Introduction: Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) represents a difficult clinical scenario, for which radical cystectomy (RC) is standard of care. Many patients are either unfit or unwilling to undergo RC, and bladder preserving treatment options are limited. We aimed to investigate the efficacy of durvalumab, a PD-L1 inhibitor, in the treatment of BCG-unresponsive carcinoma in situ (CIS) containing NMIBC.
Methods: This was a single center, open-label, phase II study of patients with BCG-unresponsive CIS of the bladder. After enrollment, patients received IV Durvalumab 1500mg IV, every 4 weeks for a total of 12 months. Cystoscopy with for-cause biopsy was performed every 3 months during the 12-month administration period, then every 4 months for a second 12 month surveillance period. Patients were taken off study if disease persistence or progression to invasive disease occurred. The primary endpoint was complete response (CR) by mapping biopsy at 6 months. Secondary outcomes were the duration of complete response and recurrence free survival (RFS). Pre- and post-treatment PD-L1 status was determined by the SP263 assay. Adverse events were captured using CTCAE v4.03.
Results: Seventeen patients were enrolled and began durvalumab for BCG-unresponsive CIS-containing NMIBC. Median age was 77 years (IQR 69-79), 13 (76.5%) patients had CIS alone, and the median number of prior BCG instillations was 12 (IQR 12-12). Four patients came off of study after 3 month bladder biopsy demonstrating persistent high grade NMIBC. Among the 13 patients who underwent 6-month mapping biopsy, 3 (18%) patients had a 6-month CR with a median duration of response of 14 months. Three (18%) patients progressed to muscle invasive or metastatic disease and 9 (53%) underwent RC. No correlation was observed between PD-L1 expression and clinical response to durvalumab. Grade 1-2 treatment-related adverse events occurred in 11 patients; most frequently fatigue (35%), diarrhea (18%), pancreatic enzyme elevation (12%), rash (6%), and hypothyroidism (6%).
Conclusions: Immune checkpoint inhibition with durvalumab in BCG-unresponsive CIS-containing NMIBC demonstrated a favorable safety profile, but a modest CR rate. Additional research is needed in a larger cohort to determine generalizable efficacy with immune checkpoint inhibitors, and to better understand the safety profile in NMIBC.
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