Efficacy of Durvalumab Among Patients with BCG-Unresponsive Urothelial Carcinoma in Situ - Expert Commentary
The study cohort consisted of seventeen patients who received at least one dose of durvalumab, but complete data was only available for thirteen patients. The median age among participants was 77 years, and 88% were male. The median number of courses of intravesical BCG received was two. At 3 months, 41% (95% CI, 18.4%-67.1%) of patients were disease-free, but most of these exhibited recurrent high-grade NMIBC at 6 months. The median follow-up time was 36.4 months, with 12% (95% CI, 1.5%-36.4%) of patients achieving complete response at 6 months. Overall, 24% (95% CI, 6.81%‐49.9%) of patients experienced progression to muscle-invasive disease, metastasis, or death. The median time to progression was 14 months (95% CI, 9-NR). The 24-month overall survival rate was 82.3% (95% CI 57.7%‐100%), with two out of three deaths considered related to bladder cancer. The median duration of durvalumab treatment was 4.5 months (IQR, 3.9‐6.0), with a median of seven administrations (IQR 6‐7) per patient. Only 12% (95% CI, 14.5%-36.4%) of patients completed the 12-month course, as treatment was discontinued in most patients due to persistent disease at 3 or 6 months. All patients experienced treatment-emergent adverse events (TEAEs). Five patients experienced immune-related AEs such as fatigue, diarrhea, and arthralgia. The investigators examined PD-L1 status in an attempt to uncover potential reasons for lack of response to treatment. Only one out of seventeen pre-treatment samples exhibited high PD-L1 expression. Three out of eight post-treatment samples exhibited high PD-L1 expression. Median tumor mutational burden was similar before and after treatment. In contrast, genes related to complement activation exhibited increased expression after treatment. Post-treatment samples also displayed enrichment in macrophage signatures and increased IL-10 levels.
Overall, the response rate to durvalumab was inadequate and was lower than rates achieved in studies with pembrolizumab or atezolizumab. This prevented the trial from proceeding to the second stage. The progression rate was also higher than those reported in other studies in BCG-unresponsive patients. The researchers suggest that this may be related to the low rate of PD-L1 positivity among patients. Limitations related to the sample and availability of biopsy specimens for all patients were also noted. Continuing research to understand the biological differences between CIS and papillary NMIBC is critical for designing effective therapeutic strategies that target this aggressive disease process.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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