Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

National Cancer Institute/Alliance
Study Design: 
This is a multicenter Alliance cooperative group trial in which BCG unresponsive NMIBC patients who refuse or are unfit for radical cystectomy undergo weekly gemcitabine intravesical instillation for 6 weeks during the first 2 cycles of concurrent IV pembrolizumab every three weeks until week 10. Patients are then evaluated with cystoscopy and cytology in Week 13 and if no evidence of disease, they then continue to receive both intravesical gemcitabine and systemic pembrolizumab concurrently every 3 weeks with cystoscopy and cytology every 3 months. Mandatory biopsies are performed in the CIS containing cohort at 6 months and all patients undergo an end of study cystoscopy and cytology at 18 months.
The current gold standard treatment for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy. However, many patients refuse radical cystectomy and some are unfit for surgery and therefore are treated with various regimens of intravesical chemotherapy or clinical trials. Until recently, many patients in this group were treated with single-agent gemcitabine based on prospective series demonstrating less disease recurrence in patients treated with gemcitabine compared with BCG again in BCG-refractory high grade NMIBC. The recent approval of pembrolizumab as a single-agent for BCG-unresponsive CIS has also widened the therapeutic options for these group of patients. This trial evaluates the combination of both gemcitabine and pembrolizumab in BCG-unresponsive high grade NMIBC (Ta, T1, and/or CIS).
There are dual primary endpoints: 6-month complete response rate for patients with a CIS tumor component and 18-month event-free survival rate for all patients. An interim analysis will be performed after 37 patients and at least 12 complete responses are required in order to proceed with the trial. The null hypothesis is a 30% 6-month complete response rate and a 25% 18-month event-free survival rate.
With efficacy of both agents as single therapies, there is optimism that some synergy will be noted with the combination approach. Unfortunately with the disease space of BCG unresponsive NMIBC crowded with several clinical trials, this trial may not be getting the much needed attention it deserves.There is great interest in immunotherapy in all stages of bladder cancer and it is hoped that prolonged responses can occur and patients will be able to maintain their bladders . Chemotherapy promotes tumor immunity by inducing immunogenic cell death as part of its intended therapeutic effect, and by disrupting strategies that tumors use to evade immune recognition. Chemotherapy may be able to stimulate neoantigens that would make immunotherapy more effective. Given the popularity of the combination off label approach of gemcitabine and docetaxel for BCG-unresponsive NMIBC, supporting this potentially practice changing trial is important in order to understand the role of combination therapy.
The trial has only accrued 10 of the planned 161 patients and a safety run-in was performed on the first 6 patients and no adverse events were noted. Unfortunatley, the trial was temporarily suspended during the COVID-19 pandemic but is now open for accrual at many centers.