Safe and Efficacious Therapies Urgently Needed for the Difficult to Treat Non-muscle Invasive Bladder Cancer Patient Population

A newly published systematic review and meta-analysis: 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 

A recently published meta-analysis in the European Urology Oncology journal1 identified the current scope of treatment options for non-muscle invasive bladder cancer (NMIBC) patients who face recurring disease despite BCG Therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.

Using evidence from 30 publications spanning 23 previously reported trials, the researchers describe an overall 12-month response rate across studies at 24% and show that treatment efficacy was highly variable. They also identified emerging treatments still under development that showed promising efficacy.

“With the plethora of emerging results in the BCG Unresponsive space, it is even more crucial now that we review the data critically to ascertain the best options for our patients,” first author of the systematic literature review (SLR) and Professor of Urology at MD Anderson Cancer Center Ashish Kamat, MD, told

This review addressed the need for a standard of care for NMIBC with high-grade disease despite BCG therapy. Only one drug, Valrubicin, had been previously FDA approved for this type of care before this meta-analysis began, but its efficacy is limited and response rates were not durable.

Pembrolizumab (KEYTRUDA®) was also approved by the FDA for patients with BCG-Unresponsive, High-Risk, NMIBC on January 8th of this year, according to the press release.2 It is referenced as the subject of a phase 2 trial in the review (Keynote-057).3 Ronald de Wit presented the results of the phase 2 trial at ASCO 2019

Table 1 of the paper is a summary of the clinical trials assessed in this review; it outlines each of the included studies, the treatment or drug they tested, their sample sizes and important findings such as efficacy results. One such study was a phase 2 trial led by Neal Shore, MD, FACS, on FerGene’s Nadofaragene Firadenovec in a 40 patient sample of which overall, across dosage schemes, 52.5% were refractory.4 In Table 2, reporting on efficacy outcomes, the trial is shown to have an efficacy of 57.5% in terms of patients achieving a 3-month relapse-free-survival (RFS) rate. 

A phase 3 trial of nadofaragene firadenovec for patients with NMIBC post-BCG was also announced to have met its primary endpoint at the 20th annual Society of Urologic Oncology meeting in December of 2019. At the time, Dr. Shore said, “These robust clinical results further demonstrate the potential of nadofaragene firadenovec as a valuable treatment option for NMIBC patients.”5 Colin Dinney, MD, who helmed the SUO-CTC Phase 3 study, reported the results as SUO 2019, sharing the phase 3 clinical trial results for the treatment (Adstiladrin®) in BCG unresponsive NMIBC. 

Other trials of nadofaragene firadenovec were also analyzed by Dr. Kamat and his colleagues. 

In order to acquire this range of data spanning many trials, a systematic review of the MEDLINE, Embase, and the Cochrane Controlled Register of Trials was done selecting trials that were published between January 2007 and June 2019 and were of relevance to this patient population.  They also searched conference databases for proceedings released between January 2016 and June 2019.

As part of the researchers concluding remarks, they note how various study design factors impact treatment decisions, including the convenience and frequency of administration of treatments. 

The review of these data sets allowed for an assessment of the most efficient or effective way to run trials for this disease. The study authors found substantial heterogeneity across trials for endpoint definition. Even when a complete response (CR) was the most often used endpoint, however, the time points varied substantially. 

"The FDA now recommends CR as the primary efficacy endpoint in patients with Carcinoma In-situ (CIS) at the initiation of therapy, and stipulates that patients should be followed every 3 mo for the first 2 yr, then every 6 mo for 2 yr, and annually thereafter. The International Bladder Cancer Group recommends using CR for CIS and RFS for papillary tumors and reporting outcomes at 6, 12, and 18 mo from treatment initiation,” the authors wrote in the manuscript. 

“The large variability observed in the literature evaluating treatments in both the clinical trial and the real-world setting also highlights the need for consistent endpoint reporting for both safety and efficacy outcomes, as well as standardized patient population definitions,” the authors wrote in the manuscript. The analysis shows how existing variability in trials and reporting mechanisms demonstrates the need for continuity in future clinical trial designs. 

“There is a high unmet need for efficacious treatments to improve clinical outcomes in patients with NMIBC that recurs after initial induction BCG,” the authors stated in the conclusion portion of the paper. 

In the paper, the authors highlight how the systematic review will help address not only this high unmet need but also the “difficult-to-treat” patient population that encompasses those with recurrent bladder cancer post-BCG treatment. 

The manuscript  concludes by noting that this meta-analysis “is the first to quantitatively assess and compare current and emerging treatments for NMIBC after BCG, and sheds light on the challenges of future NMIBC trials and the evolving treatment landscape of this disease.” 

Written by: Catherine Ryan, Brown University, Providence Rhode Island


  1. Kamat AM, 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), 
  2. Advancements in Treating NMIBC: Pembrolizumab FDA-Approved for High Risk Non-Muscle Invasive Bladder Cancer,
  3. Wit RD, Kulkarni GS, Uchio EM, et al. Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): updated follow-up from KEYNOTE-057. J Clin Oncol 2019;37 (15_suppl):4530 
  4. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNalpha/ Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol 2017;35:3410–6. 
  5. FerGene announces pivotal Phase 3 study of nadofaragene firadenovec met its primary endpoint with more than half of patients with high-grade non-muscle invasive bladder cancer (CIS ± Ta/T1) achieving a complete response at three months,
  6. Dinney CP, Fisher MB, Navai N, et al. Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for Bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. J Urol 2013;190:850–6. 

Published Date: March 2020

Written by: Catherine Ryan
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