The treatment landscape for advanced urothelial carcinoma (UC) has entered a new era. Antibody-drug conjugates (ADCs) targeting Nectin-4, HER2, and Trop-2 have rapidly transformed clinical practice, while ADCs combined with immune checkpoint inhibitors have become the new standard for first-line treatment. At the 2026 CSCO Annual Meeting, Prof. Kaiwei Yang from the Department of Urology, Peking University First Hospital presented a comprehensive overview of the current evidence supporting approved and investigational ADCs. Drawing on the latest 2026 CSCO Guidelines, he systematically reviewed first-line treatment strategies, sequencing after disease progression, breakthroughs in domestically developed ADCs, and the next generation of emerging targets, providing valuable insights into individualized treatment for advanced urothelial carcinoma.First-Line Therapy: ADC Plus Immunotherapy Redefines the Standard of Care
Prof. Yang began by reviewing the treatment recommendations outlined in the 2026 CSCO Guidelines for Metastatic Urothelial Carcinoma. Although ADCs combined with immunotherapy have demonstrated clear superiority over conventional chemotherapy, the current Chinese guidelines continue to stratify recommendations according to cisplatin eligibility, reflecting differences in drug accessibility within routine clinical practice.
For patients who are eligible for cisplatin, ADC-based combination therapy has become the preferred first-line approach with the highest level of evidence. Both enfortumab vedotin (EV) plus pembrolizumab and disitamab vedotin (RC48) plus toripalimab have been upgraded to Category I recommendations. Gemcitabine plus cisplatin combined with nivolumab also remains a recommended option, while conventional gemcitabine-cisplatin chemotherapy continues to be included in the guidelines despite its long-term outcomes increasingly being challenged by ADC-based regimens.
For patients who are ineligible for cisplatin, treatment options were previously limited to immune checkpoint inhibitor monotherapy or carboplatin-based chemotherapy. The emergence of ADC-immunotherapy combinations, particularly EV plus pembrolizumab and RC48 plus toripalimab, has substantially expanded first-line treatment options and offers this patient population new opportunities for improved clinical outcomes.
Overall survival data clearly illustrate the impact of these new treatment strategies. Historically, gemcitabine plus cisplatin achieved a median overall survival (OS) of approximately 13.8 months among cisplatin-eligible patients, while pembrolizumab monotherapy produced a median OS of approximately 11.3 months in platinum-ineligible patients. By comparison, the EV-302 trial demonstrated a median OS of 33.8 months with EV plus pembrolizumab, while the RC48-C016 study reported a median OS of 31.5 months with RC48 plus toripalimab. Importantly, these ADC-based regimens are also suitable for cisplatin-ineligible patients, highlighting their potential to substantially improve long-term survival across a broader patient population.
Prof. Yang also highlighted the rapid development of next-generation domestic ADCs. Following encouraging activity in later-line settings, several agents are now being investigated in frontline combination regimens. At ASCO 2026, a Phase Ib/II study evaluating bulumtatug fuvedotin (BFv) plus toripalimab demonstrated promising antitumor activity in advanced urothelial carcinoma, achieving an overall response rate (ORR) of 83%, a disease control rate (DCR) of 89.4%, and a median progression-free survival (PFS) of 12.9 months. Among treatment-naïve patients, the ORR reached 87.5%, while previously treated patients still achieved an ORR of 57.1%. As another Nectin-4-targeting ADC, BFv may further expand frontline treatment options in the near future.
Later-Line Therapy: First-Line Treatment Determines Subsequent Sequencing
As ADC-based combinations become increasingly adopted in the frontline setting, selecting optimal therapy after disease progression has become one of the greatest clinical challenges.
Prof. Yang reviewed the latest CSCO recommendations for second-line treatment. For patients who have progressed following chemotherapy, recommended options include immune checkpoint inhibitor monotherapy, disitamab vedotin for patients with HER2 IHC 2+ or 3+ disease, and erdafitinib for tumors harboring FGFR alterations, all receiving Category II recommendations.
For patients previously treated with both chemotherapy and immunotherapy, EV, RC48, and erdafitinib remain recommended second-line therapies.
However, patients progressing after frontline ADC-immunotherapy combinations represent the largest unmet clinical need. Currently, no high-level evidence defines the optimal treatment strategy in this setting. According to current clinical practice and the CSCO Guidelines, options include gemcitabine plus platinum chemotherapy or erdafitinib (both Category II recommendations), while taxane-based chemotherapy remains a Category III recommendation.
Prof. Yang emphasized that, regardless of prior treatment, the guidelines strongly recommend enrollment in clinical trials as the preferred strategy for patients who progress after first-line therapy, underscoring the urgent need for new therapeutic approaches.
Next-Generation ADCs Continue to Expand the Therapeutic Landscape
Beyond currently approved agents, Prof. Yang reviewed numerous ADCs presented at ASCO 2025 and 2026 that are targeting multiple pathways, including Nectin-4, HER2, Trop-2, and novel bispecific targets.
HER2-Targeted ADCs
Trastuzumab deruxtecan (T-DXd) has demonstrated encouraging activity across multiple tumor types in the DESTINY program. In the DESTINY-PanTumor02 urothelial carcinoma cohort, previously treated patients with HER2 IHC 2+/3+ tumors achieved an ORR of 39%, a median PFS of 7 months, and a median OS of 12.8 months, making T-DXd a reasonable treatment option following EV-based therapy.
Another promising domestic agent, SHR-A2102, has reported preliminary efficacy with an ORR of 38.4% and a median PFS of 5.8 months. A Phase III trial is currently underway and may establish an additional HER2-targeted option developed in China.
Nectin-4-Targeted ADCs
Prof. Yang next discussed several investigational Nectin-4 ADCs.
BT8009 (zelenectide pevedotin) is built on Bicycle Therapeutics’ proprietary peptide platform, resulting in a remarkably small molecular size of only 4.2 kDa, which may improve tissue penetration compared with conventional ADCs. The ongoing Duravelo-2 study is evaluating BT8009 alone or combined with pembrolizumab in locally advanced and metastatic urothelial carcinoma. Early findings have shown an ORR of 57% in treatment-naïve patients, with mostly Grade 1–2 peripheral neuropathy and relatively low rates of dose reduction or treatment discontinuation. Activity has also been maintained in heavily pretreated patients while appearing to produce relatively limited skin toxicity.
Prof. Yang then introduced LY4052031, a next-generation Nectin-4 ADC carrying a novel topoisomerase I inhibitor payload. Preclinical studies demonstrated that tumors progressing after EV frequently continue expressing Nectin-4, suggesting that resistance is largely related to the payload rather than loss of the therapeutic target itself. Preliminary Phase I results from the NEXUS-01 study showed an ORR of 42% among patients with adequate CYP2D6 activity and 33% among patients previously treated with EV. Notably, within the 3.6 mg/kg cohort, EV-pretreated patients achieved an ORR approaching 47%, suggesting encouraging activity even after prior Nectin-4-directed therapy.
Another investigational Nectin-4 ADC, SYS6002 (CRB-701), incorporates a redesigned linker and optimized drug-antibody ratio while retaining an MMAE payload. Early clinical data have demonstrated an ORR of 37.6% and a disease control rate of 77.6%, and randomized studies comparing SYS6002 directly with EV are currently in progress.
EGFR × HER3 Bispecific ADC
Among emerging technologies, Prof. Yang highlighted BL-B01D1 (izalontamab brengitecan), the first EGFR × HER3 bispecific ADC to enter clinical development. Equipped with a topoisomerase I inhibitor payload, the agent demonstrated promising activity in previously treated advanced urothelial carcinoma, achieving an ORR of 44.1%, a DCR of 88.2%, a median PFS of 7.3 months, and a median duration of response of 11.3 months. Particularly impressive responses were observed among patients receiving only one prior line of therapy, where the ORR reached 80%. These encouraging findings have supported the initiation of the randomized IZABRIGHT-Bladder01 study.
Trop-2-Targeted ADCs
Finally, Prof. Yang reviewed datopotamab deruxtecan (Dato-DXd), a Trop-2-targeted ADC carrying a DXd payload. Although previous attempts to target Trop-2 in urothelial carcinoma encountered setbacks, Trop-2 remains broadly expressed across this disease, making it an attractive therapeutic target. In the urothelial carcinoma cohort of the Phase I TROPION-PanTumor01 trial, Dato-DXd achieved an ORR of 27.8% and a DCR of 77.8%, supporting further clinical development. The ongoing Phase III TROPION-Urothelial03 study is currently evaluating Dato-DXd combined with platinum chemotherapy versus gemcitabine plus platinum chemotherapy in patients progressing after EV plus pembrolizumab.
Conclusion
The treatment landscape for advanced urothelial carcinoma has rapidly evolved from conventional chemotherapy to an era in which ADC-based precision therapy has become the cornerstone of first-line management. Alongside globally established agents, domestically developed ADCs—including RC48, BFv, and SYS6002—are making remarkable progress and have the potential to significantly improve treatment accessibility for patients in China.
Despite these advances, important challenges remain. Optimizing treatment after ADC resistance, improving management of ADC-specific toxicities, and refining biomarker-driven patient selection will represent the next major frontiers in advancing precision medicine for advanced urothelial carcinoma.
Prof. Kaiwei Yang
