Editor’s Note: The treatment landscape for muscle-invasive bladder cancer (MIBC) is undergoing profound transformation. Although cisplatin-based neoadjuvant chemotherapy remains the traditional standard of care, the pathological complete response (pCR) rate has long remained at approximately 30%–40%, and a substantial proportion of patients cannot receive cisplatin due to factors such as renal insufficiency. Consequently, more effective preoperative treatment strategies are urgently needed.In recent years, the combination of antibody–drug conjugates (ADCs) with immune checkpoint inhibitors has emerged as one of the most promising areas of exploration in genitourinary oncology. The RC48-C017 study, the first prospective clinical trial worldwide to evaluate a HER2-targeted ADC combined with a PD-1 inhibitor as neoadjuvant therapy for MIBC, not only achieved a pCR rate of 63.6% (reaching 84.6% among patients with high HER2 expression) but also demonstrated encouraging survival outcomes with longer follow-up: a 2-year overall survival rate of 91.3% and an 18-month event-free survival rate exceeding 81.5%.
Notably, this study employed entirely China-developed innovative agents—disitamab vedotin combined with toripalimab—marking China’s transition in genitourinary oncology drug development from a follower to a global leader. With the RC48-C011 study published in The New England Journal of Medicine and positive results emerging from international trials such as EV-303 and EV-304, ADC-immunotherapy combinations are actively being explored in the neoadjuvant setting for MIBC and are providing a solid evidence base for the long-sought goal of bladder preservation.
Oncology Frontier invited Professor Xinan Sheng from Peking University Cancer Hospital to provide an in-depth interpretation of the updated data from the RC48-C017 study and its implications for clinical practice.
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The RC48-C017 study combined a HER2-targeted ADC with immunotherapy in the neoadjuvant treatment of MIBC, achieving a pCR rate of 63.6%, with an even higher rate of 84.6% among patients with high HER2 expression. From a clinical perspective, what does such a pathological response rate mean for patients’ long-term outcomes? Could you share your insights?
Professor Xinan Sheng: The RC48-C017 study is the first prospective clinical trial worldwide to evaluate the combination of an ADC and an immune checkpoint inhibitor as neoadjuvant therapy for muscle-invasive urothelial carcinoma. At the 2025 ASCO GU meeting, our team first reported the preliminary results of this study, showing a pCR rate of 63.6%, which attracted considerable attention. At this year’s ASCO GU meeting, we presented updated long-term follow-up data with a median follow-up exceeding 26 months.
In terms of survival outcomes, this regimen demonstrated encouraging long-term efficacy: the 18-month event-free survival (EFS) rate exceeded 81%, and the 2-year overall survival (OS) rate reached 91%. These findings suggest that ADC combined with immunotherapy is rapidly advancing in the treatment of urothelial carcinoma and may potentially become a new standard of care.
In fact, this combination strategy has become a major research focus in the neoadjuvant treatment of MIBC. The EV-303 study was reported at the 2024 ESMO Congress, and the EV-304 study was presented at this year’s ASCO GU meeting. Both studies evaluated PD-1 inhibitors combined with the Nectin-4–targeted ADC enfortumab vedotin and also achieved high pathological complete response rates.
Although the RC48-C017 study has a relatively small sample size, the 63.6% pCR rate represents a significant milestone in MIBC treatment. Historically, cisplatin-based chemotherapy or chemo-immunotherapy as neoadjuvant therapy achieved pCR rates of only 30%–40%. ADC-immunotherapy combinations now raise this rate to over 60%, representing a substantial improvement in treatment efficacy and signaling a fundamental shift in the therapeutic landscape for MIBC.
From a clinical standpoint, this breakthrough carries several important implications. First, immunotherapy combined with ADCs is gradually replacing traditional platinum-based chemotherapy as the preferred neoadjuvant strategy, representing a generational shift in treatment paradigms. Second, higher pathological response rates mean that more patients may become eligible for organ-preserving treatment.
Although radical cystectomy remains the standard treatment for MIBC, it significantly impacts patients’ quality of life. Such a high pCR rate provides an important basis for identifying patients who may benefit from bladder-preserving approaches, opening new possibilities for precision strategies aimed at preserving bladder function. In clinical practice in China, we have already observed a gradual decline in the proportion of patients undergoing radical cystectomy in recent years, reflecting the growing interest in bladder-preserving treatment.
Of course, bladder preservation is a complex and systematic approach that cannot rely solely on drug therapy. It also requires well-defined patient selection criteria, multidisciplinary collaboration, and rigorous follow-up and monitoring. Nevertheless, immunotherapy combined with ADCs has clearly opened a fast track toward organ-preserving treatment. With further refinement of patient selection and optimization of treatment strategies, we hope to provide MIBC patients with bladder-preserving options that outperform traditional treatment approaches.
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You presented the updated results of this study on behalf of the research team. What do the long-term safety data show?
Professor Xinan Sheng: Regarding safety, when we first reported the results at last year’s ASCO GU meeting, we observed that the regimen was generally well tolerated. The incidence of grade ≥3 serious adverse events was less than one-third, and the rate of surgery-related complications was relatively low. With a median follow-up of 26 months, the updated safety data presented this year revealed no new safety signals.
For neoadjuvant and perioperative treatments, safety assessments primarily focus on adverse events during the neoadjuvant phase, surgical complications, and the safety of postoperative adjuvant therapy. All patients in this study have now completed treatment, and long-term follow-up confirms that this regimen is clinically feasible and practical, with no evidence of delayed toxicity or cumulative adverse effects. These findings provide important safety evidence supporting its broader application in clinical practice.
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This study used a fully China-developed treatment regimen. How do you view China’s international position and contributions in innovative drug development for genitourinary cancers?
Professor Xinan Sheng: In recent years, China has achieved remarkable progress in innovative drug development, particularly in the ADC field. A landmark event occurred at the 2025 ESMO Congress, where Professor Jun Guo presented the key findings of the RC48-C016 study during the Presidential Symposium.
This study evaluated the combination of the China-developed anti-HER2 ADC disitamab vedotin and the PD-1 inhibitor toripalimab as first-line treatment for patients with HER2-expressing advanced urothelial carcinoma, demonstrating significant improvements in patient outcomes. The results were subsequently published in The New England Journal of Medicine, marking a major breakthrough for HER2-targeted therapy combined with immunotherapy in the first-line treatment of advanced urothelial carcinoma and opening a new chapter in this therapeutic field.
Importantly, the RC48-C016 study is the first first-line trial in urothelial carcinoma to achieve positive results using biomarker-based patient selection (HER2 expression). This represents a critical shift from a broad treatment approach to precision medicine. Through a series of clinical studies, China has now emerged as a global leader in HER2-targeted ADC therapy.
At the same time, several other China-developed ADCs are actively being explored in urothelial carcinoma and have demonstrated promising results. For example, Baili-Bio has initiated clinical research on the globally innovative EGFR × HER3 bispecific ADC BL-B01D1. Akeso has also reported encouraging results for AK146D1, a Trop2/Nectin-4 bispecific ADC, in urothelial carcinoma.
In addition to already approved Nectin-4–targeted ADCs, Hengrui Pharmaceuticals has developed SHR-A2102, a Nectin-4–targeted ADC conjugated with a topoisomerase I inhibitor payload. Early data presented at the 2025 ASCO GU meeting showed a relatively high objective response rate, offering new insights into ADC development using novel payloads targeting established targets.
Notably, many of the innovative ADCs currently under investigation in urothelial carcinoma originate from Chinese companies, and key clinical data are being generated by Chinese researchers and clinical teams. In this specialized field, we are witnessing a transition from following global research trends to running alongside—and even leading—them. With the innovation capacity and clinical expertise of Chinese investigators, we are confident that China will continue to expand new frontiers in urothelial carcinoma treatment and contribute Chinese innovation and Chinese solutions to patients worldwide.
Professor Xinan Sheng
