HER2 has become an increasingly important therapeutic target in urothelial carcinoma, but its role in this disease is different from the classic HER2-driven biology seen in breast and gastric cancers.
A new review article, titled “Targeting HER2 in urothelial carcinoma: from pathway inhibition to antibody–drug conjugates,” was published in Cancer Treatment Reviews on June 18, 2026.
Authors: Hamed Wafaa, Nils C.H. van Creij, Michael Guenther, Maxim Noeparast, Jose Daniel Subiela, Angelika Terbuch, Dora Niedersuess-Beke, Zoran Culig, Steffen Ormanns, and Renate Pichler.
Why HER2 Matters in Urothelial Carcinoma
Urothelial carcinoma remains a challenging disease, particularly in locally advanced and metastatic settings. Platinum-based chemotherapy, immune checkpoint inhibitors, and antibody–drug conjugates have improved treatment options, but durable disease control remains limited for many patients.
HER2, encoded by ERBB2, has re-emerged as a potential target in urothelial carcinoma. However, HER2 biology in this disease is complex. HER2 expression is heterogeneous, varies across histological and molecular subtypes, and is not always linked to gene amplification or pathway dependence.
This helps explain why early HER2-targeted strategies, including tyrosine kinase inhibitors and monoclonal antibodies, showed limited and inconsistent activity in urothelial carcinoma.
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HER2 Expression Is Highly Variable
HER2 protein overexpression is the most frequently reported HER2 alteration in urothelial carcinoma, but reported rates vary widely depending on the cohort, disease stage, tissue source, and testing method.
HER2 IHC positivity, defined as 2+ or 3+, has been reported in approximately 20% to 40% of urothelial carcinoma cases. Strong HER2 overexpression, or IHC 3+, is seen in about 6% to 15% of tumors.
HER2 expression is more common in muscle-invasive and metastatic disease than in non–muscle-invasive bladder cancer. It is also strongly influenced by histology. The highest HER2 positivity rates are reported in micropapillary urothelial carcinoma, ranging from 56% to 87.5%, while much lower rates are seen in tumors with squamous differentiation.
ERBB2 gene amplification is less common than protein overexpression, occurring in about 5% to 10% of urothelial carcinoma cases. Importantly, HER2 protein expression and ERBB2 amplification do not always match. Some IHC 3+ tumors do not show amplification, while some amplified tumors may have low or negative IHC staining.
Activating ERBB2 mutations are another distinct category. Large sequencing studies report ERBB2 mutations in approximately 1% to 3% of unselected urothelial carcinoma cases, with higher rates in advanced or metastatic cohorts. More than 70% of ERBB2 mutations may occur without HER2 overexpression or gene amplification, meaning they can be missed by conventional IHC or ISH-based testing.
HER2 Testing Remains a Major Challenge
Accurate HER2 assessment is essential for selecting patients for HER2-directed therapy, but testing in urothelial carcinoma remains difficult.
Unlike breast or gastric cancer, urothelial carcinoma does not yet have a fully validated, disease-specific HER2 testing algorithm. Current testing often relies on IHC, with ISH used in equivocal cases, but HER2 staining in urothelial carcinoma is frequently incomplete, basolateral, and heterogeneous.
HER2-low disease, generally defined as IHC 1+ or IHC 2+ without ERBB2 amplification, accounts for about 25% to 35% of urothelial carcinoma tumors. This category is becoming increasingly important because HER2-directed antibody–drug conjugates may show activity beyond HER2-high tumors.
Standardized HER2 scoring in urothelial carcinoma, clearer definitions of HER2-low disease, and testing strategies that reflect current disease biology remain important needs, especially in metastatic or progressing disease.
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Why Earlier HER2 Inhibition Was Disappointing
Early HER2-targeted therapies in urothelial carcinoma mainly focused on pathway inhibition. These included HER2-directed tyrosine kinase inhibitors and monoclonal antibody-based approaches.
Afatinib showed limited activity in platinum-refractory metastatic urothelial carcinoma, with an objective response rate of 8.7% and a median progression-free survival of 1.4 months in one phase 2 study. Lapatinib maintenance after chemotherapy did not improve progression-free or overall survival. Neratinib also failed to show meaningful responses in ERBB2-mutated urothelial carcinoma.
Trastuzumab-based chemotherapy produced responses in an early phase 2 study, but the results did not clearly establish a randomized benefit, and cardiac toxicity was a concern. Dual HER2 blockade with pertuzumab plus trastuzumab showed proof of concept in selected patients, but the level of activity did not surpass what has been achieved with modern antibody–drug conjugates.
Overall, these findings support the idea that HER2 in urothelial carcinoma is often not a dominant oncogenic driver. Instead, HER2 may function more effectively as a surface target for drug delivery.
HER2-Directed ADCs Changed the Field
The major progress in HER2 targeting in urothelial carcinoma has come from antibody–drug conjugates. These agents use HER2 as a tumor-associated antigen to deliver a cytotoxic payload directly to cancer cells. This approach is less dependent on HER2 pathway addiction and may be more effective in tumors with heterogeneous or low HER2 expression.
Trastuzumab Deruxtecan
Trastuzumab deruxtecan showed activity in HER2-expressing advanced urothelial carcinoma in the DESTINY-PanTumor02 trial. In the urothelial carcinoma cohort, the objective response rate was 39%, increasing to 56.3% among patients with HER2 IHC 3+ disease.
Median progression-free survival was 7.0 months, and median overall survival was 12.8 months.
A separate phase 1b/2 study evaluated trastuzumab deruxtecan plus nivolumab in metastatic urothelial carcinoma after platinum-based chemotherapy. In the HER2-positive cohort, the confirmed objective response rate was 36.7%.
Disitamab Vedotin
Disitamab vedotin is the most extensively studied HER2-directed ADC in urothelial carcinoma. In pooled phase 2 data from RC48-C005 and RC48-C009, disitamab vedotin monotherapy achieved an objective response rate of 50.5% in patients with HER2 2+ or 3+ locally advanced or metastatic urothelial carcinoma after chemotherapy. Median progression-free survival was 5.9 months, and median overall survival was 14.2 months.
Activity was also reported in HER2-low or HER2-negative tumors. In an exploratory cohort with HER2 0–1+ disease, disitamab vedotin achieved an objective response rate of 26.3%, with a median progression-free survival of 5.5 months.
In the global RC48G001 study, disitamab vedotin monotherapy showed similar activity in HER2-positive and HER2-low cohorts. The objective response rate was 54.9% in the HER2-positive cohort and 52.6% in the HER2-low cohort.
Combination strategies have also shown promising results. In an exploratory first-line cohort, disitamab vedotin plus pembrolizumab achieved an objective response rate of 75% and a complete response rate of 35%.
The phase 3 RC48-C016 trial compared disitamab vedotin plus toripalimab with chemotherapy in previously untreated HER2-expressing locally advanced or metastatic urothelial carcinoma. Median progression-free survival was 13.1 months with disitamab vedotin plus toripalimab versus 6.5 months with chemotherapy. Median overall survival was 31.5 months versus 16.9 months. The objective response rate was 76.1% versus 50.2%.
Read more about RC48-C016 at ESMO 2025 on OncoDaily.
Safety Considerations
HER2-directed ADCs have different toxicity profiles depending on their payload and linker technology. Disitamab vedotin and MRG002 are MMAE-based ADCs, with toxicities mainly including peripheral neuropathy, hematologic toxicity, fatigue, alopecia, and liver enzyme elevation.
Trastuzumab deruxtecan has a different safety profile, with interstitial lung disease or pneumonitis identified as the key toxicity requiring careful monitoring.
T-DM1 showed limited tolerability in a small urothelial carcinoma study, while SYD985 was associated with ocular adverse events, including conjunctivitis, keratitis, and dry eye symptoms. These differences are important because HER2-directed ADCs are not interchangeable. Their clinical use will require careful patient selection, toxicity monitoring, and treatment sequencing.
Resistance and Unanswered Questions
Despite encouraging activity, resistance remains a major issue. HER2 expression can vary within tumors and between primary and metastatic sites. HER2 loss or downregulation may occur under treatment pressure. Resistance may also involve impaired ADC internalization, altered lysosomal processing, drug efflux pumps, changes in payload sensitivity, and tumor microenvironment factors.
One important unanswered question is how HER2-directed ADCs should be used after enfortumab vedotin plus pembrolizumab. This is especially relevant because disitamab vedotin and enfortumab vedotin both use MMAE-based payloads, raising concern about potential cross-resistance. Prior exposure to enfortumab vedotin was not permitted in RC48G001, so the activity of disitamab vedotin after enfortumab vedotin remains insufficiently defined.
Takeaway
HER2 targeting in urothelial carcinoma has moved from limited pathway inhibition to a more clinically meaningful ADC-based strategy. HER2-directed antibody–drug conjugates have shown activity in HER2-positive disease and, importantly, in HER2-low tumors. This broadens the potential role of HER2 as a treatment target in urothelial carcinoma.
However, the field still needs standardized HER2 testing, better biomarker strategies, clearer definitions of HER2-low disease, and prospective data on sequencing after enfortumab vedotin–based therapy.
For now, HER2 in urothelial carcinoma should be viewed not as a simple breast cancer-like driver, but as a heterogeneous and clinically relevant target whose therapeutic value is being reshaped by antibody–drug conjugates.
The full article is available in Cancer Treatment Reviews.
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