Following the clinical success and approval of disitamab vedotin (RC48) plus toripalimab in locally advanced or metastatic urothelial carcinoma, attention has shifted toward improving outcomes for patients with muscle-invasive bladder cancer (MIBC) in the perioperative setting, where substantial unmet clinical needs remain. Against this backdrop, the HOPE research program continues to expand. HOPE-07, the world’s first randomized perioperative trial evaluating a HER2-targeted antibody-drug conjugate (ADC) combined with a PD-1 inhibitor, has officially been launched. The study is expected to introduce a novel treatment strategy for the comprehensive perioperative management of HER2-expressing MIBC.
To mark this milestone, UroStream invited investigators from participating centers across China—including Prof. Peng Zhang and Prof. Ping Tan (West China Hospital, Sichuan University), Prof. Qiang Lü (Jiangsu Provincial People’s Hospital), Prof. Shi Fu and Prof. Qiao Xiong (The Second Affiliated Hospital of Kunming Medical University), Prof. Hailong Hu (The Second Hospital of Tianjin Medical University), Prof. Zheng Liu (Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), and Prof. Mengni Zhang (West China Hospital, Sichuan University)—to discuss the study’s scientific rationale, patient selection, biomarker exploration, and real-world clinical implications.
Building a Comprehensive Chinese Framework for Urothelial Cancer Management
UroStream: From the bladder-preserving strategies explored in HOPE-02 (chemo-immunotherapy) and HOPE-03 (targeted immunotherapy) to the perioperative focus of HOPE-07 in MIBC, the HOPE program is progressively establishing a comprehensive management framework for urothelial carcinoma in China. Could you introduce the overall design philosophy behind the HOPE series? What strategic role does HOPE-07 play within this research program?
Prof. Peng Zhang
West China Hospital, Sichuan University
Over the past decade, the treatment landscape for urothelial carcinoma has undergone remarkable transformation, driven by the continuous development of innovative therapies and treatment strategies. From the emergence of immune checkpoint inhibitors around 2015, to the introduction of antibody-drug conjugates (ADCs), and more recently the rapid evolution of targeted immunotherapy combinations, therapeutic options have expanded significantly. In muscle-invasive bladder cancer (MIBC), the perioperative treatment paradigm has also evolved substantially. Current practice emphasizes a comprehensive management approach consisting of neoadjuvant therapy, standardized radical surgery, and postoperative adjuvant treatment—a “sandwich” strategy that has increasingly become the accepted standard of care.
Against this background, we initiated the HOPE clinical research program to systematically investigate treatment strategies across the spectrum of urothelial carcinoma. Our work has included comparisons of immunotherapy versus chemotherapy, evaluation of chemotherapy plus immunotherapy versus chemotherapy alone followed by bladder-preserving radiotherapy, and exploration of ADC-based neoadjuvant immunotherapy followed by adjuvant radiotherapy for bladder preservation. These studies have already generated encouraging preliminary findings.
Despite these advances, important unmet clinical needs remain. This provided the rationale for launching HOPE-07, the world’s first randomized controlled trial comparing HER2-targeted ADC plus immunotherapy with chemotherapy plus immunotherapy as neoadjuvant treatment for HER2-positive MIBC. The study is designed to determine whether a HER2 ADC-based regimen can outperform conventional chemotherapy-based treatment, ultimately offering patients with HER2-expressing disease a more precise and effective perioperative therapeutic option that improves long-term clinical outcomes.
As the first randomized controlled study within the HOPE program, HOPE-07 represents a landmark milestone in the evolution of this research platform. We sincerely appreciate the collaboration and commitment of the principal investigators from all participating centers. Through close cooperation, we hope to ensure the successful execution of this important trial and look forward to sharing its results in the near future.
UroStream: HOPE-07 investigates a comprehensive perioperative strategy using disitamab vedotin (RC48) plus toripalimab in both the neoadjuvant and adjuvant settings. Compared with the conventional approach of gemcitabine/cisplatin (GC) chemotherapy plus immunotherapy, what potential advantages do you anticipate from this HER2 ADC plus immunotherapy strategy in terms of achieving deeper pathological responses, eliminating micrometastatic disease, and improving long-term survival outcomes?
Prof. Peng Zhang
West China Hospital, Sichuan University
As discussed earlier, the overall treatment strategy for urothelial carcinoma has progressively evolved toward a comprehensive continuum-of-care model, with the primary goal of maximizing long-term survival through systematic and standardized treatment pathways. Over recent years, several landmark randomized clinical trials—including the EV-303 and EV-304 studies evaluating targeted immunotherapy combinations, as well as the NIAGARA and CheckMate-901 trials investigating chemo-immunotherapy—have produced highly encouraging results.
At the same time, China’s homegrown HER2-targeted antibody-drug conjugate (ADC), disitamab vedotin (RC48), has accumulated nearly eight years of clinical evidence. Across the RC48-C clinical development program—including RC48-C005, RC48-C009, RC48-C011, RC48-C014, RC48-C016, and RC48-C017—the drug has consistently demonstrated robust antitumor activity in multiple clinical settings, including later-line therapy, first-line treatment for advanced disease, and perioperative treatment for early-stage urothelial carcinoma.
For patients with HER2-expressing MIBC, currently available evidence suggests that targeted therapy combined with immunotherapy may offer greater therapeutic potential than conventional chemotherapy plus immunotherapy. However, this hypothesis has yet to be confirmed by high-level clinical evidence. The HOPE-07 study was therefore designed to address this important clinical question through a rigorous randomized controlled trial. We would also like to extend our sincere appreciation to all investigators and collaborators participating in this study for their invaluable contributions to advancing the treatment of urothelial carcinoma.
UroStream: HOPE-07 is the world’s first randomized controlled trial evaluating a HER2-targeted ADC combined with a PD-1 inhibitor in the perioperative treatment of muscle-invasive bladder cancer. If the study ultimately demonstrates positive results, how do you believe it will reshape the perioperative treatment landscape for HER2-positive MIBC in China, and what impact could it have on future clinical guideline recommendations?
Prof. Ping Tan
West China Hospital, Sichuan University
As Prof. Peng Zhang highlighted earlier, HOPE-07 represents a further refinement and advancement over previous perioperative ADC studies. From the outset, the research team established a clear objective: if we were going to undertake this study, it had to address the field’s most important clinical questions with the highest level of scientific rigor. Our goal has always been to generate compelling evidence that can directly inform clinical practice.
Should HOPE-07 ultimately demonstrate positive results, its most immediate impact could be a fundamental shift in the perioperative management of muscle-invasive bladder cancer (MIBC). ADC plus immunotherapy may become a treatment strategy spanning the entire perioperative course, while the role of conventional chemotherapy could gradually become more limited, potentially being reserved primarily for later-line treatment. Such a transition would represent a major milestone in the evolution of MIBC treatment.
Positive findings could also have important implications for future clinical guidelines. If the study confirms its anticipated benefits, targeted therapy combined with immunotherapy may emerge as a new standard neoadjuvant regimen and be incorporated into authoritative guideline recommendations. This would represent a significant advancement in the perioperative treatment pathway for MIBC.
Beyond establishing a new treatment standard, the study is expected to provide valuable insights for future bladder-preservation strategies. We hope that HOPE-07 will help usher in a new era of precision bladder preservation by identifying patients most likely to benefit from ADC-based immunotherapy, while laying the groundwork for further optimization of bladder-preserving approaches and promoting more personalized and effective perioperative treatment.
UroStream: Following the approval of disitamab vedotin (RC48) plus toripalimab as first-line treatment for advanced urothelial carcinoma, with clinical benefit extending to patients with HER2 IHC 1+ tumors, the clinical significance of HER2-low expression is being redefined. HOPE-07 likewise includes patients with HER2 IHC 1+ MIBC. In your opinion, what is the significance of this study design in expanding the role of HER2-targeted ADCs in the perioperative setting? Could patients with HER2 IHC 1+ disease become an important population to target with ADC plus immunotherapy during perioperative treatment?
Prof. Qiang Lü
Jiangsu Provincial People’s Hospital
Based on the findings from the RC48-C016 study, we have clearly observed that patients with HER2 IHC 1+ disease can still derive meaningful clinical benefit from treatment. In fact, across multiple participating centers, clinical experience has shown that patients previously classified as having HER2-low expression—including those with HER2 IHC 2+/ISH-negative and HER2 IHC 1+ tumors—and even a subset of patients with HER2-zero expression, may also benefit from targeted therapy combined with immunotherapy.
During the early planning stages of HOPE-07, we devoted considerable attention to the value of preserving tumor tissue specimens for future translational research. We anticipated that the trial would include a meaningful proportion of patients with HER2 IHC 1+ disease, and retaining these samples provides an important opportunity for further investigation. Should these patients demonstrate clinical benefit, we will be able to explore potential predictive biomarkers that identify which HER2 IHC 1+ patients are most likely to respond to targeted immunotherapy. Such work would represent an important step toward more precise patient selection.
As an example, the single-cell sequencing studies conducted by Prof. Ping Tan’s team have already generated preliminary insights in this area. If we can identify the specific biological characteristics or co-expressed molecular markers associated with treatment response in HER2 IHC 1+ patients, we may be able to further expand the population eligible for ADC-based therapy, allowing more patients to benefit from precision treatment.
UroStream: HOPE-07 incorporates cisplatin dose stratification based on creatinine clearance, recognizing that a substantial proportion of patients with bladder cancer have impaired renal function, limiting their eligibility for conventional cisplatin-based chemotherapy. What is the significance of this study design in improving treatment accessibility and maximizing clinical benefit for real-world patients?
Prof. Shi Fu
The Second Affiliated Hospital of Kunming Medical University
The HOPE-07 study incorporates renal function stratification, highlighting the investigators’ careful attention to clinically relevant patient characteristics. In real-world practice, renal impairment is common among patients with bladder cancer. Many of these individuals are elderly, have multiple comorbidities, or present with advanced disease complicated by urinary tract obstruction, all of which can compromise kidney function and make treatment more challenging.
For this patient population, clinicians frequently need to adjust treatment during both the neoadjuvant and adjuvant settings by modifying drug doses or extending dosing intervals to accommodate reduced renal function. However, these strategies are largely based on clinical experience rather than high-level evidence.
This is precisely why HOPE-07 has prospectively incorporated a dedicated subgroup analysis for patients with impaired renal function. The study is expected not only to generate robust evidence to guide precision treatment for this underserved population, but also to establish a new benchmark for future clinical trial design by systematically addressing a common real-world clinical challenge. Ultimately, this approach has the potential to improve treatment outcomes for patients with urothelial carcinoma.
UroStream: Looking ahead, do you believe HOPE-07 could pave the way for a new standardized perioperative treatment option for patients who are ineligible for full-dose cisplatin?
Prof. Shi Fu
The Second Affiliated Hospital of Kunming Medical University
I believe HOPE-07 holds tremendous promise. Although the study is still in its early stages, as enrollment and follow-up progress, the subgroup data for patients with reduced creatinine clearance will provide much stronger scientific evidence to guide clinical practice and may ultimately inform future guideline updates, helping to refine perioperative treatment standards.
We are particularly looking forward to the long-term follow-up results in this patient population, including 2-year and 5-year event-free survival (EFS) and disease-free survival (DFS) outcomes. These data will allow us to comprehensively evaluate the durability of treatment benefit and long-term survival. At the same time, careful assessment of treatment-related adverse events in patients with impaired renal function will be equally important.
If the study demonstrates both superior efficacy and an acceptable safety profile, this innovative regimen could eventually become a viable alternative to conventional chemotherapy or chemo-immunotherapy for patients with reduced creatinine clearance or renal insufficiency, offering a much-needed new perioperative treatment option for this challenging patient population.
UroStream: HOPE-07 allows the enrollment of patients with HER2 IHC 1+ tumors. Based on your center’s clinical experience, do you have concerns that ADC therapy may be associated with insufficient efficacy or increased off-target effects in this subgroup? What are your recommendations for selecting HER2 IHC 1+ patients, and how might patient selection be further optimized in the future to improve the precision of ADC-based combination therapy?
Prof. Hailong Hu
The Second Hospital of Tianjin Medical University
This is a highly relevant topic and one that clinicians encounter frequently in daily practice. Several factors can influence the accuracy of HER2 testing in routine clinical specimens, including tumor heterogeneity, thermal artifacts caused by transurethral resection, the quantity and quality of tissue obtained, and the characteristics of the diagnostic assay itself. From a surgeon’s perspective, our responsibility is to provide pathologists with adequate, high-quality tissue specimens, as this is the foundation for achieving accurate biomarker assessment and precision treatment.
In clinical practice, HER2 IHC 1+ tumors are relatively common. Based on the results of the RC48-C016 study, patients with HER2 IHC 1+ disease achieved a median progression-free survival (PFS) of 12.3 months, compared with 13.1 months for patients with HER2 IHC 2+/3+ tumors. Although numerically lower, the difference was not statistically significant. Similarly, overall survival (OS) was comparable between the two groups. These findings have increased our confidence in treating patients with HER2 IHC 1+ disease.
Importantly, in the neoadjuvant setting, patients with HER2 IHC 1+ tumors may derive even greater benefit from targeted therapy combined with immunotherapy than those treated in the first-line metastatic setting or with unresectable locally advanced disease. This suggests that earlier intervention may further enhance treatment efficacy in this population.
Therefore, for patients with HER2-expressing tumors, our priorities are twofold. First, we must ensure the accuracy and reliability of HER2 testing. Second, through the HOPE-07 study, we aim to further determine whether ADC plus immunotherapy offers superior efficacy compared with chemotherapy plus immunotherapy. We are optimistic about the potential of this trial, while recognizing that conducting a large randomized study inevitably presents challenges. Under the leadership of the coordinating center and through close collaboration among all participating institutions, we are committed to successfully completing HOPE-07 and generating high-quality evidence that will ultimately benefit more patients.
UroStream: Looking ahead, how can we further optimize HER2 patient selection to improve the precision and effectiveness of ADC-based combination therapy?
Prof. Hailong Hu
The Second Hospital of Tianjin Medical University
This is another area where substantial preparatory work will be required. One of the key challenges is addressing tumor heterogeneity, which can significantly affect biomarker assessment. To overcome this issue, strong support from the central pathology laboratory will be essential, along with standardized training for pathologists across all participating centers to ensure consistency in HER2 evaluation.
At present, immunohistochemistry (IHC) remains a mature, reliable, and clinically valuable method for assessing HER2 expression in patients with muscle-invasive bladder cancer (MIBC). Looking ahead, however, continued advances in diagnostic technology—including artificial intelligence-assisted pathology, liquid biopsy, and other emerging molecular testing platforms—may help overcome the limitations imposed by tumor heterogeneity and provide more robust evidence to support precision clinical decision-making.
UroStream: HOPE-07 includes an exploratory biomarker program as one of its exploratory endpoints. Beyond HER2 expression, what other biomarkers do you believe may predict the efficacy of disitamab vedotin (RC48) plus toripalimab in the perioperative setting? How can biomarker research continue to evolve to enable more precise, individualized treatment strategies?
Prof. Zheng Liu
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Prof. Zheng Liu: Regarding the HOPE-07 study and individualized treatment strategies, I would like to address this topic from three perspectives.
First, we need to focus on treatment accessibility and patient benefit. Although remarkable advances have been made in bladder cancer therapy in recent years, patients’ access to innovative treatments remains limited. Among the patient population eligible for HOPE-07, only a few regimens, such as gemcitabine plus cisplatin (GC), are currently covered by national medical insurance. While promising agents such as disitamab vedotin (RC48) and toripalimab have been reimbursed for patients with advanced disease, their use in the perioperative setting often requires out-of-pocket payment. HOPE-07 provides patients with access to these innovative therapies through a clinical trial platform that substantially reduces treatment costs, enabling more patients to receive potentially more effective therapies and improve clinical outcomes.
Second, HOPE-07 is an investigator-initiated trial (IIT), which distinguishes it from industry-sponsored studies. Many large ADC trials are designed to compare an ADC plus immunotherapy regimen directly against chemotherapy alone, aiming to demonstrate clear differences in efficacy. In contrast, HOPE-07 builds upon the current standard of care by incorporating immunotherapy into both the neoadjuvant and postoperative maintenance settings. Although the separation of survival curves may ultimately be less pronounced than in some pivotal ADC trials, patients in both treatment arms are expected to receive greater clinical benefit than would be achieved with conventional treatment alone. This reflects the patient-centered philosophy underlying investigator-led clinical research.
Finally, HOPE-07 also incorporates an exploratory biomarker program. Biomarker research has long been one of our major areas of interest. While numerous studies have explored potential biomarkers, the lack of controlled validation has limited their translation into routine clinical practice. HOPE-07 offers a rigorous framework for validating these biomarkers, helping bridge the gap between laboratory findings and real-world clinical application. We hope this study will successfully achieve its objectives and generate meaningful advances in the treatment of bladder cancer.
UroStream: In clinical practice, HER2 expression heterogeneity is commonly observed among TURBT specimens, radical cystectomy specimens, and metastatic lesions in patients with muscle-invasive bladder cancer (MIBC). How can clinicians improve the consistency and accuracy of HER2 testing? For patients undergoing perioperative treatment, which aspects of quality control should receive particular attention during HER2 assessment? Furthermore, as the population benefiting from HER2-targeted ADCs continues to expand, how can we improve the detection of HER2-positive patients in real-world practice, particularly those with low HER2 expression (IHC 1+)?
Prof. Mengni Zhang
West China Hospital, Sichuan University
Prof. Mengni Zhang: Thank you to all the clinical experts for your valuable insights. As the pathway toward comprehensive bladder cancer management becomes increasingly well defined, extending this concept into the field of pathology places higher demands on tissue assessment. Pathologists must take into account both the spatial and temporal heterogeneity of tumors.
HER2 testing should therefore be performed across different disease stages and specimen types, including initial TURBT specimens, radical cystectomy specimens, lymph node metastases, and other metastatic lesions. Systematic testing allows us to accurately track the dynamic changes in HER2 expression throughout the course of disease while characterizing the spatial heterogeneity of metastatic sites. This comprehensive approach provides a complete HER2 expression profile for each patient and offers a robust pathological basis for selecting HER2-targeted therapies, ultimately supporting more precise clinical decision-making.
Quality control requires close collaboration between clinicians and pathologists. From the clinical perspective, excessive cautery during TURBT should be avoided to preserve specimen quality. For radical cystectomy specimens, standardized tissue sampling should be performed immediately after surgery, followed by adequate fixation using a sufficient volume of fixative. Once specimens reach the pathology laboratory, automated immunohistochemical (IHC) staining can ensure consistent and reliable HER2 assessment.
Importantly, the 2026 Expert Consensus on Clinical Pathology Practice for HER2 Immunohistochemical Testing in Urothelial Carcinoma, published earlier this year, establishes standardized testing procedures and recommends best practices for HER2 evaluation. Pathology departments are encouraged to follow these recommendations to improve standardization and quality assurance.
To further enhance testing accuracy, pathology practice should focus on two key priorities. First, standardized HER2 testing must be implemented according to the latest guidelines and expert consensus to ensure consistency and reproducibility across institutions. Second, accurate interpretation remains critical, particularly when distinguishing HER2 IHC 0 from IHC 1+. The greatest challenge lies in accurately identifying the 10% threshold for faint, incomplete membranous staining. At present, this largely depends on the expertise of experienced pathologists. However, we are actively exploring the integration of artificial intelligence-assisted image analysis with conventional pathological interpretation to improve the accuracy of identifying this critical threshold, thereby increasing the detection rate of HER2 IHC 1+ tumors and providing stronger pathological support for precision medicine.
UroStream: In recent years, perioperative treatment for muscle-invasive bladder cancer (MIBC) has gradually evolved from conventional cisplatin-based chemotherapy toward immunotherapy and ADC-based combination strategies. HOPE-07 is evaluating a comprehensive perioperative approach using disitamab vedotin (RC48) plus toripalimab throughout both the neoadjuvant and adjuvant settings. From a clinical perspective, what do you believe is the most important challenge that still needs to be addressed in perioperative treatment decision-making? For patients with different risk profiles, how can treatment intensity be optimally balanced against clinical benefit to truly advance precision perioperative management?
Prof. Qiao Xiong
The Second Affiliated Hospital of Kunming Medical University
Prof. Qiao Xiong: Since 2019, Prof. Peng Zhang has led the establishment of the Sichuan Urothelial Carcinoma Database, driving continuous research to address key clinical challenges. The launch of the HOPE-07 study represents another important step toward answering critical questions in the perioperative management of muscle-invasive bladder cancer (MIBC).
First, we need to stratify patients more precisely and define individualized treatment pathways. This means identifying which patients are most likely to benefit from HER2-targeted therapy combined with immunotherapy, which are better suited to chemotherapy-based approaches, and which should proceed directly to radical cystectomy. Preliminary evidence has suggested that targeted-immunotherapy combinations may outperform chemoimmunotherapy, but these observations still require confirmation through high-quality prospective clinical trials. Accordingly, HOPE-07 is designed not only to evaluate treatment efficacy but also to perform detailed subgroup analyses, including patients with neuroendocrine tumors, squamous differentiation, glandular differentiation, and other uncommon histological variants, providing more precise evidence to guide individualized treatment decisions.
Second, we aim to establish a dynamic monitoring system. In routine clinical practice, treatment responses vary considerably between patients. Some achieve excellent outcomes with initial chemotherapy, while others derive limited benefit even from targeted-immunotherapy combinations. This highlights the need for continuous treatment monitoring. Therefore, from the outset, HOPE-07 was designed to go beyond a simple comparison of chemoimmunotherapy versus targeted-immunotherapy. The study also incorporates urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) as dynamic biomarkers. By continuously tracking molecular changes throughout treatment, we hope to evaluate therapeutic response more accurately and ensure that patients receiving either targeted-immunotherapy or chemoimmunotherapy achieve not only an optimal initial response but also durable long-term clinical benefit. Previous experience from the RC48-C, HOPE, and TRUCE study programs has already provided valuable insights into multiple treatment strategies and serves as an important foundation for this work.
Finally, I would like to highlight the current treatment challenges faced by bladder cancer patients in western China. At The Second Affiliated Hospital of Kunming Medical University, one of the largest urological centers in Yunnan Province, we routinely encounter newly diagnosed patients with MIBC complicated by renal insufficiency. Treatment options for this population remain extremely limited. Although patients with significant renal impairment are currently excluded from HOPE-07, this represents an important area for future investigation. Given the relatively high prevalence of renal dysfunction among bladder cancer patients in western China, we hope future studies will explore innovative treatment strategies that can improve long-term outcomes for this underserved patient population.
Prof. Peng Zhang
West China Hospital, Sichuan University
Prof. Peng Zhang: HOPE-07 is designed as a randomized controlled trial (RCT). According to the study’s eligibility criteria, patients must be eligible for cisplatin-based chemotherapy, which is why individuals with significant renal insufficiency are currently excluded from enrollment.
However, the issue you raised is highly relevant to everyday clinical practice. Across multiple participating centers, we frequently encounter the reality that nearly half of patients are unable to tolerate cisplatin-based chemotherapy. This also highlights the rigor of the study design: only patients who meet the predefined chemotherapy eligibility criteria can be enrolled and randomized, while those who are ineligible for cisplatin cannot enter the randomization process.
Regarding the randomization procedure, Prof. Tan Ping has previously provided a detailed explanation. Participating centers perform randomization directly through the electronic data capture (EDC) system, after which the coordinating center reviews and verifies the allocation. Once approval is completed, each participating site proceeds strictly according to the assigned treatment arm, ensuring both the scientific integrity and standardized execution of the trial.
Looking ahead, we hope to explore targeted-immunotherapy combinations and other novel treatment strategies specifically for patients with renal insufficiency. Such studies have the potential to expand therapeutic options for this underserved population, improve patient outcomes, and further enhance the overall management and survival of patients with urothelial carcinoma.
