Editor's Note: The 2026 Pujiang Urologic Oncology Academic Conference was held in Shanghai. The rapid development of antibody–drug conjugates (ADCs) and immunotherapy is moving the treatment of urothelial carcinoma beyond later-line advanced disease to first-line treatment, the perioperative setting, and even non-muscle-invasive disease. At the same time, the clinical introduction of ADCs with multiple targets and payloads has raised new challenges, including treatment sequencing, cross-resistance, and cumulative toxicity. Oncology Frontier – UroStream invited Professor Xiaojie Bian of Fudan University Shanghai Cancer Center for an interview to discuss the earlier use of ADCs, sequencing strategies, perioperative investigations, and comprehensive safety management throughout the treatment continuum.Moving Treatment Earlier: From Advanced Disease to the Perioperative Setting in Response to Clinical Needs
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ADCs are gradually moving from later-line treatment of advanced urothelial carcinoma into first-line and perioperative settings. What is the core evidence-based rationale driving this transition? How should clinicians develop individualized treatment strategies for patients at different disease stages?
Professor Xiaojie Bian: The development of ADCs for urothelial carcinoma is fundamentally driven by unmet clinical needs. Although patients with advanced disease account for a relatively small proportion of the overall population at initial diagnosis, they generally have a poor prognosis and limited survival. Therefore, early studies initially focused on patients whose disease had progressed after multiple prior lines of therapy, with the goal of prolonging survival and improving quality of life. After single-agent ADCs demonstrated activity in later-line settings, their use gradually expanded into second-line and first-line treatment of advanced disease, followed by combination strategies with immunotherapy.
Once first-line studies in advanced disease demonstrated high tumor response rates and deep responses, research naturally extended into the perioperative setting. The clinical focus is not simply on whether a tumor can be reduced in size, but, more importantly, on whether treatment can improve the quality of curative surgery, reduce the risk of postoperative recurrence, and explore the possibility of organ preservation for selected patients. Therefore, moving treatment earlier does not mean simply transferring regimens used in advanced disease to earlier stages. Instead, endpoints, treatment duration, and safety requirements must be redefined according to the disease stage.
At the individual patient level, treatment decisions should still take into account disease stage, tumor burden, pathological and molecular characteristics, performance status, renal function, comorbidities, prior treatment, and the patient’s preferences regarding organ preservation. In advanced disease, the priorities are rapid disease control and survival benefit. In the perioperative setting, treatment must balance pathological response, surgical safety, and recurrence risk. Organ-preservation strategies, particularly bladder-preservation approaches, require even more rigorous response assessment and follow-up. All treatment decisions should be grounded in the patient’s disease characteristics and genuine clinical needs.
Breaking Through Sequencing Challenges: Target, Payload, and Patient Selection Are All Essential
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As more ADCs enter first-line treatment, clinicians are increasingly confronted with questions regarding subsequent treatment sequencing and cross-resistance. Is cross-resistance between ADCs primarily determined by the target, antibody design, or payload? Which patients are more likely to benefit from sequential ADC therapy?
Professor Xiaojie Bian: The ADCs most commonly used in urothelial carcinoma currently include enfortumab vedotin (EV), which targets Nectin-4, and disitamab vedotin (DV), which targets HER2. Although they have different targets, both use monomethyl auristatin E (MMAE) as their payload. Whether switching to another ADC with the same MMAE payload after prior treatment with an MMAE-based ADC may compromise efficacy because of payload-related resistance is an important clinical concern.
Current evidence is still largely based on early-phase studies and exploratory analyses, but some directional signals have emerged. After treatment with EV, switching to an ADC carrying a topoisomerase I inhibitor payload has been associated with tumor responses in approximately 30% of patients in some studies. By contrast, sequential treatment with ADCs sharing the same MMAE payload has not consistently produced satisfactory outcomes. These findings suggest that ADC sequencing should not be guided solely by whether the targets differ. Payload mechanism, linker characteristics, depth of prior response, and resistance patterns should also be considered. These conclusions still require validation in larger studies and prospective trials.
Target expression can also help refine patient selection. Nectin-4 is generally highly expressed in urothelial carcinoma, and routine target testing is not typically a prerequisite for the clinical use of EV. For DV, however, HER2 expression may have more direct value in patient stratification. In previous studies, patients with higher HER2 expression have often shown more favorable response signals. Future assessments should incorporate target expression, spatial heterogeneity, and changes in expression following treatment, rather than relying solely on a single baseline test.
Therefore, I view ADC sequencing as a multidimensional decision-making process: it requires consideration of both the target and the payload, as well as tumor biology, prior treatment response, and residual toxicity. Where appropriate, priority should be given to switching to a different payload mechanism. Clinical studies are also needed to determine the optimal treatment sequence, interval between therapies, and potential combination strategies.
Summary
Professor Xiaojie Bian noted that ADCs are driving the treatment of urothelial carcinoma from later-line advanced disease into first-line, perioperative, and earlier-stage settings, including non-muscle-invasive bladder cancer (NMIBC). In the era of multiple targets and payloads, clinical decision-making must account for target expression, payload mechanisms, prior treatment response, residual toxicity, and disease stage, rather than relying on a single factor to determine treatment sequencing.
The move toward earlier treatment must also go hand in hand with standardized perioperative multidisciplinary collaboration, rigorous organ-preservation assessment, and comprehensive safety management throughout the treatment continuum. Only by maintaining a dynamic balance among efficacy, dosage, treatment duration, and quality of life can the innovative potential of ADCs be consistently translated into long-term patient benefit.
Professor Xiaojie Bian
