Editor's Note: Urothelial carcinoma (UC) is one of the most common malignancies in the urinary system. With the increasing availability of ADC (antibody-drug conjugate) drugs in clinical practice, optimizing ADC drug selection and combination therapies, as well as managing treatment-related adverse events, have become critical issues. Following the successful 2024 Annual Meeting of the Urological Surgeons Branch of the Chinese Medical Association (CUDA) in Xi'an, Urology Frontier invited Dr. Wei Yu from Peking University First Hospital to share insights on optimal ADC strategies for the systemic treatment of UC.From Classical Chemotherapy to the Era of Precision Medicine
The systemic treatment of UC has evolved through three major phases: traditional chemotherapy, immunotherapy, and precision medicine. In the 1980s and 1990s, cytotoxic drugs and platinum-based chemotherapy became key strategies for treating UC, with regimens like GC (gemcitabine-cisplatin) and MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) widely used across various stages, including first-line treatment and perioperative management of muscle-invasive bladder cancer (MIBC). Platinum-based chemotherapy achieved an overall response rate (ORR) of around 40%, but also brought significant bone marrow suppression, with a high incidence of grade ≥3 adverse events.
Since 2015, with the introduction of immune checkpoint inhibitors like nivolumab and pembrolizumab, as well as the development of domestic PD-1 inhibitors, UC treatment has entered the immunotherapy era. For patients with locally advanced or metastatic UC, second-line monotherapy with immune checkpoint inhibitors has achieved an ORR of about 20%. Immunotherapy has also shown some efficacy in platinum-intolerant patients as first-line treatment. However, despite multiple trials exploring immunotherapy in the perioperative setting for MIBC, positive results have been limited. Thus, while immunotherapy offers benefits, it has not replaced or surpassed chemotherapy in terms of efficacy for MIBC patients.
The advent of ADCs, small molecule tyrosine kinase inhibitors (TKIs), and other novel drugs has ushered UC treatment into the precision medicine era. ADC monotherapy in second-line treatment for metastatic UC has achieved ORRs of approximately 50%, and ADCs combined with immunotherapy in first-line treatment have also shown high response rates. Due to their unique structure, ADC drugs generally exhibit lower rates of grade ≥3 treatment-related adverse events (TRAEs) compared to chemotherapy. Recent trials, such as the EV-103H cohort study and the HOPE-03 study, are exploring the potential of ADCs in the neoadjuvant and adjuvant settings for MIBC, promising exciting developments in the near future.
Optimal ADC Treatment Strategies
ADCs consist of three key components: an antibody (the “radar”), a payload (the “weapon”), and a linker connecting the two. The differences in these components among various ADCs lead to variations in efficacy and safety across different tumor types and patient populations. Currently, the main ADCs approved for UC treatment globally include enfortumab vedotin (EV), sacituzumab govitecan (SG), vedicitumumab (RC48), and trastuzumab deruxtecan (DS8201). The first three have been approved for metastatic UC, but they differ in structure, clinical efficacy, and safety profiles. How should clinicians select the optimal ADC for their patients?
Analyzing ADC Targets and Prognostic Significance
From a target perspective, both RC48 and DS8201 target HER2, requiring HER2 immunohistochemistry (IHC) testing before treatment. In contrast, EV and SG target Nectin-4 and Trop2 proteins, respectively, with data showing these targets are expressed in about 80% of UC patients. Routine testing before using these drugs is not recommended.
HER2 has been identified as a poor prognostic marker in UC. Studies have shown that approximately 80% of Chinese UC patients express HER2, and those with HER2 overexpression are more likely to progress from non-muscle-invasive bladder cancer (NMIBC) to MIBC. Additionally, high-risk NMIBC and MIBC patients with HER2 overexpression have shorter disease-free survival (DFS) and worse prognoses than those without HER2 expression. Therefore, analyzing HER2 IHC expression can guide targeted treatment for HER2-positive patients.
Research indicates that ADC therapy targeting HER2 can significantly improve clinical outcomes in patients with HER2 overexpression or low expression. In these patients, ADC monotherapy or combined immunotherapy has demonstrated superior ORR compared to chemotherapy or immunotherapy alone. Trop2, on the other hand, does not require IHC testing before clinical use. However, studies have shown varying levels of Trop2 expression in UC patients, with higher ORRs observed in patients with high Trop2 expression. For the Nectin-4 target, low or absent expression has been associated with significantly shorter progression-free survival (PFS) in patients treated with EV, and those with low or absent Nectin-4 expression have a fourfold increased risk of progression compared to those with medium or high expression.
These findings suggest that the efficacy of ADC treatment is correlated with the expression levels of target molecules in tumor tissues, whether the target is HER2, Trop2, or Nectin-4. This understanding aids in identifying patients who are most likely to benefit from ADC therapy and helps explain cases of primary or acquired resistance to treatment.
Evaluating Differences in Payload Molecules
Beyond target molecules, the type of payload carried by an ADC also significantly influences efficacy. RC48 and EV both carry MMAE, a potent cytotoxic agent with high efficacy against microtubules. In contrast, SG and DS8201 (not yet approved for UC) carry topoisomerase I inhibitors, which act during the S phase of the cell cycle. These payloads differ significantly from MMAE, requiring higher doses to achieve optimal antitumor activity. Consequently, the standard dosages, efficacy, resistance, and durability of different ADCs vary.
Managing Treatment-Related Adverse Events
In addition to efficacy, safety is a critical concern for clinicians. ADC-related adverse events can arise from both the antibody’s interaction with the target antigen and the payload’s toxicity. The toxicity of RC48 and SG primarily stems from their payloads, while EV has both MMAE-related toxicity and toxicity from the Nectin-4 antibody’s interaction with non-tumor tissues.
Among the ADCs approved for UC, most studies involving EV and SG have included non-Chinese patients. The incidence of grade 3-4 adverse events in these studies was 73% for EV and 68% for SG. Peripheral neuropathy is a common adverse reaction for both RC48 and EV, while skin-related adverse events are more frequent with EV. SG’s common adverse events include gastrointestinal toxicity, particularly severe diarrhea (caution should be exercised when interpreting these data, as they come from different patient populations and are not directly comparable).
Future Outlook
First-Line Treatment: The CSCO UC guidelines have been updated since 2022, including specific recommendations for first-line, second-line, and subsequent treatments for metastatic UC (mUC). Vedicitumumab combined with toripalimab has achieved an ORR of over 70% in HER2 IHC 1/2/3+ patients and has been recommended as a first-line treatment. Given its accessibility and affordability in China, it has become the preferred treatment option for HER2-positive patients.
Second-Line Treatment: For second-line treatment, the guidelines include traditional chemotherapy, immunotherapy, ADC monotherapy, and ADC combined with immunotherapy. For patients who have failed chemotherapy or immunotherapy, RC48 and EV monotherapy are recommended as second-line options. For patients who have only failed chemotherapy and not yet received immunotherapy, combining ADC with immunotherapy may achieve an efficacy rate of 50-70%.
In clinical practice, effectively selecting patients who are most likely to benefit from treatment and devising the most appropriate therapeutic strategy is crucial. The recently published Chinese Expert Consensus on HER2 Testing in Urothelial Carcinoma and the CSCO Guidelines for the Diagnosis and Treatment of Urothelial Carcinoma (2023 edition) recommend HER2 protein expression testing for all patients with locally advanced or metastatic UC. Routine HER2 testing is also recommended for all patients with muscle-invasive UC (≥pT2 stage). These guidelines provide essential guidance for personalized treatment planning in UC patients.
In the future, clinical decisions regarding ADC use should fully consider the characteristics of available drugs, including patient selection criteria, efficacy range, and safety profile. With current knowledge, we can reasonably stratify patients using HER2 IHC, a relatively mature and straightforward method, into three categories: HER2 overexpression, HER2 low expression, and HER2 no expression, each with its own optimal treatment strategy. As more drugs become available, these options will further enrich the clinical arsenal, offering patients better overall treatment outcomes.
About Dr. Wei Yu
- Chief Physician, Professor, and Doctoral Supervisor
- Chief Physician, Department of Urology, Peking University First Hospital
- Standing Committee Member, Urothelial Carcinoma Committee, Chinese Society of Clinical Oncology (CSCO)
- Member, Oncology Group, Urology Professional Committee, Chinese Society of Integrated Traditional and Western Medicine
- Member, Urogenital Tumor Group, Familial and Hereditary Tumor Collaboration Group, Chinese Anti-Cancer Association
- Member, Youth Committee, Renal Transplantation Branch, China Medical and Health International Exchange Promotion Association
- Member, CUA Urinary Control Young Physicians Alliance
