S1605, Phase II Trial of Atezolizumab in BCG-Unresponsive Non-muscle Invasive Bladder Cancer

National Cancer Institute/Southwest Oncology Group
Study Design: 
S1605 is a single arm, phase II registration trial testing atezolizumab (PD-L1 inhibitor) in BCG-unresponsive, high-risk non-muscle invasive bladder cancer (Ta/T1/Tis). Eligible patients will receive intravenous atezolizumab every 3 weeks for one year.
There are no established 2nd line therapies other than radical cystectomy with urinary diversion for patients with high-risk non-muscle invasive bladder cancer that is unresponsive to BCG. Building on the track record of immunotherapy in this disease in the form of BCG, as well as preclinical drug testing in animal models and the clinical efficacy of checkpoint blockade in the metastatic setting, this protocol aims to test the efficacy of atezolizumab in BCG-unresponsive high risk NMIBC.
There are two primary endpoints: 1) the complete response rate at 6 months in patients with carcinoma in situ (CIS; with or without concomitant Ta/T1 tumors) and 2) the event-free survival rate at 18 months in the overall cohort. To the first endpoint, the trial aims to accrue at least 70 patients with CIS. Secondary endpoints include the following: bladder cancer-specific survival, cystectomy-free survival, event-free survival at 18 months in the Ta/T1 subset, incidence of adverse events, toxicity assessment, overall survival, and progression-free survival. Correlative endpoints include expression of PD-L1 status on tumor and immune cells and CD8 in tumor and normal cells by immunohistochemistry (IHC) and expression of immune signatures by RNA sequencing.
This trial moves checkpoint blockade therapy into the high-risk non-muscle invasive BCG unresponsive disease setting after demonstrating success in metastatic disease. These patients do have an option for radical cystectomy, which is likely curative and so patients must be appropriately counseled. However, most patients can be carefully screened for enrollment with imaging and strict criteria for previous BCG treatment and can likely be salvaged with surgery or trimodal therapy in the event of disease recurrence or progression. A potential concern is whether a systemically delivered therapy will have activity locally within the bladder and whether it will come at the cost of systemic toxicity.