Trial Design Considerations for Intermediate Risk Non Muscle-Invasive Bladder Cancer

( The AUA’s Drug Development in NMIBC From Scientific, Regulatory, Clinician, and Patient Perspectives virtual meeting session on clinical dilemmas in the management of non-muscle-invasive bladder cancer (NMIBC) included a discussion of clinical trial design considerations for intermediate-risk non-muscle-invasive bladder cancer (NMIBC) by Dr. Trinity Bivalacqua. 

Dr. Bivalacqua notes that this specific subset of NMIBC revolves primarily around papillary low-grade Ta disease. Intermediate risk NMIBC according to the AUA guidelines includes:

  • Recurrence of <1 year for low-grade Ta disease
  • Solitary low-grade Ta >3cm
  • Multifocal low-grade Ta
  • High-grade Ta <3 cm
  • Low-grade T1

Intermediate risk disease standard of care treatment includes a well-performed TURBT plus perioperative chemotherapy or BCG with the goal of preventing recurrence (rare for disease progression). The 1-year recurrence rate for patients is 38%, whereas the 4-year recurrence rate is 62%.

The goals of primary treatment for intermediate-risk NMIBC are to provide the patient with intravesical chemotherapy (either mitomycin C or gemcitabine) to reduce the risk of recurrence and the need for future endoscopic procedures (ie. repetitive surgery). Dr. Bivalacqua highlights that the risk of reclassification to high-risk NMIBC is low at only 10-15% and that the current paradigm is aimed at adjuvant therapy and not primary therapy. However, Dr. Bivalacqua notes that a TURBT can be a morbid operation, especially in the highly comorbid, elderly bladder cancer population. Readmission rates may be as high as 3.7% and 30-day complication rates of grade 3 or higher may be as high as 5% for those undergoing TURBT. Furthermore, surveillance cystoscopy and TURBT are expensive and contribute to financial toxicity, as well as anesthesia necessary for repetitive procedures potentially leading to cognitive decline in the elderly. There are several therapeutic alternatives to surgery for patients with NMIBC, including delivering drugs more effectively to the bladder urothelium. For example, this incorporates improving tissue penetration facilitated by an energy source, nanoparticles, increasing the frequency of drug administration or enhancing exposure time of the urothelium to a therapeutic agent, and molecular targets such as FGFR3. 

Dr. Bivalacqua then discussed several clinical trials that are available in this disease space, including two in the primary treatment of the disease (UGN-102 and pemigatinib) and one in the adjuvant setting (ABLE-32). For decades, we have known that there are FGFR3 mutations associated with papillary urothelial carcinoma as highlighted in the following figure: 1


To this extent, pemigatinib (an FGFR inhibitor) is being tested in this disease space in the “A Phase 2 Window of Opportunity Study of Pemigatinib in Non-muscle Invasive Bladder Cancer Patients with Recurrent Low- or Intermediate-Risk Tumors (NCT03914794) Primary Treatment” trial:


Dr. Bivalacqua notes that there are several key features to this trial, including:

  • No biopsy is required, simply a cytology documenting no high-grade urothelial carcinoma; archived former tumor tissue will be collected
  • No mutation testing is required, but will be analyzed retrospectively
  • There is optional adjuvant treatment in patients with a complete response
  • Multiple translational objectives will include pre-/post-treatment PBMC TCR sequencing to understand immunologic effects in FGFR3mut and FGFR3wt patients

Published last year, the OLYMPUS trial assessed the use of UGN-101 for primary chemoablation of low-grade upper tract urothelial carcinoma.2 In this trial, there were 110 patients screened, 74 were enrolled and 71 patients received treatment. Among the 71 patients who received at least one dose, 42 patients (59%, 95% CI 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, 8 (11%) had a partial response, 12 (17%) had no response, 6 (8%) had newly diagnosed high-grade disease, and 3 (4%) had an indeterminate response. The UGN-102 ATLAS Trial is studying a differentiated therapeutic option versus standard of care surgery – a phase 3 open label primary treatment. Patients enrolled in this trial include those diagnosed with low-grade intermediate-risk NMIBC defined as one or two of the following criteria: (i) multiple tumors, (ii) solitary tumor >3 cm, and (iii) >=1 occurrence of low-grade NMIBC within 1 year of the current diagnosis. The treatment arms include UGN-102 +/- TURBT versus TURBT +/- TURBT, with a primary endpoint of disease-free survival. The trial schema for the UGN-102 ATLAS trial is as follows:


In the adjuvant setting, there has been interest in the ability to enhance immunogenicity. Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. Adenoviruses provide short-term, high but transient expression of the gene of interest in a relatively broad range of host cells. The phase III trial of nadofaragene firadenovec for BCG unresponsive NMIBC was a multi-center study to investigate the safety and efficacy of intravesical nadofaragene firadenovec 75 mL once every 3 months in 157 patients with high-grade, BCG-unresponsive NMIBC.3 The study met its primary endpoint with 53.4% of patients with CIS ±Ta/T1 achieving a complete response, all by 3 months. A key secondary endpoint was the durability of response in high-grade recurrence-free survival in patients who achieved a complete response:


The genetic landscape of NMIBC is such that CDKN2A deletion is enriched in patients with T1 disease who recur or progress, and deletions of CDKN2A are linked to the type 1 interferons, which are a common genetic alteration present in about 60% of NMIBC. Thus, the hypothesis is that a loss of IFN-signaling promotes tumor growth in tumors harboring CDKN2A deletions and thus IFN-replacement therapy with adjuvant-IFN may be effective. As such, Dr. Bivalacqua is the lead-PI of the ABLE-32 trial a “Phase 3 randomized controlled study of nadofaragene firadenovec versus observation in intermediate-risk non-muscle-invasive bladder cancer patients.” The primary endpoint for this study is recurrence-free survival, with a key secondary endpoint being recurrence-free survival at 12 and 24 months for cross-over patients. The trial schema for the ABLE-32 trial is as follows:


Dr. Bivalacqua notes that there are several potential meaningful endpoints for trials in intermediate-risk NMIBC, including (i) patient-reported outcomes, (ii) recurrence-free survival, (iii) reclassification rate (ie. progression to high-grade disease), (iv) decrease in surveillance cystoscopy and TURBT, and (v) toxicity. 

Dr. Bivalacqua concluded his presentation with the following take-home messages:

  • We as a community have to acknowledge that some NMIBC have chronically relapsing non-life threatening disease and the harms of standard treatment may outweigh the benefits at times
  • The role of primary treatment versus adjuvant treatment will be addressed in active large phase 3 trials
  • The role of targeted therapies to FGFR3 are evolving

Presented by: Trinity Bivalacqua, MD, Ph.D., Director of Urologic Oncology, Associate Professor of Urology, Johns Hopkins Medicine, Baltimore, Maryland, United States

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md during the 4th annual bladder cancer translational research meeting, co-sponsored by the American Urological Association (AUA) and the Johns Hopkins Greenberg Bladder Cancer Institute, March 4-6, 2021


  1. Knowles MA. Role of FGFR3 in urothelial cell carcinoma: Biomarker and potential therapeutic target. World J Urol. 2017 Dec;25(6):581-593.
  2. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): An open-label, single-arm, phase 3 trial. Lancet Oncol2020 Jun;21(6):776-785.
  3. 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. 2020 Nov 27:S1470-2045(20)30540-4.
email news signup