Data from A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder

Purpose: Immune checkpoint blockade holds promise for treating BCG-unresponsive non-muscle invasive bladder cancer. In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive CIS. Patients and Methods: Patients with BCG-unresponsive CIS containing non-muscle invasive bladder cancer received durvalumab IV at 1500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response rate at month 6, defined by negative cystoscopy, urine cytology and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a complete response rate of 18% and alternative hypothesis 40%. According to the Simon 2-stage design, if ≤3/13 patients achieved complete response during stage 1, the trial is stopped due to futility. Results: Between 03/8/2017 and 1/24/2020, 17 patients were accrued while 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. 2 of 17 (12%) achieved a complete response at month 6, with duration of response of 10 and 18 months, respectively. A single Grade 3 lipase elevation was attributed to durvalumab, and immune related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high PD-L1 expression pre-treatment. On RNAseq, complement activation genes were elevated post-treatment, along with enrichment of tumor associated macrophage signature. Conclusions: Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6mo complete response of 12%. Complement activation is a potential mechanism behind treatment resistance.