For many years, systemic treatment of locally advanced or metastatic urothelial carcinoma has relied primarily on platinum-based chemotherapy. However, the recently reported EV-302 study has disrupted the traditional treatment paradigm. This study highlights the potential of novel antibody-drug conjugates (ADCs) combined with immune checkpoint inhibitors (ICIs) as a first-line treatment, showing promising trends in both progression-free survival (PFS) and overall survival (OS).At the 5th CUDA Yanqi Lake Meeting—held from April 11 to 13, 2025, by the Chinese Urological Doctor Association—Professor Wasilijiang Wahafu from the Cancer Hospital, Chinese Academy of Medical Sciences, delivered an insightful presentation titled "Enfortumab Vedotin: Ushering in a New Era in First-Line Therapy for Locally Advanced/Metastatic Urothelial Carcinoma." In an exclusive interview with Oncology Frontier – UroStream, Professor Wahapu further discussed the clinical implications of the EV-302 study and shared his perspectives on future directions in this evolving field.UroStream: Chemotherapy has long been the backbone of treatment for advanced urothelial carcinoma, yet many unmet needs persist. Based on your clinical experience, could you share why cisplatin-based chemotherapy is often limited in this patient population? What are the main challenges in treating these patients?
Professor Wasilijiang Wahafu: Chemotherapy remains the mainstay of treatment for advanced urothelial carcinoma, although new therapies are gradually emerging. Current clinical guidelines still recommend chemotherapy as the standard first-line approach. However, there are notable limitations.
First, chemotherapy eligibility depends heavily on renal function. Approximately 30% to 50% of patients with advanced urothelial carcinoma present with renal impairment. In such cases, cisplatin cannot be used, and carboplatin becomes the alternative. For patients with a glomerular filtration rate (GFR) below 30, even carboplatin is contraindicated, making platinum-based therapy unsuitable.
Second, many of these patients—particularly those with bladder cancer—are elderly and frail, often with an ECOG performance status of ≥2 and multiple comorbidities. These factors further limit their ability to tolerate chemotherapy.
Additionally, chemotherapy can lead to various complications, including peripheral neuropathy and hearing loss. But beyond toxicity, the key issue is efficacy. Median progression-free survival (PFS) for cisplatin-based regimens is typically under 10 months, and overall survival (OS) is around 12–24 months. For carboplatin-based regimens, outcomes are even worse, with PFS often less than 6 months and OS approximately 10 months. These limitations underscore the need for more effective and tolerable treatment options.
UroStream: With the rise of ADCs, the EV-302 trial has introduced a new first-line option for these patients. How does this combination approach overcome traditional treatment limitations? What are the clinical implications of combining immunotherapy with ADCs?
Professor Wasilijiang Wahafu: The EV-302 trial represents a major breakthrough. It’s a global, phase III study evaluating the combination of enfortumab vedotin and pembrolizumab (EV+P) versus standard platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic urothelial carcinoma. The results have been remarkable.
With a median follow-up of 29.1 months, EV+P nearly doubled both progression-free survival and overall survival:
- Median PFS: 12.5 vs. 6.3 months (HR=0.48; 95% CI: 0.41–0.57; P<0.00001)
- Median OS: 33.8 vs. 15.9 months (HR=0.51; 95% CI: 0.43–0.61; P<0.00001)
Objective response rates were also significantly higher in the EV+P arm (67.5% vs. 44.2%), with complete response rates of 30.4% compared to 14.5%. In terms of safety, grade ≥3 treatment-related adverse events occurred in 55.9% of patients in the EV+P group versus 69.5% in the chemotherapy arm. Clearly, this combination not only improves outcomes but also reduces toxicity—offering an excellent new first-line option.
Mechanistically, this combination leverages synergistic effects. ADCs like enfortumab vedotin deliver cytotoxins directly to tumor cells, leading to cell death and the release of tumor antigens, which can enhance the immune response. Enfortumab vedotin targets the Nectin-4 protein and uses the cytotoxic agent MMAE to disrupt microtubules. By inducing immunogenic cell death, it boosts the efficacy of pembrolizumab, a PD-1 inhibitor. This dual mechanism creates a “1+1>2” effect, offering a new model for combination therapy.
Another key takeaway from EV-302 is its broad applicability. Previous treatments often required patient stratification based on PD-L1 expression or other biomarkers. However, EV-302 showed consistent benefits regardless of PD-L1 status. Exploratory analyses presented at last year’s ESMO Congress also demonstrated that the combination is effective across all levels of Nectin-4 expression. Moreover, the regimen proved effective in patients with liver metastases and renal impairment—groups traditionally considered difficult to treat.
In summary, EV-302 not only presents a new therapeutic paradigm but also expands our understanding of treatment possibilities in urothelial carcinoma. It brings renewed hope for improved survival and better quality of life for patients with this challenging disease.
UroStream: What are the potential strategies for treatment beyond enfortumab vedotin? How can we further optimize the overall management of patients with advanced urothelial carcinoma?
Professor Wasilijiang Wahafu: We’ve already seen the strong efficacy of enfortumab vedotin in combination with pembrolizumab, but this is just the beginning. Future directions may involve exploring additional combination strategies—such as integrating radiotherapy or cellular therapies. The key questions are: Can these modalities be incorporated? If so, how should we combine them, and when is the optimal timing? These are essential considerations for improving treatment outcomes and must be the focus of future research.
Another important area is treatment duration. In the EV-302 trial, pembrolizumab was administered for up to 35 cycles—approximately two years. The question is: what comes after those two years? Data presented at this year’s ASCO GU, with a median follow-up of 29.1 months, showed sustained benefit with EV+P, and 74.3% of patients who achieved complete response (CR) remained in remission. However, as with any treatment—whether traditional chemotherapy or EV+P—resistance may eventually develop. Once resistance emerges, the choice of subsequent therapy becomes a crucial challenge. We’re paying close attention to post-EV-302 treatment strategies, including combining additional modalities, investigating resistance mechanisms, and selecting the next line of therapy for long-term disease control.
Beyond individual therapies, comprehensive management of advanced urothelial carcinoma is becoming increasingly vital. First, patient stratification is essential—identifying who benefits most from which treatment. While EV+P has shown benefit across the entire study population, other targets like HER2 and TROP-2 may lead to new ADC developments. Future research may explore these targets and evaluate potential domestic immunotherapy combinations. We also need to consider whether testing the tumor immune microenvironment or biomarkers is necessary, and whether tools like ctDNA or liquid biopsy can guide real-time monitoring and treatment decisions.
Additionally, we must address adverse event management throughout the treatment course. At this year’s EAU Congress, a dedicated “Patient Day” highlighted how drug-related side effects can significantly impact patients with advanced disease. This underscores the importance of toxicity management—not allowing the therapy to weaken the patient and compromise outcomes. Effective toxicity control requires coordinated efforts from a multidisciplinary team, including surgery, medical oncology, radiation oncology, pathology, imaging, rehabilitation, and even psychosocial support. Multidisciplinary tumor boards (MDTs) play a key role in ensuring a structured and holistic approach to care.
In summary, the EV-302 study has opened a new chapter in the treatment of advanced urothelial carcinoma, revealing the promise of novel treatment paradigms. Going forward, we must focus on patient stratification, toxicity management, and the implementation of multidisciplinary care models to further improve outcomes and quality of life for patients.
Professor Wasilijiang Wahafu
Deputy Chief Physician, Department of Urology Surgery, Cancer Hospital, Chinese Academy of Medical Sciences
- Doctorate in Urology, Peking University First Hospital
- Doctorate in Urology, General Hospital of the People’s Liberation Army
- Visiting scholar, Department of Urology, University Hospital Hamburg-Eppendorf, Germany
- Member, Bladder Cancer Collaboration Group, Urology Branch, Chinese Medical Doctor Association (CUDA)
- Member, Genitourinary Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Committee Member, Kidney Cancer Expert Panel, CACA Genitourinary Oncology Branch
- Committee Member, Rare Kidney Tumor Collaboration Group, CACA Genitourinary Oncology Branch
- Member, Urologic Engineering Group, CUDA
- Member, Kidney Research Collaboration Group, Chinese Urological Association (CUA)
- Member, Working Group on Enhancing Diagnosis and Treatment Capabilities of Rare Diseases, National Health Commission of China
- Member, Cross-Strait Medical Exchange Association, Urology Committee
- Member, Beijing Society of Clinical Oncology
- Executive Editor, JCO Chinese Edition Special Issue on Systemic Therapy for Urologic Oncology
