Intravesical BCG therapy is the gold standard treatment for patients with high-grade non–muscle-invasive bladder cancer. BCG has been used in this setting for decades, with very good initial response rates. Despite optimal utilization of BCG therapy, a significant percentage of patients will have recurrence of noninvasive disease. BCG-unresponsive patients are defined as those with: persistent or recurrent CIS alone or with recurrent Ta/T1 papillary tumors within 12 months of completion of adequate BCG therapy; recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; or high-grade T1 disease at the initial evaluation following induction BCG. Until recently, BCG-unresponsive patients had limited therapeutic options. The complete durable response rates for other intravesical agents in the BCG-unresponsive setting has been underwhelming. Standard-of-care treatment for BCG-unresponsive disease is radical cystectomy and urinary diversion. However, a legitimate percentage of BCG-unresponsive patients are either unwilling or unfit to undergo this major operative procedure. Additionally, not all BCG-unresponsive patients require cystectomy, although current clinical prediction models do not adequately predict those who are likely to most benefit from cystectomy precisely enough on an individual level.
Clearly there is a need for additional therapeutic options in the BCG-unresponsive space, particularly for those patients who are at high risk for cystectomy. With this in mind, there has been intense interest in novel therapeutic agents for patients with BCG-unresponsive bladder cancer, and we have seen a significant increase in the number of clinical trials in this space. The FDA approved pembrolizumab in January of 2020 for the treatment of BCG-unresponsive bladder cancer, and the KEYNOTE-057 clinical trial provided the critical evidence to support the approval.1 In this trial, 102 patients with BCG-unresponsive bladder cancer received 200 mg every 3 weeks for up to 2 years. The primary endpoint was complete response rate. A complete response was seen in 40.6% of the study population, with a median duration of response of 16.2 months. There were no patients who progressed to muscle-invasive or metastatic disease while on study treatment. At 12 months, progression-free survival was 82.7% and overall survival was 97.9%. Roughly a third of the study population ultimately went on to radical cystectomy. Treatment-related adverse events were reported in 65.7% of the patients, with grade 3/4 events occurring in 12.7%.
The KEYNOTE-057 data have now provided patients with an FDA-approved therapeutic alternative to radical cystectomy for BCG-unresponsive bladder cancer. While there remains a significant amount of work to be done for this challenging patient population given the 55% nonresponder rate in the KEYNOTE-057 study population, this is a major advance in the treatment of patients with BCG-unresponsive disease. While radical cystectomy should continue to remain the gold-standard option for patients with BCG-unresponsive bladder cancer, pembrolizumab is a viable alternative for those who cannot undergo cystectomy or desire to pursue bladder preservation.