A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects With High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

Merck Sharp & Dohme Corp
Study Design: 
This is a phase II, multicenter trial for patients with high risk NMIBC (T1, CIS, and/or high-grade Ta) who are deemed BCG-unresponsive after adequate BCG therapy who are either unfit or refuse radical cystectomy. This was a single-arm study in which all patients were treated with intravenous pembrolizumab, 200 mg, every 3 weeks until recurrence of high-risk disease or unacceptable toxicity for up to 24 months. Assessment of tumor status was performed by cystoscopy and cytology and for cause biopsies every 3 months.
PD-L1 and PD-1 inhibitors are now established treatments both for 1st line treatment of patients with locally advanced or metastatic bladder cancer that are cisplatin-ineligible or experiencing disease progression after platinum-based chemotherapy. Recently, data from 2 small phase II trials suggest their potential efficacy when given as neoadjuvant therapy prior to radical cystectomy. Several ongoing trials have also evaluated this immunotherapy in the treatment of BCG-unresponsive NMIBC. This trial by Merck Sharp & Dohme specifically evaluated the safety and efficacy of its PD-1 inhibitor, pembrolizumab, in the treatment of patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) given the already encouraging results in other disease states of urothelial cancer (neoadjuvant prior to cystectomy and metastatic).
Primary outcomes were complete response rate and disease-free survival rate. Complete response rate (CR) was defined by a negative cystoscopy or bladder biopsies performed for an abnormal cystoscopy, negative urine cytology, and normal CT urogram. Secondary outcome was duration of response.
This trial led to the approval of pembrolizumab in patients with BCG-unresponsive CIS. Although this is a valuable advance in the treatment of NMIBC, it does raise several potential concerns. Will this be used as first line therapy for patients with BCG unresponsive disease or will urologists choose alternative intravesical therapies such as gemcitabine/docetaxel. Two other intravesical therapies, vicinium and adenoviral mediated interferon mediated gene therapy, are currently under review by the FDA. The cost of immunotherapy will raise the cost of bladder cancer care astronomically imploring us to evaluate whether such treatment justifies the cost. This is especially sobering when one considers that on follow-up, only 19% of the entire cohort of CIS-treated patients continued with a CR of at least one year begging the question whether this is an appropriate benchmark for new therapies in the BCG-unresponsive disease state.
At the time of analysis, the trial enrolled 148 patients of whom 96 patients had BCG-unresponsive CIS either with or without papillary tumors. The 3-month CR rate in the 96 patients with CIS was 41% (95% CI: 31-51) and the median duration of response was 16.2 months (range 0-30.4 months). Among the 39 patients with a CR, 18 (46%) and 19% among all patients with CIS maintained a CR of at least 12 months after starting treatment [Reference: fda.gov 1/8/2020]. The safety profile was in line with other PD-1 inhibitor studies, however, 99 patients experienced 1 or more adverse events (AEs) and treatment-related AEs were seen in up to 65.7% of patients. Although grade 3-5 AEs were only seen in 29.4% of patients, two patients died while on therapy during the course of the trial, but only one of these deaths was deemed to be immune-related.