- Having received at least two courses of BCG – 5/6 instillations of induction and 2/3 maintenance doses, except for patients that have high-grade T1 disease at first evaluation after induction
- Within 6 months of last exposure to BCG
- Have high-grade T1 and/or CIS of the bladder or CIS of the prostatic urethra
What do the AUA/SUO guidelines advise regarding BCG unresponsive disease?1 A clinician should offer a radical cystectomy. Cystectomy should be considered for these patients based on multiple studies demonstrated that patients with high-risk NMIBC undergoing “early” cystectomy have been found to have better survival than patients treated with cystectomy later after diagnosis. However, not all patients will be fit or willing to undergo a radical cystectomy. The AUA/SUO guidelines also suggest that for these patients a clinical trial should be considered.
There are several targeted therapies that have been assessed for BCG unresponsive disease. Vicinium is a novel fusion protein that has an antibody fragment targeting EpCAM fused cells to a pseudomonas toxin that is specific for intracellular delivery. The phase III VISTA trial has been completed – cohort 1 had patients with CIS +/- papillary disease within 6 months of BCG (n=86). There was a 39% complete response rate at 3 months and a 14% complete response rate at 12 months. Inodiftagene Vixteplasmid (BC-819) is a targeted gene therapy made up of recombinant DNA plasmid containing regulatory sequences from the H19 gene driving expression of diphtheria toxin A chain gene found only in malignant cells. H19 oncofetal gene is expressed at substantial levels in a variety of human cancer, including bladder cancer, but not normally in adult tissues. There is an ongoing phase II study with a targeted sample size of 140 patients and a primary endpoint of complete response after 12 weeks of treatment among patients with CIS. There are also several checkpoint inhibitors that are being tested in the BCG unresponsive space. The pre-clinical rationale is that PDL-L1 expression is highest in CIS and is increased after BCG. Furthermore, PD-1 expression on tumor-infiltrating lymphocytes increases in patients treated with BCG. As follows are the trial designs for these ongoing studies:
Dr. Boorjian was part of phase II intravesical rAd-IFNalpha/Syn3 trial that was published two years ago.2 This was an open label, parallel arm US multicenter (13) trial conducted from 2012-2015; eligible patients (n=40) were those with high-grade NMIBC after BCG. They were randomized 1:1 to receive intravesical Nadofaragene firadenovec (Adstiladrin®) at a dose of 1 vs 3 x 1011 vp/mL and patients maintaining a complete response could be retreated every 3 months, up to month 12. The primary endpoint was high-grade recurrence-free survival defined by bladder biopsy. There were 14 patients (35%) that were high-grade recurrence free after 12 months and no significant difference was noted between treatment dosage arms (p=0.55). The median time to high-grade recurrence was longer with the higher dose (11.7 months) vs the low dose arm (3.5 months). These patients also showed durable 2-3 year responses among patients with a complete response. There were no grade 4 or 5 adverse events; the most common drug related adverse events were micturition urgency (n=16), dysuria (n=16), and fatigue (n=13). The phase III trial is a SUO-CTC trial with Dr. Boorjian as the PI and enrolment (n=157) was completed in June 2018.
Dr. Boorjian concluded with several take-home messages:
- The definition of BCG unresponsive disease is critical in counseling and managing patients—this is defined as a high-grade tumor after at least 2 courses of BCG within 6 months of the last BCG dose
- Radical cystectomy is the optimal cancer treatment option in this setting
- Intravesical chemotherapy is an option if the patient is unwilling/unable to undergo a cystectomy and no trials are available at the treatment site
- Clinical trials represent an option if the patient is unwilling/unable to undergo a radical cystectomy – targeted agents and checkpoint inhibitor trials are ongoing, and the interferon adenoviral trial has completed enrolling and we are awaiting data
Presented by: Stephen Boorjian, MD, Mayo Clinic, Rochester, MN, USA
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia, Augusta, GA, USA, Twitter: @zklaassen_md, at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois
- Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline. J Urol 2016;196(4):1021-1029.
- 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 Oct 20;35(30):3410-3416.