A rare and notoriously aggressive form of bladder cancer may be more treatable than previously believed, according to a new real-world study from Mayo Clinic. Researchers report that the combination of enfortumab vedotin and pembrolizumab produced substantial tumor responses in patients whose cancers contained squamous features—a population largely absent from the prospective clinical trials that established the treatment. The findings offer an important signal for oncologists confronting difficult-to-treat urothelial cancers, while also highlighting the need for carefully designed studies focused specifically on these unusual tumor types.
The study examined adults with either urothelial carcinoma containing squamous divergent differentiation or pure squamous cell carcinoma of the urinary tract. Urothelial carcinoma begins in the cells lining the bladder and urinary system, whereas pure squamous cell carcinoma is composed entirely of squamous cells, which are flatter, scale-like cells that can emerge after chronic irritation or other biological changes. Both forms are uncommon, and their aggressive behavior has historically left clinicians with limited evidence to guide systemic therapy, particularly after the disease has spread beyond the bladder.
The investigators retrospectively reviewed 49 patients treated with enfortumab vedotin plus pembrolizumab across Mayo Clinic sites. Thirty-five patients, or 71.4 percent, received the combination as their first-line treatment for metastatic disease. Unlike a conventional randomized clinical trial, the analysis relied on medical records and imaging performed during routine care. Tumor responses were assessed retrospectively from a mixture of computed tomography, magnetic resonance imaging, and positron emission tomography reports rather than through a uniform, prospective RECIST 1.1 evaluation. This distinction is crucial because real-world imaging schedules and reporting practices can vary considerably.
Even with those limitations, the reported activity was striking. Twenty-nine patients, representing 59.2 percent of the cohort, achieved a complete response, meaning that no detectable disease remained on follow-up imaging. Four additional patients, or 8.2 percent, experienced a partial response, while another four had stable disease. Twelve patients, or 24.5 percent, had progressive disease. Taken together, the retrospectively adjudicated objective response rate was 67.3 percent, although the unusually high proportion of complete responses should be interpreted cautiously because of the study’s small size, retrospective design, and potential differences in how patients were selected and followed.
The treatment combines two distinct biological strategies. Enfortumab vedotin is an antibody–drug conjugate, a targeted therapy designed to carry a potent cell-killing drug directly to tumor cells. Its antibody component recognizes Nectin-4, a protein commonly found on the surface of urothelial cancer cells. After binding, the cancer cell internalizes the drug complex, allowing the attached cytotoxic payload to disrupt cellular structures involved in division and survival. Pembrolizumab works differently: it blocks the PD-1 immune checkpoint, a molecular “brake” that tumors can exploit to suppress T cells. By releasing that brake, the drug may help the immune system identify and attack malignant cells.
The two agents may therefore create a complementary assault. Enfortumab vedotin can directly damage tumor cells, while the resulting tumor-cell death may expose cancer-associated signals to the immune system. Pembrolizumab may then enhance T-cell activity against residual disease. However, the study was not designed to prove how the combination works in squamous tumors, and the biological behavior of these cancers may differ from conventional urothelial carcinoma. Squamous differentiation could influence Nectin-4 expression, immune-cell infiltration, or the tumor’s capacity to evade immune attack, making laboratory and translational research an essential next step.
Patients who responded also appeared to benefit for a meaningful period. The median duration of response was 23.7 months, with a 95 percent confidence interval extending from 16.0 months to a point that had not yet been reached. Median overall survival was 24.5 months, while median progression-free survival was 23.8 months. Overall survival measures the time until death from any cause, whereas progression-free survival measures the time until the cancer worsens or the patient dies. Because confidence intervals for survival estimates extended to “not reached,” some outcomes remained immature at the time of analysis, meaning that longer follow-up could change the precise estimates.
The clearest prognostic factor was the amount of metastatic disease. In multivariable analysis, each additional metastatic site was associated with a higher risk of death, with a hazard ratio of 2.37 and a 95 percent confidence interval of 1.55 to 3.62. A hazard ratio above one indicates greater risk, and the reported association was statistically strong, with a p-value below 0.001. In practical terms, the results suggest that the burden and distribution of metastatic cancer may matter more for survival than the presence or extent of squamous differentiation itself. Still, this interpretation is exploratory and cannot establish that metastatic burden directly causes poorer outcomes.
The researchers found no statistically discernible survival difference based on how extensively the tumor showed squamous divergent differentiation. Yet the comparison was underpowered because the overall cohort contained fewer than 50 patients and the disease subgroups were small. The study also included limited pretreatment testing for Nectin-4: only 12 patients had available analyses. Those results were descriptive rather than definitive, so they cannot determine whether Nectin-4 levels predict response to enfortumab vedotin. This is particularly important because a biomarker that helps select patients could be valuable in a rare cancer where treatment decisions are often made with incomplete evidence.
The findings arrive as enfortumab vedotin plus pembrolizumab becomes an increasingly important treatment strategy for advanced urothelial carcinoma, but they should not be mistaken for proof that every squamous bladder cancer will respond. The investigators emphasize that their data come from a single health-care system, lack a control group, and were generated through retrospective review of heterogeneous clinical records. Selection bias may have favored patients healthy enough to receive combination therapy, while inconsistent imaging could have affected response classification. Nevertheless, the study provides one of the more substantial real-world datasets for this neglected population and suggests that squamous histology alone should not automatically exclude patients from consideration of the regimen. Prospective multicenter research, standardized response assessment, longer follow-up, and integrated Nectin-4 and immune profiling will be needed to determine which patients are most likely to experience durable benefit.
Subject of Research: Enfortumab vedotin plus pembrolizumab in urothelial carcinoma with squamous divergent differentiation and pure squamous cell carcinoma
Article Title: Real-world outcomes and prognostic determinants of enfortumab vedotin plus pembrolizumab in urothelial carcinoma with squamous divergent differentiation and pure squamous cell carcinoma
Article References: Zarka, J., Tabiim, A., Lucien, F. et al. “Real-world outcomes and prognostic determinants of enfortumab vedotin plus pembrolizumab in urothelial carcinoma with squamous divergent differentiation and pure squamous cell carcinoma.” Cancer Immunology, Immunotherapy (2026).
Image Credits: AI Generated
DOI: 10.1007/s00262-026-04535-4
Keywords: Urothelial carcinoma; squamous cell carcinoma; squamous divergent differentiation; enfortumab vedotin; pembrolizumab; antibody–drug conjugates; immunotherapy; Nectin-4; treatment outcome; metastatic cancer
