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HER2 ADCs in HER2 Pos Adv Bladder Cancer
Experts Answer Questions on HER2-Targeted ADCs in HER2-Positive Advanced Bladder Cancer

Released: December 17, 2025

Matthew D. Galsky
Matthew D. Galsky, MD
Vadim S. Koshkin
Vadim S. Koshkin, MD
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Key Takeaways
  • HER2 testing should be performed on available biopsy or cystectomy samples for patients with advanced urothelial carcinoma.
  • Antibody–drug conjugates are changing the treatment landscape of urothelial carcinoma and approved, guideline-recommended therapies such as trastuzumab deruxtecan are available for patients with HER2-positive tumors.

The treatment landscape for advanced urothelial carcinoma is rapidly changing with the incorporation of antibody–drug conjugates (ADCs) into clinical practice. Standard of care first-line therapy for most patients with advanced bladder cancer is enfortumab vedotin plus pembrolizumab unless contraindicated. Approximately 20% of bladder cancers are HER2-positive and more than 50% exhibit some level of HER2 expression. Targeted therapy, including HER2-directed agents, is a guideline-recommended option as second-line or later therapy. The recent tumor agnostic approval of the HER2-targeted ADC trastuzumab deruxtecan (T-DXd) for HER2-positive tumors after previous therapy necessitates that healthcare professionals (HCPs) incorporate HER2 testing into clinical practice to identify patients who may benefit from T-DXd. Regulatory approval for this indication was based in part on data from the phase II DESTINY-PanTumor02 trial that included patients with bladder cancer. Disitamab vedotin is another HER2-targeted ADC with approval in China. Recent phase III evidence on disitamab vedotin in combination with an anti–PD-1 agent as first-line therapy for advanced urothelial carcinoma is promising and additional trials are ongoing. In this commentary, Vadim S. Koshkin, MD and Matthew D. Galsky, MD address questions selected by an HCP audience during a satellite symposium on effectively incorporating HER2 testing and HER2-targeted therapy into clinical practice for patients with advanced urothelial carcinoma.

How do you incorporate routine HER2 testing into your clinical practice?
Vadim S. Koshkin, MD:
This is an important question, and I think it is important to test for HER2 expression as early as possible. By the time patients have metastatic disease, I want to know the HER2 status of their tumor. That often involves testing the tissue that is readily available and frequently that is archival samples from radical cystectomy. I think it is important, if possible, to test a metastatic sample if one is available. Among our pathologists there is a lot of experience and expertise with HER2 testing for breast cancer, and more recently gastric cancer. The adoption of HER2 testing for urothelial cancer at my institution has been fairly seamless. There are also reliable commercial panels available.

Matthew D. Galsky, MD:
We have been routinely performing HER2 expression testing as a reflex test on cystectomy specimens over the past couple of years and that information helps us plan a treatment sequence. HER2 testing can be done locally and results come back within a matter of days.

How do you envision HER2-targeted ADCs affecting future clinical practice? 
Vadim S. Koshkin, MD:
ADCs are already shaping current clinical practice in both the first-line and later line settings for advanced disease. T-DXd is a guideline-recommended option for patients with HER2-positive tumors and we currently use T-DXd for patients with treatment-refractory disease and high HER2 expression. With the really encouraging data on disitamab vedotin in combination with toripalimab from the phase III RC48-C016 trial in treatment-naive advanced urothelial carcinoma and the early data from the phase II RC48 G001 trial of disitamab vedotin in combination with pembrolizumab for previously treated patients, we are probably going to be using disitamab vedotin in combination for a broader subset of patients than those with HER2 IHC3+ once approved.

Based on available data, more than 50% of patients with urothelial carcinoma exhibit some degree of HER2 expression that may qualify for therapy with disitamab vedotin in combination with pembrolizumab, if that combination is eventually approved. Now the question becomes in what setting we would use this combination? There is an ongoing global phase III trial of disitamab vedotin with pembrolizumab vs chemotherapy (SGNDV-001; NCT05911295) in treatment-naive advanced urothelial carcinoma with HER2 expression of 1+ or greater. If this trial produces similar encouraging results as the RC48-C016 trial of disitamab vedotin plus toripalimab, then this combination may be an option in the frontline setting. If so, then we will have to make a decision for patients with HER2 expression of whether standard of care enfortumab vedotin and pembrolizumab or disitamab vedotin plus pembrolizumab is optimal therapy. Moreover, we potentially would consider using this combination in earlier-stage disease, like we are using enfortumab vedotin plus pembrolizumab earlier for patients with muscle-invasive disease.

How important is sequencing of therapies in the evolving treatment landscape of bladder cancer?
Vadim S. Koshkin, MD:
The sequencing of therapy is an important question for which, with the currently available therapies, we have limited data. For a patient with HER2-positive disease who had progressed on prior therapy—usually enfortumab vedotin and pembrolizumab—we then have to decide whether they get T-DXd or perhaps platinum-based chemotherapy as their next line of therapy. We do not necessarily have the data to support either approach. I generally use T-DXd earlier on because we see good activity with this therapy.

Matthew D. Galsky, MD: That is similar to my approach as well.

What clinical strategies may help to mitigate treatment-related adverse events in patients undergoing therapy with HER2-targeted treatments?
Vadim S. Koshkin, MD:
In terms of clinical strategies to mitigate treatment-related adverse events, it is important to be aware of the specific toxicity associated with any drug. With T-DXd we are concerned about cytopenias and those events can happen even early during treatment. We need to monitor for cytopenias and address as needed. For many patients, I use G-CSF support. Though rare, pneumonitis is always a concern, because it is potentially a significant adverse event. For anyone with symptoms suggestive of pneumonitis, we try to move quickly and assess any dyspnea or cough with urgent imaging to make sure that we can address it quickly if it occurs.

Your Thoughts
What challenges do you face in incorporating HER2 testing and HER2-targeted ADCs for your patients with advanced urothelial carcinoma? Join the conversation and leave a comment below.

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