Upcoming data for the HER2-ADC Disitamab Vedotin will test if its efficacy is enriched in HER2-high patients. This trial spotlights a key field-wide dilemma: is specific enrichment necessary, or does a "bystander effect," as seen in breast cancer, mean even low HER2 expression is enough, complicating patient selection and the drug's positioning.

When immunotherapy is not an option for metastatic bladder cancer, enfortumab vedotin (EV) monotherapy is an attractive choice over traditional cisplatin chemotherapy, especially if a rapid tumor response is critical or if the patient has baseline neuropathy or renal issues that make chemotherapy tolerance uncertain.

Although enfortumab vedotin (EV) targets nectin-4, its expression level is a poor predictive biomarker. Even patients with no detectable nectin-4 have achieved complete responses. This makes expression testing clinically unhelpful for patient selection, a counterintuitive finding for a targeted therapy.

New research on paired tumor biopsies suggests a mechanism for rapid resistance to enfortumab vedotin. In early progressors, Nectin-4 expression appears to shift from the cell surface to the cytoplasm, preventing the ADC from effectively binding and delivering its payload.

The combination of enfortumab vedotin and pembrolizumab is not just improving median survival in metastatic bladder cancer; it's creating a "tail on the curve," suggesting a subset of patients may achieve long-term durable responses, a rarity in this advanced setting.

The current pipeline for antibody-drug conjugates (ADCs) in bladder cancer focuses on incremental changes. These include creating "me-too" drugs similar to Enfortumab Vedotin, or swapping its toxic payload for a different one while keeping the same Nectin-4 target. No immediate practice-changing breakthroughs are expected.

A next-generation Nectin-4 targeting ADC demonstrated a 33% response rate in patients who had already progressed on enfortumab vedotin (EV). This indicates that Nectin-4 remains a viable therapeutic target post-EV, suggesting resistance is not always due to target loss.

The demonstrated superiority of the enfortumab vedotin (EV) and pembrolizumab combination over platinum chemotherapy has effectively made the Galski criteria, used for determining cisplatin eligibility, irrelevant. This marks a major paradigm shift in how frontline bladder cancer is approached, moving beyond platinum-based decisions.

In mixed histology bladder cancers treated with standard urothelial therapy, the variant component (e.g., squamous) is hypothesized to be the source of the resistant clone that emerges after treatment. This suggests post-progression biopsies are key to understanding resistance.