About 70,000 new bladder cancer cases are diagnosed annually in the United States, and about 15,000 patients die as a result.[1) Approximately 60% to 70% of cases are non-muscle invasive bladder cancer (NMBIC). Because the incidence of NMIBC substantially exceeds its mortality rate, the best indicator of its impact is its prevalence of about 700,000 cases nationwide.
Patients with NMIBC face a high risk of recurrence (40% to 80%) and progression (10% to 50%), despite intravesical therapy with bacillus Calmette-Guérin (BCG). This makes NMIBC one of the most expensive cancers to treat from diagnosis until death, and underscores the need for more therapeutic options, particularly for high-risk tumors.
DEFINING RISK
High-risk NMIBC tumors include all minimally invasive (T1) and high-grade noninvasive (TaHG) tumors, as well as carcinoma in situ (CIS). About 20% of NMIBC meet this description.[2] Another 50% of NMIBCs are low-risk. These are solitary, primary Ta low-grade tumors that may recur, but are less likely to progress. The remaining 30% of NMIBCs include recurrent or multiple low-grade Ta tumors classified as intermediate-risk.
For high-grade NMIBC, numerous peer-reviewed meta-analyses support the use of 1 to 3 years of intravesical immunotherapy to reduce the risk of recurrence [3,4,5,7,9], progression,[6, 8,9), and death. Maintenance BCG therapy remains the most effective first-line therapy, significantly improving recurrence-free survival through at least 120 months compared with induction BCG alone.[10]
BCG NONRESPONSE
Therapy with BCG decreases NMIBC recurrence, delays progression, and improves survival, with toxicity that is moderate, but usually acceptable. However, more than 50% of patients ultimately fail two or more courses of BCG, and 35% die of bladder cancer as a result. Recurrence of NMIBC after adequate BCG (6-week induction plus maintenance therapy) is considered BCG failure.[11] Patients who relapse after a disease-free interval of less than 6 months are considered early relapsers, and should be directed toward cystectomy or, in some cases, clinical trials. Patients who remain tumor-free for more than 2 years before recurrence (late relapse) can be safely re-induced with a second BCG course. Patients who relapse at an intermediate time point represent a grey area of uncertainty. Additionally, some NMIBC tumors are completely refractory to BCG therapy. All four of these subgroups are now considered “BCG unresponsive.”
BCG nonresponse is a seminal moment for a patient. Data clearly indicate that a third course of BCG is not of value, and electing aggressive second-line therapy over cystectomy can lead to tumor progression and death. Cystectomy, however, increases comorbidity and can represent overtreatment. It is crucial to carefully discuss these life-altering decisions with patients. Unfortunately, the American Urological Association (AUA) guidelines offer little direction. Given the lack of rigorous data, many NMIBC experts see cystectomy as the safest option for high-grade BCG nonresponsive NMIBC, and for patients with high-grade NMIBC who cannot tolerate full-dose BCG induction and maintenance.
When NMIBC recurs despite adequate BCG therapy, the first question to ask is whether there is time to try something else before proceeding to radical cystectomy. Data suggest that most patients do indeed have about 1 year before their prognosis drops.[12,13] In another study, researchers found no difference in 5-year rates of overall or cancer-specific survival between patients who enrolled in clinical trials and those who proceeded immediately to cystectomy.[14] Patients with any degree of lymphovascular invasion or prostatic urethral involvement fared poorly, however, and probably should not be considered for second-line therapy.
WHICH SECOND-LINE OPTION?
Currently available second-line options for BCG unresponsive NMIBC are insufficient. Valrubicin, the only FDA-approved drug for this purpose, has a 1 year of no evidence of disease (NED) rate of only 8%.[15] Off-label second-line options include interferon-alpha (1-year rate of no evidence of disease, 12%),[24] gemcitabine (21%),[17] and mitomycin C (23%)16]. When we consider that multiple studies have reported 5-year NED rates of 40% to 90% for radical cystectomy, cystectomy clearly remains the safest option.
BCG with interferon deserves mention. A multicenter trial of this regimen in patients who were either BCG-naïve or had failed BCG therapy found no statistical difference in recurrence-free survival during median 24-month follow-up (57% vs. 42%; p=.06).[18,19] A closer look at the data showed, however, that only 44% of patients had high-grade BCG failure, and 61% had received only one course of BCG. Patients who were BCG unresponsive did not do well with a combination of BCG and interferon; this option should not be considered for these patients.
CHECKPOINT BLOCKADE INHIBITOR THERAPY
These options are of increasing interest to the bladder cancer community. Both Merck and Roche have trials in BCG unresponsive NMIBC. Urologists need to take leadership in these trials: they treat these patients and understand their natural history. Important safety questions include whether checkpoint blockade inhibitors could delay or alter the operative plan, with negative implications for patients, and whether toxicity is commensurate with NMIBC lethality. In NMIBC, anything short of CR will be considered treatment failure. Currently, trials are underway for the PDL-1 inhibitors atezolizumab and pembrolizumab in BCG unresponsive NMIBC.
GENE THERAPY
Intravesical gene therapy has promise in NMIBC. The bladder as an ideal organ for gene therapy: the vector has direct contact with the tumor, and urine and tissue can be easily sampled for correlative studies and monitoring. Animal models also are available to optimize therapy. Early work indicated that when administered with Syn3 (a surfactant molecule), adenoviral interferon alpha (Ad-IFNα) gene induced human bladder cancer regression in athymic mice; dosing every 3 months led to high sustained therapeutic levels of interferon alpha.[21,22] Ad-IFNα/Syn3 gene therapy exhibited both direct and bystander effects, with no major toxicity in rodent or primate studies.
In a phase 1 trial of 14 high-grade NMIBC patients who had failed BCG, Ad-IFNα/Syn3 gene therapy induced complete CR in six patients at 3 months, and 36% of the total cohort had durable CR at 12 months.[23] In a phase 2 trial, 50% of patients with papillary Ta and T1 tumors were alive and recurrence-free at 12 months, as were 30% of patients with CIS – a four-fold improvement over valrubicin. The most common adverse effects were urinary urgency (38%), dysuria (28%), frequency (28%), fatigue (23%) and nocturia (20%). No patient discontinued therapy because of toxicity, although there were three serious treatment-related adverse events, all of which resolved: grade 3 diarrhea, and acute renal failure secondary to grade 3 urinary tract infection. For the intention-to-treat population, relapse-free survival was 35% at 12 months, with responses maintained up to 36 months. Median time to recurrence was 4 months in the low-dose group, and 12 months in the high-dose group. Based on these findings, a registration trial with the SUO CTC is ongoing.
REGISTRATION STRATEGY FOR BCG UNRESPONSIVE NMIBC
It is clear that the traditional clinical trial registration pathway does not work in the NMIBC setting. During the past six decades, the FDA has approved only four agents for NMIBC: thiotepa (1959), doxorubicin (1974), BCG (1989/1990), and valrubicin (1998/2007). To address this critical gap, the Society of Urologic Oncology (SUO) and AUA worked with FDA to create a trial registration strategy for BCG unresponsive NMIBC. Stakeholders agreed to enroll patients with a mix of high grade tumors (CIS, Ta, and T1), at least 50% of which have some element of CIS. A mixed registration population is necessary because three-quarters of patients typically go directly to radical cystectomy, and there distinct treatment goals exist for CIS (treatment) and papillary tumors (adjuvant therapy).
Consensus for a single-arm trial design also was reached based on the lack of an acceptable comparator. A majority of attendees (75%) agreed that a clinically meaningful response must last at least 12 months, and should consist of CR or 25% free from high-grade recurrence. An ad hoc panel assembled at the request of FDA defined BCG unresponsive for labeling purposes as patients with persistent high-grade disease at 6 months despite adequate (5+2) BCG; recurrence of high-grade disease within 6 months despite adequate BCG; or persistent or progression to T1 disease after BCG induction.
STATUS UPDATE: MCNA IMMUNOTHERAPY
In 2015, investigators reported promising results from a single-arm, open-label trial of intravesical mycobacterial cell wall nucleic acid complex (MCNA) in patients with high-risk NMIBC that recurred after BCG therapy.[20] Rates of 1-year disease-free survival were 21% for CIS and 35% for papillary tumors. The SUO Clinical Trials Consortium (SUO-CTC) had met repeatedly with FDA to discuss trial design and meaningful clinical endpoints. Despite this, in November 2015, reviewers voted against approval of MCNA for high-risk NMIBC after BCG. The standing FDA panel included primarily medical oncologists, who lacked experience in NMIBC and were uncomfortable with the concept of a single-arm trial. Seven ad-hoc experts joined the panel, with a final vote of 18-6 against approval.
This outcome raised concerns in the bladder cancer community about the review process for new second-line therapies for high-risk NMIBC. In March 2016, SUO-CTC met with FDA to again clarify trial design and endpoints, particularly BCG unresponsive disease. Our discussions made it clear that a single-arm trial with a mixed population is still a viable option. As it stands, FDA will approve MCNA for CIS, but the label could be expanded to include prophylaxis of papillary disease. The patient mix needed to achieve that label expansion remains under discussion, but we are confident that FDA is aware of the importance of assembling an appropriate review panel and leaving it up to investigators to define the metrics for a registration trial.
Based on these discussions, a multicenter, open-label, single-arm phase 3 trial of Ad-IFNα/Syn3 gene therapy is underway, with dosing every 3 months for 12 months as long as CR is maintained. A total of 135 patients at 35 sites will be enrolled, comprising a mixed high-grade NMIBC population weighted such that at least 50% have some element of CIS. The primary endpoint is 25% survival without high-grade recurrence at 12 months. Safety and long-term follow-up will continue for up to 4 years, and patients who maintain CR will be eligible for continued treatment.
SUMMARY
BCG unresponsive NMIBC is a potentially fatal disease that clearly needs more treatment options. Currently, cystectomy remains the safest approach. For select patients, there may be a window of opportunity to evaluate novel second-line therapy.
Written by Colin P. N. Dinney, MD
Chairman of the Department of Urology and a Professor in the Division of Surgery at The University of Texas M. D. Anderson Cancer Center.
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