibitor immunotherapy is regularly used for patients with urothelial carcinoma for many disease states now. Although the research started in the advanced disease scenarios, these immune-oncology agents have been imported earlier and earlier in the treatment paradigm. Monoclonal antibodies targeted PD-(L)1 now hold regulatory approvals in the United States for patients with metastatic disease who are 2nd-line and beyond,1 for maintenance therapy using avelumab for patients with stable disease or response after platinum chemotherapy,2 for first-line platinum-ineligible patients,3 most recently for first-line cisplatin-ineligible patients with metastatic disease using pembrolizumab in combination with enfortumab vedotin,4 for adjuvant therapy with nivolumab,5 and for BCG unresponsive non-muscle invasive bladder cancer with pembrolizumab.6

Interestingly, there is no indication for the neoadjuvant disease state for muscle invasive bladder cancer. Although, cisplatin combination chemotherapy contributes survival benefit,7 the cisplatin-ineligible population is left with no systemic therapy to improve outcomes, and fit patients generally proceed to radical cystectomy alone. In a recent Urotoday Clinical Trials Portal article, I summarized some of the key clinical trials that are open for accrual of patients with high-risk, cisplatin-ineligible muscle-invasive urothelial carcinoma.8 The vast majority of the trials highlighted in that article included an immune checkpoint inhibitor.

The rationale for use of a checkpoint inhibitor in the neoadjuvant setting derives from a couple of trials where the agent was administered in a neoadjuvant fashion prior to radical cystectomy. The ABACUS trial administered atezolizumab to patients who were ineligible for or refused neoadjuvant cisplatin combination chemotherapy. Only 1-2 cycles were administered to the 95 treated patients and the pathologic complete response rate was 31%.9 The PURE-01 trial administered 3 cycles of pembrolizumab prior to radical cystectomy and treated 50 patients. The pathologic complete response rate was 42%, with tumor downstaging to <pT2 in 54% of the population.10

An obvious area of investigation for immune checkpoint inhibitor therapy for patients with urothelial bladder cancer is in combination with radiation therapy. I have previously discussed the hope of an “abscopal effect” using radiation therapy in combination with immune-oncology therapeutic agents in a prior Clinical Trials Portal article, although that article was focused on advanced prostate cancer.11 In the situation of urothelial carcinoma, the use of radiation is commonly employed in combination with chemotherapy with the goal of bladder preservation. The foundation of this combination approach is based on the potential for synergistic effect between radiation and immune checkpoint inhibitors. For example, radiation may upregulate PD-L1 expression and release tumor antigens to facilitate antigen presentation.12,13 Additionally, it is common to have a patient who is not a fit candidate for a major surgery and/or chemotherapy. Therefore, the concept of bladder preservation with radiation, including an immune-oncology agent, yields promise when considering both biology and practical considerations.

There are a few published or presented data using immune-oncology agents with radiation. One such publication treated 8 patients with atezolizumab, concurrent radiation, and gemcitabine chemotherapy.14 However, dose reduction of atezolizumab from 1200 to 840 mg was necessary, and the trial was terminated due to 3 patients suffering grade 3 adverse events, generally gastrointestinal toxicities, 2 of which were actual dose limiting toxicities. Durvalumab was tested with radiation in the phase II BTCRC-GU15-023 trial.15 Twenty-six patients were treated with combination therapy followed by adjuvant durvalumab. A complete response rate of 54.5% was noted with a median progression-free survival of 21.8 months. Another recent abstract presented data on the use of pembrolizumab with radiation, treating 9 cisplatin-ineligible patients with cT2-4 urothelial cancer.16 Seven of 9 (77%) had a complete response by cystoscopy, cytology and histology, although one patient developed pneumonitis and another had elevation of liver function tests. A phase 2 trial of concurrent nivolumab with radiation for chemotherapy ineligible patients is ongoing and has enrolled 17 patients, with 6 of 14 demonstrating complete response.17 Another phase 2 trial combined neoadjuvant nivolumab with gemcitabine and cisplatin chemotherapy and has shown a complete response in 49% of 51 enrolled patients.18

With these early successful bladder preservation results with PD-(L)1 antibody therapy yielding some efficacy in combination with radiation for urothelial bladder cancer, it seems logical to launch additional clinical trials. Ongoing clinical trials are further exploring various combinations of immune-oncology agents with chemoradiotherapy, and some have advanced to the randomized, phase 3 setting. Below, I highlight multiple such ongoing immune-oncology with chemoradiotherapy trials for patients with localized muscle-invasive urothelial carcinoma of the bladder.

Select trials with immune-oncology and chemoradiotherapy for patients with muscle-invasive urothelial cancer

  • KEYNOTE-992 – Randomized phase 3 trial of chemoradiotherapy with or without pembrolizumab (NCT04241185)
  • INSPIRE – Phase 2 trial of chemoradiotherapy with durvalumab for those with regional lymph node involvement (NCT04216290)
  • Hellenic GU Cancer Group randomized phase 2 trial of chemoradiotherapy with or without nivolumab (NCT03993249)
  • CRIMI – Phase 1b/2 trial of mitomycin C/capecitabine chemoradiotherapy with nivolumab or nivolumab with ipilumumab (NCT03844256)
  • SWOG 1806 – Randomized phase 3 trial of chemoradiotherapy with or without atezolizumab (NCT03775265)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Bellmunt J, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-26.
  2. Powles T, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020; 383:1218-30.
  3. Balar AV, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483-92.
  4. Hoimes CJ, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol 2023; 41:22-31.
  5. Bajorin DF, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021; 384:2102-14.
  6. Balar AV, 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. Lancet Oncol 2021; 22:919-30.
  7. Grossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349:859-66.
  8. Yu EY. Cisplatinum-Ineligible Patients with Muscle-Invasive Localized Urothelial Carcinoma Still Do Not Have Good Systemic Therapy Options for Neoadjuvant Treatment. Urotoday Clinical Trials Portal; September 28, 2022. 
  9. Szabados B, et al. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. Eur Urol 2022; 82:212-22.
  10. Necchi A, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018; 36:3353-60.
  11. Yu EY. Abscopal Effect for Prostate Cancer? Does This Really Hold Promise? Urotoday Clinical Trials Portal; August 2, 2021.
  12. Wu CT, et al. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep 2016; 6:19740.
  13. Sharabi AB, et al. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol Res 2014; 3:345-55.
  14. Marcq G, et al. Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer. Int J Radiat Oncol Biol Phys 2021; 110:738-41.
  15. Joshi M, et al. Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: Results from phase II study, BTCRC-GU15-023. J Immunother Cancer 2023; 11:e006551.
  16. Gupta NK, et al. J Clin Oncol 38, no. 15_suppl.e17020 (May 25, 2020).
  17. Vaishampayan UN, et al. Ann Oncol 31, suppl 4, S596, September 2020.
  18. Kim H, et al. Cancer Res Treat 2023; 55:636-42.