A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer.

Background: Intravenous immune checkpoint inhibition achieves a 40% three-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). Yet only half of early responders will continue to be disease free by 12 months, and resistance mechanisms are poorly defined. Objective: We assessed the molecular features associated with response to immunotherapy in BCG unresponsive non-muscle invasive bladder cancers treated with pembrolizumab. Design Setting and Participants: We performed digital spatial profiling (DSP) of BCG unresponsive NMIBC tumors before and after IV pembrolizumab therapy. Intervention: Pembrolizumab was administered intravenously in patients with NMIBC at the time of recurrence after BCG therapy. Biopsies were obtained before starting IV pembrolizumab and three months post-treatment. Outcomes and Statistical Analysis: Spatial gene expression profiling of the tumor niche pre- and post IV pembrolizumab. Results and Limitations: We evaluated 119 regions of interest (ROIs) from five patients, which included 60 epithelial (PanCK+) and 59 stromal segments (PanCK-). ROIs from responders had distinct expression signatures from non-responders for both the tumor and TME. Responders were more likely to have a dynamic change in expression after pembrolizumab than non-responders. A major limitation of this study was the number of patients evaluated. Conclusion: For the first time, we have identified distinct expression signatures associated with response and resistance to IV pembrolizumab in NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. Patient Summary: We identify the molecular features of tumors associated with response to pembrolizumab for patients with BCG unresponsive NMIBCs.