An expert speculates that the durable responses and plateauing four-year survival curve from the EV302 trial indicate a potential cure rate of 30% in metastatic bladder cancer, a dramatic improvement over historical outcomes of 5-10%.
Data from a novel Nectin-4 ADC trial showed zero responses in patients with prior topoisomerase therapy. This strongly suggests that payload resistance, not just the ADC target, is a critical mechanism that will dictate future treatment sequencing.
The EV302 trial update established a new, robust benchmark for second-line therapy. Platinum chemotherapy after EV/Pembrolizumab progression showed only a 21% response rate, which is lower than prior retrospective estimates and highlights the need for better sequencing options.
In patients achieving a complete response on EV-pembrolizumab, leading oncologists are using circulating tumor DNA (ctDNA) clearance in clinical practice to increase confidence and facilitate shared decision-making around stopping treatment, despite it not being standard of care.
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.
A trial for a new Nectin-4 ADC was amended to include mandatory, prospective CYP2D6 genotyping after a few patients experienced life-threatening toxicities. This highlights the growing importance of pharmacogenomics for ensuring the safety of novel ADCs.
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.
Success with shorter, fixed-duration ADC regimens in perioperative bladder cancer trials is prompting oncologists to evolve their thinking in the metastatic setting. The conversation is shifting away from indefinite treatment towards stopping therapy earlier for patients with deep responses.