Examining Squamous Urothelial Carcinoma Responsiveness to Novel Therapies

Ivan de Kouchkovsky, MD, University of California, San Francisco (UCSF), explains his reason and design for studying the impact of squamous histology on clinical outcomes and molecular profiling in patients with metastatic urothelial carcinoma who are treated with immune checkpoint inhibitors or enfortumab vedotin.

What was your reason for examining outcomes relative to new therapies for patients with squamous versus pure histology urothelial carcinoma?

Dr. de Kouchkovsky: Urothelial carcinoma, unlike many other cancers, exhibits a particular preference for variant histologies or differentiations. The most common variant is urothelial carcinoma with squamous differentiation.

Historically, these patients tend to have worse outcomes, more advanced disease at diagnosis, and a poorer prognosis compared to patients with pure urothelial carcinoma. Some evidence suggests that patients with squamous histology do not benefit from perioperative chemotherapy before cystectomy.

With this background, we aimed to assess the outcomes of these patients in the era of newer systemic therapies for bladder cancer, specifically focusing on immune checkpoint inhibitors and the antibody-drug conjugate enfortumab vedotin. It’s worth noting that many therapeutic trials for urothelial carcinomas exclude patients with predominant variant histology. They may include some patients with a component of variant histology in their biopsy, typically if it’s less than 50%, but outcomes are generally not reported or stratified by the presence of variant histology.

Therefore, there is a lack of prospective data on how to best treat these patients, leaving an open question about whether these new therapies would yield similar benefits or if, as observed with platinum-based chemotherapy, squamous histology would still be associated with increased resistance to immune checkpoint inhibitors or enfortumab vedotin. This motivated us to conduct this retrospective analysis to examine outcomes in more detail.

Please describe the design of the study. How were patients sampled and what did you hope to achieve?

Dr. de Kouchkovsky: This was a retrospective study conducted at a single institution, spanning from 2014 to 2022, involving patients with metastatic urothelial carcinoma treated with either a checkpoint inhibitor or enfortumab vedotin. Our focus was on patients with either pure urothelial carcinoma in their biopsies or those with some squamous histology component in their biopsies. Pathology review was performed by a dedicated genitourinary pathologist at UCSF.

Patients were categorized based on the presence of squamous histology in their biopsies, with no other variant histologies present. We further stratified them into three groups: those with a focal squamous histology component, those with predominant squamous histology, and those with pure squamous histology.

Our primary objective was to compare outcomes between patients treated with immune checkpoint inhibitors and those treated with enfortumab vedotin. We assessed objective response rate, progression-free survival, and overall survival. Additionally, we explored potential genomic differences between the two groups by analyzing the tumors’ genomic profiles using Lyra certified assays. This analysis aimed to provide insights into the biological factors contributing to any observed outcome differences between the patient groups.

View Dr. de Kouchkovsky’s further comments on the study.