With the rapid evolution of antibody-drug conjugates (ADCs) and immunotherapy, the treatment paradigm for urothelial carcinoma (UC) is undergoing profound transformation. During the recent China Clinical Oncology Annual Advances Symposium (BOC) and Best of CSCO 2026 China, leading oncology experts gathered to discuss the latest international advances and their translation into clinical practice.At the meeting, UroStream invited Prof. Xinan Sheng from Peking University Cancer Hospital for an exclusive interview to discuss emerging opportunities for bladder-preserving treatment in muscle-invasive bladder cancer (MIBC), the impact of the landmark RC48-C016 study on the management of advanced urothelial carcinoma, and future directions for treatment after progression on first-line antibody-drug conjugate–immunotherapy combinations.
UroStream:
Many patients with muscle-invasive bladder cancer (MIBC) wish to preserve their bladder, yet disease progression still occurs after conventional perioperative treatment. Given the success of ADC–immunotherapy combinations in advanced disease, what new opportunities might these regimens offer patients with MIBC?
Prof. Xinan Sheng:
The emergence of novel therapies over the past several years has brought new hope for bladder-preserving treatment.
Organ preservation has become an important direction in modern oncology. In other malignancies, such as breast and rectal cancer, breast-conserving surgery and sphincter-preserving strategies have been validated through extensive clinical research and have fundamentally changed treatment standards, benefiting large numbers of patients.
In contrast, although bladder-preserving strategies have long been explored in urothelial carcinoma, their adoption has been limited because of suboptimal efficacy.
More recently, ADC-based immunotherapy combinations have demonstrated remarkable pathological response rates in the neoadjuvant treatment of MIBC. In the Phase III KEYNOTE-B15 trial, enfortumab vedotin plus pembrolizumab achieved a pathologic complete response (pCR) rate of 55.8%. Likewise, the Phase II RC48-C017 study reported a pCR rate of 63.6% with disitamab vedotin plus toripalimab. Both regimens achieved substantially higher pCR rates than conventional chemotherapy, providing a strong rationale for exploring selective bladder-preservation strategies in the future.
However, bladder-preserving treatment still faces significant challenges. High-level evidence remains limited, and neither China nor the international community has yet established standardized treatment pathways. Nevertheless, these gaps also create broad opportunities for future research.
Future studies should not focus solely on clinical outcomes but should also integrate translational research. Biomarker-guided patient selection will be essential for identifying individuals most likely to benefit from bladder preservation. Biomarker-driven individualized treatment strategies are expected to play a pivotal role in refining bladder-preservation protocols, making this one of the most important areas of genitourinary oncology research over the next five to ten years.
At present, clinicians must also apply bladder-preserving strategies judiciously rather than pursuing organ preservation indiscriminately. Although novel targeted and immunotherapy combinations have substantially improved outcomes, patients differ considerably in their baseline disease characteristics.
Patients whose tumors are highly sensitive to systemic therapy may be appropriate candidates for bladder preservation, whereas those with more advanced-stage disease or a high tumor burden should not be encouraged to preserve the bladder at the expense of oncologic control. For these patients, radical cystectomy remains the preferred option for maximizing survival.
Ultimately, the future of bladder preservation is not simply about how to preserve the bladder—it is about identifying which patients are appropriate candidates.
UroStream:
The RC48-C016 study, which you co-led with Prof. Jun Guo, was published in The New England Journal of Medicine. The regimen has now entered routine clinical practice and has been incorporated into treatment guidelines. What major changes has this Chinese-developed study brought to clinical practice in urothelial carcinoma?
Prof. Xinan Sheng:
The complete results of the RC48-C016 study were reported last year and subsequently published in The New England Journal of Medicine, representing a landmark achievement for the management of urothelial carcinoma in both China and globally. The study established China as an international leader in HER2-targeted therapy for urothelial carcinoma.
First, it has transformed clinical guidelines.
The 2026 CSCO Guidelines for Urothelial Carcinoma now recommend disitamab vedotin plus toripalimab as a Category I first-line treatment for advanced urothelial carcinoma. Clinical data indicate that approximately 70% of patients with advanced urothelial carcinoma express HER2 protein, meaning this recommendation applies to the majority of patients with advanced disease.
Second, this domestically developed innovative therapy has significantly improved treatment accessibility. Physicians across hospitals of all levels, as well as patients with advanced urothelial carcinoma, can now directly benefit from the results of this Chinese clinical research.
Third, the success of the RC48 program has greatly strengthened confidence in China’s capacity for innovative drug development. These achievements demonstrate that Chinese investigators are fully capable of generating original, high-quality clinical evidence capable of shaping global standards of care in urothelial carcinoma, while also providing valuable direction for future therapeutic development across the entire disease continuum.
UroStream:
Following progression on first-line targeted therapy plus immunotherapy, treatment of advanced urothelial carcinoma remains challenging. Could you share your clinical experience, and how do you foresee the treatment landscape evolving?
Prof. Xinan Sheng:
With the publication of the EV-302 and RC48-C016 studies, the treatment paradigm for advanced urothelial carcinoma is undergoing fundamental change.
Today, PD-1 inhibitors combined with ADCs have become a major first-line treatment strategy, meaning that increasing numbers of patients will eventually experience disease progression after receiving these combinations. Consequently, identifying optimal post-progression treatment strategies has become one of the most important challenges in clinical practice and a major focus of future second-line research.
At present, however, there remains a lack of high-level evidence to guide treatment in this setting.
Currently, chemotherapy remains an important therapeutic option. Although platinum-based chemotherapy is no longer the preferred first-line treatment in the era of PD-1 inhibitor–ADC combinations, it continues to demonstrate meaningful activity after failure of immunotherapy plus ADC treatment and remains recommended by both Chinese and international clinical guidelines and expert consensus statements.
Recent real-world data presented at ASCO have shown that chemotherapy achieves an objective response rate (ORR) of approximately 20%–40% in this patient population, with a median progression-free survival (PFS) of 5–6 months. Therefore, although chemotherapy has declined in importance as first-line therapy, its value in later-line treatment remains significant.
At the same time, as urothelial carcinoma enters the ADC era, sequential ADC therapy has emerged as one of the most promising areas of investigation.
Multiple ongoing studies are evaluating different sequencing strategies following progression on immunotherapy plus ADC, including:
- Sequential use of ADCs targeting the same antigen but carrying different payloads.
- Sequential use of ADCs targeting different antigens with different payloads.
- Sequential use of ADCs targeting different antigens while using the same payload.
Current evidence suggests that differences in the cytotoxic payload may be particularly important in determining treatment efficacy. Even when two ADCs target the same antigen, switching to an ADC with a different payload may help overcome resistance and improve therapeutic outcomes.
Among the available data, the largest body of evidence currently involves Nectin-4-targeted ADCs conjugated to Topoisomerase I inhibitors following prior treatment with enfortumab vedotin (EV).
At the same time, studies are also evaluating ADCs directed against different targets and carrying different payloads, including investigations of SHR-A2102 in patients whose disease has progressed after disitamab vedotin (RC48). Nevertheless, these strategies require further confirmation through prospective clinical trials and real-world evidence.
Beyond sequential ADC therapy, participation in clinical trials represents another important treatment avenue.
Numerous innovative therapeutic approaches are currently under investigation, including next-generation ADCs, bispecific antibodies, multispecific antibodies, and multi-target ADCs. For patients who experience disease progression after standard therapy, enrollment in clinical trials may provide valuable access to these emerging treatments.
Looking forward, ADC-based combination strategies are also expected to expand further. Potential future approaches include ADC plus bispecific antibody combinations and even ADC plus ADC combinations.
Overall, for patients with advanced urothelial carcinoma who progress after PD-1 inhibitor plus ADC therapy, three principal treatment strategies currently exist:
- Chemotherapy.
- Sequential ADC therapy.
- Enrollment in clinical trials investigating novel agents.
Although no universally accepted, high-level evidence currently exists to define the optimal approach, these ongoing investigations are steadily expanding treatment options and offer increasing hope for improving patient outcomes in the future.
Prof. Xinan Sheng
