Editor's Note: The 2026 European Society for Medical Oncology (ESMO) Congress featured several important advances in urothelial carcinoma, with Nectin-4-targeted therapies continuing to attract considerable attention. A total of 34 studies involving enfortumab vedotin were presented.For many years, the standard treatment approach for muscle-invasive bladder cancer (MIBC) has centered on neoadjuvant chemotherapy followed by radical surgery, leaving considerable room for further exploration of perioperative systemic treatment. The breakthrough findings from the EV-303 and EV-304 studies extend beyond demonstrating that enfortumab vedotin-based combination regimens can significantly improve event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) rates. More importantly, these studies have explored an integrated perioperative treatment model in which the same combination regimen is administered across preoperative neoadjuvant therapy, radical surgery, and postoperative adjuvant treatment, establishing a continuous perioperative treatment pathway. This approach offers a new option for perioperative MIBC management.
Both studies were subsequently published in The New England Journal of Medicine (NEJM), and the corresponding treatment regimens have received US Food and Drug Administration (FDA) approval in stages. Their study populations included both patients eligible for cisplatin-based treatment and those who were ineligible for or declined cisplatin. In this issue, we invited Professor Dingwei Ye of Fudan University Shanghai Cancer Center to provide an in-depth interpretation of the clinical value and future research directions of this treatment model in light of the latest findings presented at the 2026 ESMO Congress.
From Sequential Interventions to Integrated Treatment: The Continued Evolution of Perioperative MIBC Management
For many years, MIBC treatment has followed a three-stage structure involving separate decisions before surgery, during surgery, and after surgery. Neoadjuvant chemotherapy, typically cisplatin-based, is administered before surgery to achieve tumor downstaging; surgery provides local disease control; and the decision of whether to administer adjuvant treatment, as well as the choice of regimen, is often reconsidered at a new postoperative assessment. This approach has left two notable gaps in the clinical evidence. First, the recurrence risk in patients with high-risk postoperative features is not adequately addressed by the preceding treatment strategy. Second, patients who are ineligible for or decline cisplatin have long lacked randomized trial-validated treatment options in the preoperative setting.
Integrated perioperative treatment brings preoperative deep tumor response, timely surgical implementation, and postoperative risk management into a unified evaluation framework. The perioperative design of enfortumab vedotin-based combination therapy follows precisely this rationale. It extends the focus of treatment beyond any single stage to encompass the entire perioperative period, potentially enabling patients to achieve deeper tumor responses and more durable disease control.
From Deep Responses to Long-Term Benefit: EV-303 and EV-304 Strengthen the Evidence for Integrated Perioperative Treatment
Among patients eligible for cisplatin-based treatment, the Phase III EV-304 study compared perioperative treatment with an enfortumab vedotin-based combination regimen against surgery following neoadjuvant gemcitabine plus cisplatin chemotherapy. At a median follow-up of 33.6 months, the 2-year EFS rate in the combination treatment group reached 79.4%, representing a 47% reduction in the risk of disease progression, recurrence, or death. The pCR rate increased from 32.5% to 55.8%, and an OS benefit was also observed.
Among patients who were ineligible for or declined cisplatin, the Phase III EV-303 study further expanded the applicability of this treatment model. Compared with radical cystectomy alone, perioperative treatment with enfortumab vedotin plus pembrolizumab increased the 2-year EFS rate from 39.4% to 74.7% and the pCR rate from 8.6% to 57.1%, while also demonstrating an OS benefit.
Together, these two Phase III studies cover different cisplatin eligibility populations and demonstrate that enfortumab vedotin-based combination regimens can achieve deeper pathological responses while extending clinical benefits to long-term outcomes such as EFS and OS. They are helping move MIBC treatment away from a focus on individual treatment stages toward an integrated perioperative approach connecting preoperative therapy, surgery, and postoperative treatment.
The intention-to-treat (ITT) population analysis of EV-303 presented at the 2026 ESMO Congress further supplemented this evidence. The 2-year EFS rate in the enfortumab vedotin combination group was 75.8%, and the pCR rate was 58.8%, providing further support for the value of this perioperative approach from the perspective of the broader study population.
From Efficacy Benefits to Comprehensive Perioperative Benefits: Multidimensional Evidence Enriches Treatment Evaluation
The feasibility of integrated perioperative treatment first depends on whether preoperative therapy can be successfully followed by surgery. In EV-303, the proportions of patients undergoing radical cystectomy were 87.6% in the combination treatment group and 89.7% in the control group. In EV-304, the corresponding proportions were 86.7% and 89.6%. The similar surgical rates in both studies suggest that this strategy can be successfully integrated with radical surgery.
However, feasibility does not mean zero risk. In EV-304, 3.2% of patients were unable to undergo surgery because of adverse reactions, and approximately 7% experienced a delay of more than eight weeks between their last neoadjuvant treatment and surgery. Skin reactions, peripheral neuropathy, and hyperglycemia are key adverse events requiring attention during enfortumab vedotin treatment, while immune-related adverse events also require ongoing assessment. Pretreatment risk evaluation, dynamic monitoring during treatment, and timely intervention are essential to translating the goal of “on-schedule surgery” from clinical trial data into routine practice.
The ctDNA analysis of EV-304 presented at this year’s ESMO Congress showed that the ctDNA clearance rate was 82.1% in the combination treatment group, compared with 66.7% in the gemcitabine plus cisplatin group. Regardless of ctDNA status before neoadjuvant treatment or after surgery, the enfortumab vedotin combination group demonstrated better EFS, and patients who achieved ctDNA clearance had more favorable outcomes. These findings suggest that ctDNA may help researchers better understand the relationship between molecular residual disease and treatment outcomes. However, this remains exploratory evidence, and the potential use of ctDNA to guide perioperative treatment decisions and patient stratification requires further validation.
The health-related quality-of-life (HRQoL) analysis of EV-304 showed that at postoperative week 42, no clinically meaningful differences were observed between the two groups in overall health status/quality of life, physical functioning, role functioning, or several other domains, including bowel, urinary, and sexual function. Sexual function scores declined in both groups, consistent with the impact of radical cystectomy itself.
Therefore, the evaluation of perioperative treatment should not stop at preoperative tumor shrinkage or pathological findings after surgery. It should comprehensively consider disease control, survival outcomes, molecular indicators, and patients’ long-term quality of life. As additional follow-up data and patient-reported outcomes accumulate, clinicians will have a more comprehensive evidence base for understanding the benefits experienced by different patient populations and further optimizing treatment decisions.
Continued Exploration of Combination Strategies: Further Expanding the Perioperative Evidence for Enfortumab Vedotin
As evidence from EV-303 and EV-304 continues to accumulate, the body of evidence supporting enfortumab vedotin-based perioperative treatment for MIBC is expanding. The Phase III VOLGA study presented at this year’s ESMO Congress further extended this investigation. Among patients who were ineligible for or declined cisplatin, enfortumab vedotin combined with durvalumab significantly improved EFS and OS, further confirming the clinical value of enfortumab vedotin in perioperative MIBC treatment.
Unlike the perioperative approach in EV-303 and EV-304, in which enfortumab vedotin plus pembrolizumab was administered across the perioperative period, VOLGA adopted a different immunotherapy combination and treatment schedule. These Phase III studies, through their distinct treatment designs, continue to enrich the evidence supporting enfortumab vedotin-based perioperative treatment and further expand its potential applications in MIBC.
Focusing on Long-Term Disease Control: Further Exploring Bladder-Preserving Treatment
When preoperative systemic therapy achieves a sufficiently deep response, a natural follow-up question arises: Must all patients who achieve a deep response undergo radical cystectomy?
Radical cystectomy remains a cornerstone of treatment for muscle-invasive bladder cancer. However, this procedure may have long-term adverse effects on urinary function, body image, and quality of life. Therefore, exploring bladder-preserving strategies tailored to individual patients, while maintaining adequate tumor control, represents another important direction in comprehensive MIBC management.
Bladder preservation is not a new concept. Classical trimodality therapy generally refers to a bladder-preserving approach combining maximal transurethral resection of bladder tumor with radiotherapy and concurrent chemotherapy. Meanwhile, clinical studies are also exploring strategies to avoid radical cystectomy after systemic treatment, provided that patients undergo rigorous assessment and close monitoring. The designs of the EV-209 and EV-309 studies presented at ESMO 2026 reflect continued progress in this direction.
EV-209 is a single-arm Phase II study evaluating the bladder-preserving potential of enfortumab vedotin-based combination therapy in patients with MIBC. Its primary endpoints include the clinical complete response (cCR) rate in the overall population and the 2-year bladder-intact event-free survival rate among patients who achieve cCR. EV-309 is a randomized Phase III study comparing enfortumab vedotin-based combination therapy with a chemoradiotherapy strategy, further evaluating outcomes including bladder-intact event-free survival and OS.
Expert Perspective: From Integrated Perioperative Treatment to Comprehensive Long-Term Management
Driving Innovation in Perioperative Treatment Through an Integrated Care Pathway
From the perspective of surgery and comprehensive long-term management, the significance of EV-303 and EV-304 lies not merely in adding another perioperative treatment option. More importantly, enfortumab vedotin-based combination regimens connect preoperative deep response, radical surgery, continued postoperative treatment, and long-term outcomes into a comprehensive treatment pathway.
This shifts the clinical focus from determining “how to treat at a particular stage” to considering “how to coordinate the entire treatment pathway around the patient’s long-term benefit.” This strategy requires deeper preoperative responses to support appropriately timed and standardized surgery, postoperative treatment to consolidate durable disease control, and meticulous management of adverse events, surgical eligibility, and postoperative recovery to ensure a smooth transition between treatment and surgery.
Dimensions such as ctDNA and HRQoL further expand treatment evaluation beyond tumor response itself to encompass molecular risk and the patient’s overall treatment experience. In this way, perioperative treatment is evolving from a sequence of separate stages toward comprehensive management centered on long-term benefit.
Conclusion
From the encouraging results of EV-304 in patients eligible for cisplatin-based treatment, to the perioperative evidence provided by EV-303 for patients who are ineligible for or decline cisplatin, and the continued exploration of ctDNA, quality of life, and bladder-preserving strategies, research on enfortumab vedotin-based combination therapy is steadily enriching the evidence base for comprehensive MIBC treatment.
The key to perioperative MIBC management lies not only in selecting the appropriate systemic therapy, but also in integrating preoperative treatment, radical surgery, and postoperative adjuvant therapy into a coordinated pathway, while developing individualized treatment plans based on patients’ disease characteristics, treatment tolerability, and quality-of-life needs. As longer-term follow-up data and further research findings become available, the clinical positioning of integrated perioperative treatment and bladder-preserving strategies will continue to evolve.
