As urologists, we all now recognize that when performing TURBT, we should use enhanced visualization techniques to enhance the detection and reduce the risk of recurrence of bladder tumors; this modality is now guideline-recommended and available in both outpatient and hospital settings.3-8 In 2020, its sensitivity was confirmed by an updated analysis of the prospective, multicenter Cysview registry study: Among more than 3,500 bladder lesions, 23% were detectable by blue light, but not by white light.9 However, the upfront cost of the blue light system has precluded its purchase by some hospitals and ambulatory surgery centers. This is a hurdle that needs to be overcome.
Currently, our enhanced ability to treat high-risk NMIBC (carcinoma in situ [CIS] and high-grade tumors) is hindered by the persistent and worsening bacillus Calmette-Guérin (BCG) shortage. Merck, the sole U.S. supplier of BCG, has stated that it intends to triple production by building a new manufacturing facility, but completion is expected to take several years.12 If BCG is unavailable, patients with high-risk or high-grade NMIBC have few options besides radical cystectomy, for which many are ineligible. For this reason, novel therapies are a prime area of focus. To date, most of the reported studies have focused on the BCG-unresponsive population.
In January 2020, the PD-1 inhibitor pembrolizumab became the first systemic therapy to receive FDA approval for treating NMIBC. The approval was based on the results of the single-arm, multicenter KEYNOTE-057 study, in which patients with high-risk, BCG-unresponsive NMIBC with CIS (with or without papillary tumors) who were ineligible or declined to undergo cystectomy, received intravenous pembrolizumab (200 mg every 3 weeks) for up to 24 months or until high-grade recurrence or progression. In May 2020, at the virtual ASCO meeting, investigators updated the study results covering a median follow-up time of 28.4 months.13 The overall rate of complete response (CR) was 41%, with a median duration of response of 16.2 months; in the overall efficacy analysis, 19% of patients who received pembrolizumab had a CR that exceeded 12 months.
Some have voiced concerns about the relatively low rate of durable CRs in KEYNOTE-057, especially considering pembrolizumab’s cost and potential toxicities. However, others have pointed out that some patients require months of therapy to develop a CR to an immune checkpoint inhibitor. In KEYNOTE-05, patients stopped pembrolizumab if they showed no CR at 3 months, which might have undercut the CR rate. Ongoing studies will hopefully help clarify whether longer treatment increases CR rates to a meaningful degree. In the meantime, pembrolizumab is an approved option for salvage therapy in high-risk, BCG-unresponsive NMIBC.
Novel intravesical therapies for BCG-unresponsive NMIBC are not yet approved, but data have been reported. Late last year, the FDA granted nadofaragene firadenovec fast track and breakthrough therapy designations, and a decision on its Biologics License Application (BLA) is expected this year. Nadofaragene is a non-replicating recombinant type-5 adenovirus vector-based agent that delivers a copy of the human IFNα2b gene to stimulate an innate immune response to tumor cells. In a single-arm, multicenter, phase 3 trial, patients with BCG-unresponsive NMIBC with or without CIS received nadofaragene every 3 months or until high-grade recurrence. Updated results were presented last year and covered a median follow-up time of 19.7 months.14 Among patients with CIS with or without Ta/T1 disease, CR rates were 53% at 3 months and 24% at 12 months, with a median CR duration of 9.7 months (95% CI, 9.2 months to not estimable). While these results are similar to pembrolizumab, grade 3 adverse events—including bladder spasm, micturition urgency, syncope, hypertension, and urinary incontinence—arose in only 4% of all patients.
Although this safety profile appears promising, the fact remains that only about one in four study participants experienced a durable CR to nadofaragene, which resembles the CR rate for pembrolizumab in KEYNOTE-057. As with all therapies, uptake will depend on whether long-term, clinically meaningful tumor responses outweigh any concerns about tolerability, treatment burden, or costs. It is worth noting that in 2020, the Institute for Clinical and Economic Review (ICER) reviewed data for these drugs and for the investigational intravesical agent oportuzumab monatox (which is also under review with the FDA) and concluded that while they offer a net health benefit, a lack of placebo-controlled or head-to-head trials creates “significant uncertainty around comparative benefits, and the magnitude of those benefits.”15 This is a fair assessment, but single-agent head-to-head studies of these agents might never be conducted; indeed, studies already are evaluating multimodal bladder-sparing strategies in high-risk NMIBC. On a practical note, oportuzumab monatox requires a more intensive induction phase than nadofaragene, which could sway patients toward the latter or toward pembrolizumab, if all three treatments become available.
For patients with newly diagnosed high-grade T1 NMIBC, experts continue to debate when to recommend radical cystectomy versus TURBT with intravesical BCG. The COVID-19 pandemic made this question painfully difficult—was it better to delay surgery, even if that meant exposing patients to the inherent risk of making repeated visits to a hospital or clinic to receive BCG? We can expect these dilemmas to continue into this year and possibly beyond. During the pandemic, it is especially crucial to counsel high-grade T1 patients that if they forego cystectomy, they still will require re-TURBT.
As we embark on the year 2021, I look forward to several developments. Clearly topping this list is the anticipated return to a safer environment, one in which our patients can again access their clinicians in person. However, it is vital that our patients also have access to appropriate diagnostics and therapeutics. Thus, I await the results of the S1602 study (NCT03091660), which, if positive—as many of us suspect they will be—will enable us to improve BCG access by importing another strain into the United States. I also am anticipating the approval of several of the agents discussed above and to studies of these therapies as part of combination strategies and in earlier stages of NMIBC. When we add to this the body of research on better drug delivery systems, such as heated chemotherapy or the local delivery of agents through long-lasting delivery mechanisms, it is clear that the field of study is wide open. Lastly, clinical research on muscle-invasive and metastatic bladder cancer has shed light on therapeutics such as enfortumab vedotin, an antibody-drug conjugate designed to treat cancers expressing Nectin-4, and erdafitinib, a small-molecule inhibitor of fibroblast growth factor receptor (FGFR). Based on these insights, trials of these agents in early-stage bladder cancer are only logical. Here’s to 2021!
Written by: Ashish M. Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas
Published Date: February 3, 2021
- American Cancer Society. Key Statistics for Bladder Cancer. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html Accessed January 20, 2021.
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
- Chou R, Selph S, Buckley DI, et al. Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis or surveillance of bladder cancer on clinical outcomes: systematic review and meta-analysis. J Urol. 2017;197(3 Pt 1):548-558.
- Daneshmand S, Patel S, Lotan Y, et al. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study. J Urol. 2018;199(5):1158-1165.
- Geavlete B, Jecu M, Multescu R, et al. HAL blue-light cystoscopy in high-risk nonmuscle-invasive bladder cancer--re-TURBT recurrence rates in a prospective, randomized study. Urology. 2010;76(3):664-669.
- Smith AB, Daneshmand S, Patel S, et al. Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. BJU Int. 2019;123(1):35-41.
- Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. Journal of Urology. 2016;196(4):1021-1029.
- Kamat AM, Cookson M, Witjes JA, et al. The impact of blue light cystoscopy with hexaminolevulinate (HAL) on progression of bladder cancer - a new analysis. Bladder Cancer. 2016;2(2):273-278.
- Ahmadi H, Seyedian SL, Bivalacqua TJ, et al. Role of blue light cystoscopy in detecting invasive bladder tumor: data from a multi-institutional registry. J Urol. 2020;203(supplement 4):e1125-e1125.
- Messing EM, Tangen CM, Lerner SP, et al. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018;319(18):1880-1888.
- European Association of Eurology. Guidelines: Non-Muscle Invasive Bladder Cancer. https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/?type=appendices-publications. Accessed January 24, 2021.
- American Urological Association. September 2020 Member Communication and Recommendations. https://www.auanet.org/about-us/bcg-shortage-info. Accessed January 25, 2021.
- Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non-muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. J Clin Oncol. 2020;38(15_suppl):5041-5041.
- Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117.
- Institute for Clinical and Economic Review. An Assessment of Nadofaragene Firadenovec and Oportuzumab Monatox for BCG-Unresponsive, Non-Muscle Invasive Bladder Cancer. https://icer.org/assessment/bladder-cancer-2020/. Accessed January 26, 2021.
Pembrolizumab in High-Risk, BCG Unresponsive Non-Muscle Invasive Bladder Cancer - Arjun Balar
Clinical Trial Information: NCT03091660