With the rapid advancement of ADC-based combination immunotherapies globally, the treatment landscape for advanced urothelial carcinoma has undergone a dramatic transformation, leading to multiple updates in clinical guidelines. This year’s ASCO Genitourinary Cancers Symposium (ASCO GU) was held from February 13–15 in San Francisco, where Professor Jun Guo from Peking University Cancer Hospital led a team of researchers. Professors Xinan Sheng and Bixia Tang presented two pivotal studies on Chinese innovative drugs for urothelial carcinoma, gaining international recognition.Urology Frontier invited the Peking University Cancer Hospital team to discuss key breakthroughs, ongoing challenges in the diagnosis and treatment of urothelial carcinoma, the results of the SHR-A2102 study, and the efficacy and patient benefits of RC48 in combination with toripalimab.

Urology Frontier: What do you consider the most significant breakthroughs in the field of urothelial carcinoma? Based on your clinical experience, what challenges remain to be addressed?

Professor Jun Guo: In recent years, urothelial carcinoma treatment has made remarkable strides, bringing new hope to patients. Traditionally, chemotherapy-based regimens have been the cornerstone of treatment, particularly for metastatic urothelial carcinoma (both in adjuvant and neoadjuvant settings). The emergence of immune checkpoint inhibitors (ICIs) has significantly improved patient survival, with PD-1 inhibitors showing strong efficacy in second-line therapy, leading to multiple regulatory approvals.

The era of antibody-drug conjugates (ADCs) has now arrived, marked by the introduction of China’s domestically developed disitamab vedotin (RC48) and the imported enfortumab vedotin. After demonstrating success in later-line treatment, these ADCs are gradually moving into first-line therapy. Notably, the recently approved enfortumab vedotin + pembrolizumab combination has completely reshaped the first-line treatment paradigm for advanced urothelial carcinoma.

China’s RC48 + toripalimab regimen, investigated in the RC48-C016 study, is set to present its first-line treatment results at this year’s ASCO meeting. This study is expected to further redefine first-line treatment for metastatic urothelial carcinoma. In the near future, chemotherapy may no longer be the standard first-line approach, with ADC + immunotherapy combinations poised to take center stage.

At ASCO GU 2025, a multicenter Chinese study was selected for presentation, marking the first global report on ADC + immunotherapy as a neoadjuvant therapy for urothelial carcinoma. Professor Xinan Sheng presented these groundbreaking findings, demonstrating a pathologic complete response (pCR) rate of 63.6% and an impressive event-free survival (EFS) rate. The results were met with enthusiastic responses from international experts, who described them as “really, really impressive” and “very, very impressive.”

This remarkable success stems from a significant leap forward compared to previous chemotherapy-based regimens. Historically, DVAC, GC, and even GC + immunotherapy regimens have reported pCR rates below 40%. The RC48-C017 neoadjuvant study has, for the first time, pushed the pCR rate to 63.6%, marking an exciting and transformative milestone in urothelial carcinoma treatment.

The future of neoadjuvant therapy for urothelial carcinoma is shifting towards ADC-immune combination treatments, moving beyond traditional chemotherapy, targeted therapy, pembrolizumab, or TKIs in the adjuvant setting. As neoadjuvant therapy evolves, adjuvant treatment strategies will likely undergo fundamental changes as well. This transformation extends across the entire treatment continuum, from neoadjuvant to adjuvant therapy, and from first-line to second-line treatment for advanced disease, heralding a new era in urothelial carcinoma management.

Urology Frontier: Professor Tang, your study presented at ASCO GU introduced SHR-A2102, an antibody-drug conjugate (ADC) targeting Nectin-4, in patients with advanced or metastatic urothelial carcinoma. Compared to existing treatments, what unique advantages or potential breakthroughs does SHR-A2102 offer in terms of efficacy and safety?

Professor Bixia Tang: This study enrolled patients who had failed previous treatments, with the majority experiencing multiple lines of treatment failure. A total of 81 patients were included in the study, and the efficacy data from the optimal dose groups of 6 mg and 8 mg demonstrated encouraging results. In the 6 mg group, the objective response rate (ORR) was 41.9 percent, while in the 8 mg group, it reached 50 percent. The median duration of response was 7.6 months and 5.5 months, respectively, with a progression-free survival of 5.8 months in both groups. Overall survival data is still maturing.

These preliminary findings suggest that SHR-A2102 has strong therapeutic potential, warranting further clinical investigation. Its favorable efficacy, even in heavily pretreated patients, highlights Nectin-4 as a promising target in urothelial carcinoma, and we anticipate more mature survival data to further validate its role in expanding treatment options for patients with advanced disease.

What is particularly exciting is that among the 81 patients enrolled in the study, 46 percent had previously failed ADC treatment, primarily with disitamab vedotin. Despite this, the 6 mg group of SHR-A2102 still achieved an objective response rate exceeding 50 percent in this subgroup. This finding is especially significant for Chinese patients, as treatment options remain limited for those who have failed both chemotherapy and disitamab vedotin. The promising efficacy of this investigational drug offers new hope for these patients, potentially filling a critical gap in treatment for heavily pretreated urothelial carcinoma.

From a safety perspective, current data indicate that the incidence of grade 3 or higher adverse events in the 6 mg dose group is below 40 percent, suggesting that the drug has a favorable tolerance profile. Most adverse reactions were related to hematologic and gastrointestinal toxicity, with overall tolerability remaining acceptable. Considering both efficacy and safety, SHR-A2102 demonstrates strong potential and warrants further research and exploration as a viable treatment option for advanced urothelial carcinoma.Bottom of Form

Urology Frontier: How prevalent is Nectin-4 expression in urothelial carcinoma, and did your study explore the correlation between Nectin-4 expression levels and SHR-A2102 efficacy? Are there plans for further investigation into this biomarker’s role?

Professor Bixia Tang: Nectin-4 is highly expressed in urothelial carcinoma, with literature reporting expression rates of approximately 90 to 97 percent. Enfortumab vedotin, which has been approved for clinical use, also targets Nectin-4 but does not require a specific level of Nectin-4 expression for patient eligibility. In our study, while we conducted exploratory analyses, high Nectin-4 expression was not a prerequisite for patient enrollment. We are currently summarizing preliminary expression data, and early findings suggest that Nectin-4 expression is generally high among the included patient population. However, further studies are needed to explore the role of this biomarker in greater depth.

Urology Frontier: How was the dose escalation phase designed in your study, and what factors led to the selection of the recommended phase II dose (RP2D)? How does this dose balance efficacy and safety?

Professor Bixia Tang: In the phase I study, six dose levels were established. The lowest dose group was initiated first, followed by dose escalation using an accelerated titration model. Based on data from these six dose groups, we selected 6 mg (once every three weeks), 8 mg (once every three weeks), and 4 mg (administered on days 1, 8, and 15 of each cycle) for pharmacokinetic (PK) expansion cohorts.

Using the PK expansion data, we proceeded to the efficacy expansion phase, where 6 mg and 8 mg, administered every three weeks, were chosen for further evaluation. The efficacy and safety outcomes primarily came from these two dosing groups. After comprehensive analysis of both safety and efficacy data, 6 mg per kilogram of body weight, administered every three weeks, was determined to be the recommended phase II dose.

Urology Frontier: Your study investigated the perioperative use of disitamab vedotin combined with toripalimab as a neoadjuvant treatment for muscle-invasive bladder cancer (MIBC) in HER2-expressing patients. How does this combination compare to traditional neoadjuvant chemotherapy in terms of pathologic complete response (pCR) and long-term survival?

Professor Xinan Sheng: MIBC has long been a clinical challenge, as a significant proportion of cases eventually progress to metastatic urothelial carcinoma. Delaying disease progression in MIBC remains a critical objective in clinical management. The standard treatment approach involves neoadjuvant chemotherapy followed by radical surgery. However, traditional neoadjuvant chemotherapy has shown limited benefit in improving overall survival (OS), with gains of only about five percent over five to ten years.

With the emergence of novel therapies such as immunotherapy and ADCs, multiple treatment strategies have been explored, including their integration into neoadjuvant therapy. Historically, pCR rates with immunotherapy alone, ADC monotherapy, or chemoimmunotherapy combinations have ranged between 30 and 50 percent. Our study results, presented at ASCO GU, demonstrated an overall pCR rate of 63.6 percent, the highest among all studies discussed in the conference session. This unprecedented efficacy, combined with subsequent surgery and adjuvant immunotherapy, is expected to mark a significant breakthrough in MIBC treatment. Given the impressive response rates observed, we are also considering bladder-sparing strategies for select patient populations, potentially reshaping future treatment paradigms.

Urology Frontier: In the RC48-C017 study, how was HER2 expression assessed, and how did this biomarker influence patient selection? Did you identify specific subgroups that responded particularly well or poorly to the combination therapy?

Professor Xinan Sheng: This study utilized two agents: the PD-1 checkpoint inhibitor toripalimab and the HER2-targeting ADC disitamab vedotin. PD-1 expression is an important biomarker for immunotherapy response, while HER2 expression is critical for ADC efficacy. Both clinicians and patients are keenly interested in whether these biomarkers influence treatment outcomes.

Data from previous studies in the metastatic setting suggested a potential correlation between high HER2 or PD-1 expression and improved treatment response, though the difference did not reach statistical significance. In the neoadjuvant setting, our findings indicate varying responses based on HER2 expression levels. Patients with HER2 IHC 3+ appeared to derive the most benefit. However, even patients with HER2 IHC 1+ achieved a pCR rate exceeding 50 percent.

Notably, even PD-L1-negative and HER2-negative patients showed some degree of response. One particularly interesting case involved a patient with HER2 IHC 1+ and PD-1 negativity, who still achieved complete remission. These findings suggest that it is premature to determine neoadjuvant therapy eligibility solely based on HER2 or PD-L1 expression. As more neoadjuvant treatment strategies emerge, integrating biomarker expression data will help refine treatment selection, particularly for ADC-based combination therapies. Given the strong pCR rates observed in HER2-positive populations, excluding patients from neoadjuvant therapy based on biomarker levels at this stage could limit their opportunity to benefit from effective treatment.

Urology Frontier: Safety is a crucial factor when evaluating new treatment regimens. How well was the combination of disitamab vedotin and toripalimab tolerated in your study? Did most patients complete their planned treatment cycles without requiring dose modifications, and was the therapy compatible with subsequent surgery?

Professor Xinan Sheng: Combination therapies generally have lower tolerability compared to monotherapies. However, in advanced urothelial carcinoma, we observed that the safety and tolerability profile of ADC-immunotherapy combinations was superior to traditional chemotherapy.

For instance, in the RC48-C014 study evaluating disitamab vedotin plus toripalimab in late-stage disease, the incidence of grade 3/4 adverse events was between 50 and 60 percent, lower than that observed with conventional chemotherapy. When we extended this combination into the neoadjuvant setting (RC48-C017 trial), the safety profile was even more favorable. The incidence of grade 3 or higher adverse events dropped to 17 percent, indicating that ADC-immunotherapy regimens not only offer improved tolerability in neoadjuvant therapy but also reduce the complexity of safety management.

Several factors contribute to this improved safety profile, including the shorter duration of neoadjuvant therapy and its preoperative administration, which may mitigate the cumulative toxicity often seen with prolonged treatment. These findings support the feasibility of ADC-immunotherapy combinations in neoadjuvant settings, offering a well-tolerated alternative to traditional chemotherapy while achieving superior response rates.

Conclusion

Professor Jun Guo: The field of urothelial carcinoma treatment is undergoing a rapid and transformative evolution. As new therapeutic agents emerge globally, Chinese researchers and clinicians should not merely follow established trends but actively contribute as pioneers of innovation. We must take the initiative in driving advancements to ensure that patients receive the greatest possible benefit. I firmly believe that Chinese experts and scholars will continue to develop groundbreaking therapies, bringing new hope to urothelial carcinoma patients worldwide.

Expert Profiles

Professor Jun Guo

• Chief Physician, Professor, Doctoral Supervisor
• Director, Melanoma & Sarcoma Medical Oncology, Peking University Cancer Hospital
• Director, Urologic Oncology Medical Oncology, Peking University Cancer Hospital
• Vice President and Secretary General, Chinese Society of Clinical Oncology (CSCO)
• Vice President, International Melanoma Working Group (MWS)
• Chair, Melanoma and Skin Tumors Subcommittee, European Society for Medical Oncology (ESMO)
• Chair, Melanoma Specialty Committee, National Cancer Center & National Tumor Quality Control Center
• Chair, CSCO Melanoma Expert Committee
• Vice Chair, CSCO Renal Cancer Expert Committee
• Vice Chair, CSCO Immunotherapy Expert Committee
• Vice Chair, CSCO Urothelial Carcinoma Expert Committee
• Vice Chair, CSCO Prostate Cancer Expert Committee
• National Drug Registration Review Expert, China FDA
• Member, National Health Commission Expert Committee on Rational Drug Use (Antitumor Drug Group)

Professor Xinan Sheng

• Chief Physician, Professor, Doctoral Supervisor
• Deputy Director, Urologic Oncology Medical Oncology, Peking University Cancer Hospital
• Vice Chair, Integrative Rehabilitation Committee for Urological & Genitourinary Oncology, Chinese Anti-Cancer Association
• Standing Committee Member, Urological Oncology Committee, Chinese Anti-Cancer Association
• Council Member, CSCO
• Secretary General, CSCO Renal Cancer Expert Committee
• Standing Committee Member, CSCO Urothelial Carcinoma Expert Committee
• Member, National Tumor Quality Control Center Bladder Cancer Committee
• Chair-Elect, Urological Oncology Division, Beijing Tumor Prevention and Treatment Research Society
• Chair, Youth Committee, Urological & Genitourinary Oncology Committee, Beijing Anti-Cancer Association
• Standing Committee Member, Beijing Medical Association Oncology Division

Professor Bixia Tang

• Associate Chief Physician, Peking University Cancer Hospital
• Deputy Director, Melanoma, Sarcoma & Urologic Oncology Medical Oncology
• Clinical and Basic Immunology Doctorate, Peking Union Medical College
• Visiting Scholar, University of Utah & Huntsman Cancer Institute
• Specializes in systemic therapy and management of complications in malignant melanoma and urological malignancies
• Published multiple research papers in leading oncology journals such as CCR and EJC