Dr. Kamat notes that Bacillus Calmette Guerin (BCG) is the original cancer immunotherapy with urologists administering approximately 1.2 million doses of BCG for bladder cancer. However, there are BCG failures, with ~30% failing at 1 year, and ~40% failing at 2-3 years after induction therapy. Classification of BCG failure is as follows:
- BCG refractory: a persistent high-grade disease at 6 months despite adequate BCG, which also includes any stage/grade progression by 3 months after the induction BCG cycle (ie. T1HG at 3 months after initial Ta or CIS)
- BCG relapsing: recurrence of high-grade disease after achieving a disease-free state at 6 months following adequate BCG, which had previously been subdivided based on time to recurrence after stopping BCG (ie. early (<12 months), intermediate (1-2 years), or late (>24 months))
- BCG intolerant: disease persistence due to inability to receive adequate BCG due to toxicity
- BCG unresponsive: BCG refractory + BCG relapsing disease (within 6-12 months of last BCG exposure), which is meant to denote a subgroup of patients at highest risk of recurrence and progression for whom additional BCG therapy is not a feasible option. These patients can be considered for single-arm studies
Further granularity regarding the definitions of BCG unresponsive disease include:
- Persistent or new T1HG disease - at first evaluation (3 months) following induction BCG
- Persistent or recurrent CIS – within 12 months of completion of adequate BCG therapy
- Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy
Adequate BCG therapy is defined as at least 5 of 6 doses of induction BCG plus at least 2 additional doses of maintenance BCG. The following schematic highlights the timeline of early-stage urothelial carcinoma registration trials:
The KEYNOTE-057 is a single-arm, open-label phase II study for high-risk NMIBC patients unresponsive to BCG who refuse or are ineligible for cystectomy. Additionally, patients with papillary disease must have fully resected disease at the time of study entry. This trial had two cohorts, including Cohort A (n=130) which included those with CIS with or without papillary disease (high-grade Ta or T1), and Cohort B (n=130) which included those with papillary disease (high-grade Ta or any T1) without CIS. Eligible patients were given pembrolizumab 200 mg Q3W with continued treatment until recurrence of high-grade NMIBC, progressive disease, or 24 months of treatment was completed. The primary endpoints were complete response (absence of high-grade NMIBC) in cohort A and DFS in cohort B. Secondary endpoints included complete response (absence of any disease – high-risk of low-risk NMIBC) in cohort A, duration of response in cohort A, and safety/tolerability. Among 96 patients, the median age was 73 (range 44-92), and median number of prior BCG instillations was 12.0 (range 7.0-45.0). The results for BCG unresponsive CIS patients regarding complete response are as follows:
Furthermore, the median complete response duration was 16.2 months (range 0-26.8). Additionally, when assessing subgroups for complete response rate, the majority of subgroups had a complete response rate >20%:
Based on these results, on January 8, 2020, pembrolizumab was approved for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who are ineligible for, or who elected not to undergo radical cystectomy.
First presented at the 2020 ASCO virtual scientific program, SWOG S1605 assessed atezolizumab in BCG unresponsive high-risk NMIBC. The primary endpoint was complete response at 6 months by confirmatory biopsy, which was achieved in 20/74 (27%) of patients, with an unplanned secondary endpoint of complete response at 3 months (42%, 31/74 patients).
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. First presented at GU ASCO 2020 and recently published in Lancet Oncology,1 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. The study met its primary endpoint with 53.4% of patients with CIS ±Ta/T1 achieving a complete response, all by 3 months, including 43.6% of these patients remaining free of high-grade recurrence at 15 months. The most common treatment-related adverse events were instillation site discharge (33.1%), fatigue (23.6%), bladder spasm (19.7%), micturition urgency (17.8%), and hematuria (16.6%).
Vicineum is oportuzumab monatox – anti-EpCAM + Pseudomonas exotoxin, with phase I and II studies establishing safety and complete response rates of 15.6% at 12 months. The Vista Trial was a phase 3 registration study of Vicineum for BCG-unresponsive NMIBC showing a 30-month complete response rate of 40% with CIS, with 52% of those patients retaining a complete response at 9 months, and 39% at 15 months. The median duration of response was 287 days (95% CI 154-not reached).
The KEYNOTE-676 phase III trial will randomize patients with confirmed NMIBC (T1, high-grade Ta and/or CIS) who have been treated with one adequate course of BCG induction therapy 1:1 to pembrolizumab + BCG versus BCG. The primary endpoint is complete response rate by BICR; the trial schema is as follows:
Additionally, the phase III ALBAN trial, Atezolizumab Plus One-year BCG Bladder Instillation in BCG-naive High-risk Non-muscle Invasive Bladder Cancer Patients (ALBAN), will investigate whether atezolizumab improves the outcome of patients (n=614) treated with BCG for high-risk NMIBC. The intervention arm will be BCG 6+3 (1 year) + atezolizumab (1 year) versus BCG 6+3 (1 year); the primary outcome will be recurrence-free survival.
Dr. Kamat concluded by emphasizing that the optimal management of bladder cancer requires a multidisciplinary approach.
Chair: Neal Shore, MD, FRCS, Medical Director, Atlantic Urologic Clinics, Myrtle Beach, South Carolina
Presented by: Ashish Kamat, MD, MBBS, is a Professor of Urology and Cancer Research and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas.
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
- 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.
Pembrolizumab in High-Risk, BCG Unresponsive Non-Muscle Invasive Bladder Cancer - Arjun Balar
ASCO 2020: Pembrolizumab for the Treatment of Patients with Bacillus Calmette-Guérin Unresponsive, High-Risk Non–Muscle-Invasive Bladder Cancer: Over Two Years Follow-Up of KEYNOTE-057