Editor’s Note: Non–muscle-invasive bladder cancer (NMIBC) carries a substantial risk of postoperative recurrence, particularly in high-risk and very high-risk patients, where the 5-year recurrence rate can exceed 50%. In recent years, beyond traditional Bacillus Calmette–Guérin (BCG) intravesical therapy, the emergence of immune checkpoint inhibitors (ICIs) and antibody–drug conjugates (ADCs) has provided new therapeutic options to reduce recurrence risk in high-risk NMIBC. At the 2026 European Association of Urology Congress (EAU 2026), Professor Yi-Jun Shen from Fudan University Shanghai Cancer Center presented the ongoing phase III HERO study. This trial investigates disitamab vedotin, a novel HER2-targeted ADC, in combination with BCG intravesical therapy for BCG-naïve high-risk NMIBC patients, with the aim of generating high-quality evidence to support this combination strategy in clinical practice.
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Question: TURBT followed by BCG remains the standard of care for high-risk NMIBC (HR-NMIBC), yet recurrence and progression remain common. What are the key challenges and unmet clinical needs in current practice?
Professor Yi-Jun Shen: High-risk NMIBC is the most common type of bladder cancer, accounting for approximately 75%–80% of all cases, and has long been a central focus in uro-oncology. Despite standard transurethral resection of bladder tumor (TURBT), recurrence rates remain high, representing a major clinical challenge.
In the era of intravesical chemotherapy, 5-year recurrence rates reached as high as 80%–90%. Even with current standard BCG therapy, recurrence rates remain 50%–70% at 5 years. These data highlight both the large patient population and the persistent limitations of existing treatments, underscoring a significant unmet clinical need.
Two key areas of unmet need stand out:
First, diagnostic challenges remain significant, particularly in the detection of carcinoma in situ (CIS), which is a critical prognostic factor affecting recurrence and outcomes. However, current detection rates are suboptimal. Inadequate identification of CIS can compromise treatment decisions and ultimately impact survival. Therefore, there is an urgent need to advance beyond traditional diagnostic approaches by incorporating biomarker-based strategies and novel imaging-guided cystoscopy techniques to improve detection accuracy.
Second, there is a clear need for more personalized treatment strategies. Current clinical decision-making still relies heavily on clinicopathologic features, which are increasingly insufficient in the era of precision medicine. Future efforts should focus on biomarker-driven patient stratification and individualized treatment approaches to reduce recurrence risk and improve long-term outcomes.
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Question: Your team previously reported preliminary results of a phase II study combining disitamab vedotin with BCG at EAU 2025. Could you briefly summarize those findings?
Professor Yi-Jun Shen: Despite BCG therapy, recurrence rates in HR-NMIBC still exceed 50%, prompting the exploration of more effective treatment strategies. Once patients become unresponsive to BCG, therapeutic options are extremely limited, with radical cystectomy being the only guideline-recommended approach. However, this procedure significantly compromises quality of life, and many patients are unwilling to undergo it, making bladder preservation an urgent clinical priority.
Our study focused on HER2-expressing (IHC 1+/2+/3+) BCG-naïve patients with very high-risk disease who were either ineligible for or declined radical cystectomy.
Cohort A included patients with incomplete tumor resection or concomitant CIS, while Cohort B included patients who had undergone complete tumor resection.
All patients received eight cycles of disitamab vedotin (2 mg/kg every three weeks) combined with at least one year of BCG therapy.
At EAU 2025, we reported preliminary data from 20 patients. The short-term follow-up results were highly encouraging: in Cohort A, the complete response (CR) rates at both 3 and 6 months reached 100%; in Cohort B, the event-free survival (EFS) rates at 6 and 12 months were also 100%.
These findings suggest that the combination of BCG with disitamab vedotin has the potential to significantly improve outcomes, particularly in patients with very high-risk NMIBC. Based on these promising results, we have advanced to a prospective randomized study to further validate this strategy.
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Question: Could you introduce the design of the phase III HERO study and its potential clinical impact?
Professor Yi-Jun Shen: The HERO study is an open-label, randomized, multicenter phase III trial designed to evaluate the efficacy and safety of disitamab vedotin combined with BCG in patients with HR-NMIBC.
In the control arm, patients receive the current standard of care—BCG induction followed by maintenance therapy. In the experimental arm, disitamab vedotin is added to BCG, with a total treatment duration of two years.
Disitamab vedotin has already demonstrated notable efficacy in advanced urothelial carcinoma and in the perioperative setting for muscle-invasive bladder cancer (MIBC), significantly improving patient outcomes. The key question this study seeks to address is whether adding disitamab vedotin to standard BCG therapy can further enhance treatment efficacy in HR-NMIBC.
A distinctive feature of the study is the adoption of a “stop-and-go” dosing strategy. During the BCG induction phase, patients receive disitamab vedotin intravenously at 2.0 mg/kg every two weeks for four doses. If no primary endpoint event occurs, treatment is paused. During the maintenance phase, patients receive two consecutive doses at months 3, 6, 12, 18, and 24, for a total of ten doses.
This intermittent dosing strategy differs from continuous dosing approaches used in advanced or perioperative settings. It is designed to extend treatment duration while minimizing toxicity and improving patient adherence, thereby achieving a balance between efficacy and safety.
Although previous studies combining BCG with immunotherapy have reported promising results, experts at EAU 2026 remain cautious about their ability to change clinical practice. A key unresolved issue is how to accurately identify patients who are most likely to benefit from combination therapy.
In this context, the HERO study is particularly valuable. By incorporating biomarker-driven patient selection based on HER2 expression, it aims to refine treatment strategies within a precision medicine framework and provide more robust evidence to guide clinical decision-making.
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Question: What is your perspective on the role of HER2 as a biomarker in NMIBC?
Professor Yi-Jun Shen: HER2 is emerging as an increasingly important biomarker in bladder cancer, demonstrating both predictive and prognostic value in muscle-invasive and non–muscle-invasive disease.
In NMIBC, accumulating evidence suggests that patients with HER2 overexpression tend to respond less favorably to standard BCG therapy. HER2 overexpression has been identified as an independent predictor of poor response to BCG treatment.
From a clinical perspective, the value of HER2 lies in two main areas. First, it enables more precise patient stratification. Traditional “one-size-fits-all” treatment strategies are becoming increasingly inadequate in the era of precision medicine. HER2 allows us to identify a subgroup of patients who may benefit from tailored therapeutic approaches.
Second, HER2 provides a viable target for novel therapies. Antibody–drug conjugates targeting HER2, such as disitamab vedotin, offer new opportunities to improve outcomes. Combining HER2-targeted therapy with standard BCG treatment may enhance efficacy and address the limitations of current treatment strategies.
Looking ahead, with broader implementation of HER2 testing and continued advances in targeted therapies, HER2 is expected to play an increasingly central role in risk stratification, response prediction, and individualized treatment decision-making in NMIBC.
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Question: What are your perspectives on future treatment strategies for HR-NMIBC?
Professor Yi-Jun Shen: BCG remains the cornerstone of treatment for HR-NMIBC. However, with the rapid development of new therapies, the treatment landscape is evolving.
A range of novel strategies is currently being explored, including combinations of BCG with immunomodulatory agents such as IL-15, as well as oncolytic virus therapies for patients with BCG-unresponsive disease. These innovations are reshaping the future direction of NMIBC management.
In the context of precision medicine, accurately identifying patients at high risk of progression is critical for optimizing treatment strategies. HER2, as an important biomarker, is gaining increasing recognition for its role in this process. Biomarker-driven patient selection enables the identification of individuals with poorer prognosis and suboptimal response to BCG, allowing for more aggressive and tailored combination treatment approaches.
Although several phase III trials investigating BCG combined with immune checkpoint inhibitors have reported encouraging results, there remains ongoing debate regarding their impact on clinical practice. The central issue lies in determining which patients truly require and benefit from combination therapy.
Ultimately, future research must not only focus on improving efficacy but also ensure that safety remains manageable. The goal is to enhance treatment outcomes without significantly increasing adverse events. Achieving this balance between efficacy and safety is essential to delivering meaningful and durable clinical benefit to patients with HR-NMIBC.
Professor Yi-Jun Shen
