Urothelial carcinoma (cancer of the bladder and upper urinary tract) remains one of the most common and deadly cancers worldwide. While chemotherapy has long been the standard treatment, recent years have brought checkpoint immunotherapy as a breakthrough for advanced patients. But even after chemotherapy plus immunotherapy, many patients still progress, raising a critical question: what is the next step?
A new real-world study offers an answer. Ng et al., 2025, Cancer Immunology, Immunotherapy reports on a multicenter trial across China in which 198 patients with metastatic upper tract urothelial carcinoma (mUTUC) received a combination of disitamab vedotin (an antibody-drug conjugate targeting HER2) plus immune checkpoint inhibitors. The results are encouraging and signal a new pathway for treating this aggressive disease.
What Disitamab Vedotin Does
Disitamab vedotin, also known by its research code RC48-ADC, is a “smart bomb” drug. It is an antibody-drug conjugate, meaning it pairs an antibody that recognizes HER2 (a protein overexpressed in some cancers) with a toxic payload—in this case, an antimicrotubule agent. The antibody delivers the toxin directly to HER2-positive tumor cells, sparing healthy tissues.
HER2 is overexpressed in 30-50% of urothelial cancers, making it a natural target. Unlike some solid tumors where HER2 amplification is well-established, urothelial cancer’s HER2 dependency has received less attention in the clinic until recently. Combining this targeted agent with checkpoint inhibitors like nivolumab or pembrolizumab aims to hit the tumor from two angles: directly kill HER2-positive cells and unlock anti-tumor immunity.
The Study Design and Real-World Population
This was a retrospective, multicenter study analyzing data from June 2021 to December 2023 across 23 clinical centers. The cohort was divided into two groups: 122 patients (61.6%) received RC48-ADC plus immunotherapy as first-line treatment after progressing on prior chemotherapy; 76 patients (38.4%) received it as second-line or later therapy.
Real-world studies like this differ from randomized controlled trials in that they reflect actual practice, including patient comorbidities, treatment sequencing, and access patterns. That makes them valuable for understanding how therapies perform outside the controlled trial setting, though they sacrifice some scientific rigor.
Efficacy: The Primary Finding
The primary endpoint was objective response rate (ORR), meaning the percentage of patients whose tumors shrank by at least 30% by imaging criteria.
The headline result: 58.6% ORR (95% confidence interval 51.4-65.5%).
For context, published trials of chemotherapy alone in metastatic urothelial cancer typically achieve response rates of 40-50%. A response rate above 55% with salvage therapy is noteworthy.
The study also reported median progression-free survival (PFS) of 13 months, meaning that on average, patients taking this combination did not progress (develop resistant disease) for 13 months. Median overall survival was not reached at the time of analysis, a positive signal that indicates many patients were still alive at the data cutoff.
Subgroup analyses showed consistent ORR across patient groups, suggesting the benefit was not driven by a single patient type.
Tolerability and Safety
Combination therapy brings a tolerability tradeoff: broader activity often means more side effects. Here, treatment-related adverse events occurred in 79.8% of patients, but most were manageable.
Grade 3 or 4 adverse events (severe, potentially life-threatening) occurred in 19.7% of patients. The most common side effects were:
- Neuropathy (nerve damage): 40.4%
- Fatigue: 26.8%
- Alopecia (hair loss): 25.3%
- Rash: 21.7%
The neuropathy rate is noteworthy; it reflects the antimicrotubule toxin in the ADC. This side effect is generally dose-manageable but requires monitoring. Fatigue and rash are typical of checkpoint inhibitor therapy.
Importantly, no unexpected toxicities emerged. The safety profile aligned with the known tolerability of both drug classes.
Limitations of This Study
Every study has constraints, and readers deserve clarity about what they mean.
First, this was a retrospective study of data already collected, not a prospective randomized trial. Patients were not randomly assigned to treatment. This introduces selection bias: doctors may have preferentially enrolled sicker or healthier patients based on unmeasured clinical factors. The efficacy and safety numbers are real, but we cannot definitively say the treatment caused the outcomes.
Second, the population was entirely from China. While urothelial cancer biology is universal, treatment patterns, biomarker prevalence, and patient characteristics vary by region. Results may not generalize directly to European or American cohorts.
Third, there was no control arm. We do not have a direct comparison group receiving chemotherapy alone or immunotherapy alone at the same centers during the same period. Without a concurrent control, it is harder to separate the benefit of the new combination from improvements in supportive care, patient selection, or other factors.
Fourth, long-term follow-up is limited. Median overall survival was not reached, which is positive, but the median follow-up duration was not specified. We do not yet know if responses are durable or whether late relapses are common.
Finally, biomarker selection is unclear. The study does not specify whether patients were selected for HER2 expression or if all comers received the drug. If only HER2-positive patients were included, the results are less broadly applicable.
What This Means in Practice
For oncologists, this study adds evidence that HER2-targeting, previously considered less relevant in urothelial cancer compared to gastric or breast cancer, warrants integration into real-world treatment pathways. A 58.6% response rate for patients who have progressed after standard care is clinically meaningful.
For patients with metastatic urothelial cancer progressing after chemotherapy and immune checkpoint inhibitors, this combination represents a rational next step. The mechanism makes biological sense, the response rate is solid, and the toxicity profile, while not trivial, is manageable with appropriate oversight.
For researchers in cancer genomics and precision oncology, this study reinforces a growing theme: combining immunotherapy with targeted therapy (HER2 in this case, but also PD-L1, FGFR, or DNA repair defects in other urothelial studies) consistently outperforms either strategy alone. The interplay between direct cell killing and immune activation is a frontier in cancer treatment design.
Source and Further Reading
Ng et al., 2025, Cancer Immunology, Immunotherapy, DOI: 10.1007/s00262-025-04154-5
This multicenter real-world study included 198 patients across 23 Chinese clinical centers and analyzed efficacy and safety of disitamab vedotin (RC48-ADC) plus immune checkpoint inhibitors in metastatic upper tract urothelial carcinoma.