ASCO GU 2020: Options for Bacillus Calmette-Guérin (BCG) Refractory Disease

San Francisco, California ( Treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) remains a significant clinical challenge.

At the session on Confronting Obstacles in Treating Nonmuscle-Invasive and Upper Tract Urothelial Carcinoma at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Wassim Kassouf presented an overview of treatment options available for these patients.

He began with a reminder of the definition of “BCG unresponsive” NMIBC, which was set forth by the Food and Drug Administration to identify patients who will not benefit from further BCG administration. This includes the following types of patients:
1) Patients with any high-grade recurrence after induction + 1st round of maintenance or two rounds induction BCG.
2) Patients with a HGT1 recurrence within three months after a single induction course of BCG
3) Patients who achieve a complete response with induction + maintenance BCG but then suffer a recurrence of: 
        a. HGTa or HGT1 within 6 months of last BCG OR
        b. CIS within 12 months of last BCG

Dr. Kassouf then briefly reviewed the data supporting the many options available for these patients.

First, he emphasized that cystectomy, when possible, remains the standard of care in these patients as described in the AUA guidelines. Enrollment in a clinical trial is the next preferred option. Finally, intravesical chemotherapy is an option when clinical trials are not available.

Next, Dr. Kassouf pointed out that valrubicin is the only intravesical therapy other than thiotepa and BCG approved by the FDA for the treatment of bladder cancer. However, he also emphasized that valrubicin has only an 8% disease-free rate at 30 months when used for BCG unresponsive patients.

The combination of BCG with interferon 2-alpha was studied in a multicenter Phase II trial.1 Forty-five percent of patients in this group were disease-free at 24 months, however, this was only demonstrated to be beneficial in patients who relapsed after initial cure with BCG (not those who had primarily BCG refractory disease). Dr. Kassouf also pointed out that the company that produces interferon 2-alpha has also recently announced that it will halt production in the near future, making this option essentially moot.

The SWOG S0353 Phase II trial of intravesical gemcitabine monotherapy demonstrated 28% and 20% recurrence-free survival at one and two years respectively.

However, the combination of gemcitabine with docetaxel has generated significantly more interest, especially after the recently published multi-institutional retrospective review of the use of this regimen.2 Thirty-eight percent of patients in this review were BCG unresponsive, and one and two-year survival were 65% and 52% in the overall cohort.

Heated intravesical mitomycin has also been proposed as a salvage intravesical therapy for BCG unresponsive disease and Dr. Kassouf presented two retrospective trials that demonstrated one and two-year recurrence-free survival of 60-85% and 47-56% respectively.3,4 However, the Phase III HYMN trial, which was published in European Urology in 2019 and compared heated intravesical mitomycin to re-induction BCG or institutional standard, showed no benefit in the experimental arm.5 This has significantly diminished enthusiasm for this therapy.

Chemoradiotherapy of the type administered for muscle-invasive bladder cancer (MIBC) has efficacy for the treatment of NMIBC in a BCG-naïve population.6 There was an 88% complete response rate and a progression rate in 5/10 years of 13/29% respectively. Dr. Kassouf pointed out that there is no reason to believe that BCG-refractory disease would be more radioresistant, and presumably, therefore, chemo-XRT would work in a BCG-unresponsive population. RTOG 0926 was specifically designed to answer this question, however, the results are pending.

The efficacy of pembrolizumab was recently tested in BCG unresponsive patients in KEYNOTE-057, which was a single-arm trial of q3 week 200mg pembrolizumab in patients with BCG unresponsive carcinoma in situ (CIS) with or without papillary disease (cohort A) and papillary disease without CIS (cohort B). Interim analysis of cohort A showed a 41.2% initial complete response with no progression to T2 disease. The 12-month CR was only 19%, and 12.2% of patients suffered at least one grade ≥3 adverse event. That said, the FDA recently approved pembrolizumab for this indication based on this data, making it the first drug after valrubicin to be specifically approved for this indication.

Conversely, the S1605 single-arm Phase II trial of atezolizumab in BCG unresponsive disease was recently closed due to meeting its futility endpoint.

Finally, vincinium is not yet widely available but is seeking approval from the FDA. It consists of an antibody fragment specific to EpCAM fused to Pseudomonas Exotoxin A. This was tested in the VISTA trial and demonstrated 40% three-month complete response rate in BCG unresponsive CIS and 71% in papillary disease. This fell to only 17% disease-free survival at 12 months in CIS patients and 37% at 24 months in patients with papillary disease.

Dr. Kassouf then turned the podium over to Dr. Stephen Boorjan, who presented the results of a Phase III trial of nadofaragene firadenovec (aka IFN alpha2b/Syn3 or Nadofaragene firadenovec (Adstiladrin®)), a recombinant adenovirus which induces production of interfereon alpha2b by bladder cancer cells. This demonstrated a 24% 12-month complete response rate with only 3.8% grade 3-5 adverse events. 

With a plethora of options available and poor evidence to support any one therapy, Dr. Boorjan again noted that cystectomy and clinical trials remain the standard of care. He emphasized that among other questions, one must ask whether the response rates seen with these therapies really imply cure without cystectomy or whether they simply postpone the inevitable. Further studies are clearly needed to answer that question.

Presented by: Wassim Kassouf, MD, FRCS, Senior Scientist, Research Institution - McGill University Health Center, Faculty of Medicine, Department of Surgery, Division of Adult Urology, MUHC McGill University Health Centre, McGill University, Montreal, Canada

Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia Pennsylvania, Twitter: @mcstroth at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California 


1. Joudi, Fadi N., Brian J. Smith, Michael A. O’Donnell, and National BCG-Interferon Phase 2 Investigator Group. "Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon α-2B for reducing recurrence of superficial bladder cancer☆." In Urologic Oncology: Seminars and Original Investigations, vol. 24, no. 4, pp. 344-348. Elsevier, 2006.

2. Steinberg, Ryan L., Lewis J. Thomas, Nathan Brooks, Sarah L. Mott, Andrew Vitale, Trafford Crump, Mounica A. Rao et al. "Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy of Non-muscle Invasive Bladder Cancer." The Journal of Urology (2019): 10-1097.

3. Nativ, Ofer, J. Alfred Witjes, Kees Hendricksen, Michael Cohen, Daniel Kedar, Ami Sidi, Renzo Colombo, and Ilan Leibovitch. "Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin." The Journal of urology 182, no. 4 (2009): 1313-1317.

4. Arends, Tom JH, Antoine G. van der Heijden, and J. Alfred Witjes. "Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer." The Journal of urology 192, no. 3 (2014): 708-713.

5. Tan, Wei Shen, Anesh Panchal, Laura Buckley, Adam J. Devall, Laurence S. Loubière, Ann M. Pope, Mark R. Feneley et al. "Radiofrequency-induced thermo-chemotherapy effect versus a second course of bacillus Calmette-Guérin or institutional standard in patients with recurrence of non–muscle-invasive bladder cancer following induction or maintenance Bacillus Calmette-Guérin Therapy (HYMN): a phase III, open-label, randomised controlled trial." European urology 75, no. 1 (2019): 63-71.

6. Weiss, Christian, Carolin Wolze, Dirk Gerhard Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, and Claus Rödel. "Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy?." Journal of clinical oncology 24, no. 15 (2006): 2318-2324.