Urologists, You’ll Never Walk Alone! How Novel Immunotherapy and Modern Imaging May Change the Management of Non-Muscle-Invasive Bladder Cancer - Beyond the Abstract

Management of patients with high-risk non-muscle-invasive bladder cancer (NMIBC), especially those recurring despite adequate Bacillus Calmette-Guérin (BCG) therapy, is one of the most urgent clinical unmet needs in onco-urology. Currently, there is no universally accepted standard of care for such patients, and, although radical cystectomy (RC) is strongly recommended as the preferred option by several reputed guidelines (Figure 1),1,2 many patients are either unwilling or unfit to undergo such major surgery. Moreover, even contemporary RC can be associated with high morbidity, low, still non-negligible, mortality, and reduced quality of life, and may be overtreatment for a proportion of cases.

Figure 1. Treatment options for patients with high-risk, BCG-unresponsive non-muscle-invasive bladder cancer recommended by current guidelines.

Thus, there is an increasing interest in developing agents in this patient population, which has been, in part, further fuelled by the release of guidelines from the International Bladder Cancer Group and the US Food and Drug Administration (FDA) Guidance Document on how to design clinical trials in the BCG-failure space after harmonizing definitions and endpoints.3,4 This renewed interest has also coincided with the evidence for the efficacy of the novel immune checkpoint inhibitors (ICIs) in advanced urothelial cancer.5 The use of these agents in earlier stages of the disease has been the logical next step, supported by the mounting data showing upregulation of the programmed cell death 1 and programmed cell death-ligand 1 (PD-L1) signalling pathways in BCG-unresponsive NMIBC.6 This has generated several clinical trials testing different ICIs either as single agents or in different combinations including definitive radiation therapy, which was historically considered ineffective in patients with NMIBC (Table 1). Based on the early results of the ongoing Keynote-057 trial reported for cohort A,7 on January 8, 2020, the FDA approved pembrolizumab for the treatment of patients with high-risk, BCG-unresponsive NMIBC with carcinoma in situ (CIS), with or without papillary tumours, who are ineligible for, or have elected not to undergo, RC.8 Full results for this cohort have been very recently released, with a reported promising 41% complete response rate at 3 months, and a manageable safety profile.9

Table 1. Phase II and III trials testing immune checkpoint inhibitors as single agents or in combinations for the treatment of high-risk non-muscle invasive bladder cancer (searched at clinicaltrials.gov).
BCG = Bacillus Calmette-Guerin; Cis = carcinoma in situ; CR = complete response; CRR = complete response rate; DFS = disease-free survival; EBRT = external beam radiation therapy; EFS = event-free survival; ICI = immune checkpoint inhibitor; IDO1 = indoleamine 2,3-dioxygenase 1; NMIBC = non-muscle-invasive bladder cancer; RFS = recurrence-free survival; TAR-200 = intravesical gemcitabine delivery system; TURBT = transurethral resection of bladder tumour

Additionally, novel strategies have emerged, such as intravesical combination or sequential chemotherapy, enhanced/novel device-assisted drug delivery, enhanced photodynamic therapy, gene and vaccine therapy (Table 2).10

Table 2. Phase II and III trials testing agents other than immune checkpoint inhibitors for the treatment of high-risk non-muscle invasive bladder cancer (searched at clinicaltrials.gov).
BCG = Bacillus Calmette-Guerin; Cis = carcinoma in situ; CR = complete response; CRR = complete response rate; DFR = disease-free rate; EFS = event-free survival; MMC = Mitomycin C; PFS = progression-free survival; RFR = recurrence-free rate; RFS = recurrence-free survival

All this has been running in parallel with advances in imaging for both characterization and staging of bladder cancer, with multiparametric MRI (mpMRI) emerging as one of the most promising modalities. The Vesical Imaging-Reporting And Data System (VI-RADS) has been proposed as a new standardized system aimed at discriminating NMIBC from muscle-invasive bladder cancer (MIBC), as well as monitoring treatment response.11 Specifically, VI-RADS scoring showed good accuracy in identifying patients with high-risk NMIBC who could avoid repeat transurethral resection (TUR) and in detecting those at higher risk for understaging after TUR.12 When mpMRI was tested as a tool to predict the pathological complete response to neoadjuvant pembrolizumab in patients with MIBC enrolled in the PURE-01 trial, on univariate analysis each of the three mpMRI sequences was significantly associated with pT0 status after RC.13 Additionally, the preliminary results of the BladderPath, a randomized trial comparing the standard pathway (TUR for all cystoscopy-detected bladder tumours) to a risk-stratified mpMRI-informed pathway, indicate that it may be feasible to direct patients with possible MIBC to mpMRI for staging instead of TUR, thus reducing treatment delay especially in systems where access to urologists is not well developed, and issues with operating room scheduling are common.14 While these findings seem supportive of this novel imaging modality, they require prospective validation in clinical trials to prove clinical utility before their routine use. Moreover, we urge caution when extrapolating potential advantages of mpMRI from the MIBC to the NMIBC setting.

It is in this rapidly changing landscape that urologic surgeons, who for a long time have been used to managing these patients by themselves and with limited therapies, now have access to novel treatments and a multidisciplinary team of professionals, including medical and radiation oncologists as well as functional imaging and pathology specialists.15 This paves the way to numerous unprecedented opportunities for treating providers and patients, with the potential to personalize care based on patient characteristics and preferences beyond traditional clinico-pathological features. Such collaboration creates the fertile ground for research opportunities, which should be, then, translated to clinical practice based on clinical trial results. Novel therapies are often tested in the context of metastatic disease by medical oncologists after progression on standard of care regimens. A close and synergistic collaboration between urologists and medical oncologists can help expedite testing therapies found to be effective in advanced disease in earlier disease states.

Based on the above premises, we foresee a trend towards a higher utilization of bladder-sparing treatments in patients with high-risk NMIBC. Indications for RC as primary or salvage treatment might possibly decrease, and while TUR will remain the standard surgical procedure for diagnostic, staging, and therapeutic purposes for many patients,16 it too, might be possibly spared in well-selected patients as imaging and other biomarkers continue to improve by showing higher sensitivity and specificity as well as clinical utility in prospective clinical trials.

There remain, however, several challenges in implementing the bladder-sparing paradigm in patients with high-risk NMIBC:

  1. Novel treatments might be further developed across the spectrum of the disease course, either concomitantly to BCG (in BCG-naïve or -exposed patients), or after BCG, depending on the primary or secondary resistance mechanisms. Whether the BCG-mediated immune stimulation is needed to enhance the concurrent and/or subsequent effect of novel immunotherapy agents needs further research.
  2. The currently expanding therapeutic landscape for CIS-containing BCG-unresponsive NMIBC raises the question of whether regulatory approvals of new treatments should be based on (solely) open-label phase II single-arm trials where clinical complete response rate and duration of response are the primary endpoints, or now require multi-arm randomized phase III trials.
  3. Accurate assessment of treatment response is critical. Non-invasive tests, such as sophisticated imaging (mainly mpMRI) and molecular biomarkers, hold promise but need rigorous prospective analysis before they can supplant classical “urological” examinations, such as cystoscopy with cold-cup biopsy or TUR. However, when considering the subset of high-risk patients with CIS, it appears that conventional histology is still mandatory because CIS is, by definition, a flat lesion non-visible even on current advanced imaging. The variably increasing adoption of enhanced optical cystoscopy may further add complexity to the standardized management of NMIBC, though only its consistent use in clinical trials might allow establishing its value in this context.
  4. Analysis of genomic alterations in NMIBC has revealed complex genomic patterns underlying bladder carcinogenesis, progression, and treatment resistance, with several identified possibly “actionable” pathways.17 Unfortunately, none of many candidate biomarkers has shown clinical utility yet in NMIBC. Although these biomarkers should be integrated into novel clinical trials, the level of evidence required to discern their role often remains a matter of debate. For instance, PD-L1 expression status and tumour mutational burden may currently be used for patient stratification, but not for eligibility, based on authors’ consensus.
  5. High-risk NMIBC, especially high-grade T1 disease, has a non-negligible risk of regional lymph node involvement. This could be a critical issue to consider when assessing response especially to purely intravesical treatments. Advanced imaging should further improve its accuracy for staging the disease outside the bladder, which is still suboptimal despite encouraging attempts.

In conclusion, only with the efficient cooperation of urologists with other multidisciplinary bladder cancer specialists can these challenges be surmounted, thus ushering in a new era of comprehensive evaluation and multimodal treatment of patients with NMIBC.

Written by: Gianluca Giannarini,1 Neeraj Agarwal,2 Andrea B. Apolo,3 Alberto Briganti,4,5 Petros Grivas,6 Shilpa Gupta,7 Ashish M. Kamat,8 Francesco Montorsi,4,5 Morgan Rouprêt,9 Andrea Necchi4,5,10

  1. Urology Unit, Santa Maria della Misericordia University Hospital, Udine, Italy
  2. Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
  3. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA
  4. Urology Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy
  5. Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
  6. Department of Medicine, Division of Medical Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA
  7. Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
  8. Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  9. Sorbonne University, GRC 5 Predictive Onco-Uro, AP-HP, Urology, Pitié-Salpêtrière Hospital, Paris, France
  10. Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy


  1. Babjuk M, Burger M, Comperat E, et al. EAU Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and CIS). Update April 6, 2021. Available at  https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer, accessed September 9, 2021.
  2. Flaig TW, Spiess PE, Agarwal N, et al. NCCN Guidelines on Bladder Cancer. Version 3.2021. Available at  https://www.nccn.org/professionals/physician_gls, accessed September 9, 2021.
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  4. U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry. February 2018. Available at https://www.fda.gov/media/101468/download.
  5. Andreev-Drakhlin AY, Egoryan G, Shah AY, Msaouel P, Alhalabi O, Gao J. The evolving treatment landscape of advanced urothelial carcinoma. Curr Opin Oncol 2021;33:221-230.
  6. Miyake M, Hori S, Ohnishi S, et al. Clinical Impact of the Increase in Immunosuppressive Cell-Related Gene Expression in Urine Sediment during Intravesical Bacillus Calmette-Guérin. Diseases 2019;7:44.
  7. Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). J Clin Oncol 2019;37 (no. 7_suppl):350.
  8. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer.
  9. 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. Lancet Oncol 2021;22:919-930.
  10. Kamat AM, Lerner SP, O'Donnell M, et al. Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non-muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis. Eur Urol Oncol 2020;3:318-340.
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  13. Necchi A, Bandini M, Calareso G, et al. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol 2020;77:636-643.
  14. Bryan RT, Liu W, Pirrie SJ, et al. Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study. Eur Urol 2021;80:12-15.
  15. Diamantopoulos LN, Winters BR, Grivas P, et al. Bladder Cancer Multidisciplinary Clinic (BCMC) Model Influences Disease Assessment and Impacts Treatment Recommendations. Bladder Cancer 2019;5:289-298.
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