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HER2-Positive Urothelial Carcinoma: Current Evidence on Targeted Agents and Immunotherapy-Based Combinations
Federica Ciciriello1, Gaetano Pezzicoli1, Antonello Biasi1
1Interdisciplinary Department of Medicine, University of Bari "A. Moro", Bari, Italy.
Abstract:
Despite the introduction of immunotherapy and antibody-drug conjugates (ADCs), 5-year survival rates for advanced urothelial cancer (UC) remain unsatisfactory. Modest results with conventional systemic treatments have prompted the need for tailored therapies that exploit actionable mutations, such as those involving the human epidermal growth factor receptor (HER)-2 proto-oncogene, which plays a key role in regulating cell growth, differentiation, and survival. HER2-positive UC accounts for 13-25% of all locally advanced/metastatic UC. HER2 overexpression in UC varies widely by tumour stage and is usually a late phenomenon associated with poorer prognosis. Given the crucial biological role of HER2 in UC and the proven activity of anti-HER2 drugs in other solid tumours (e.g. breast and gastric cancer), in this comprehensive review, we analyse clinical trials using HER2-targeting strategies in HER2-positive metastatic UC. Clinical trials of anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors in UC have shown limited efficacy. On the other hand, HER2-targeted ADCs such as trastuzumab deruxtecan and disitamab vedotin have shown encouraging results. However, the most interesting data come from the combination of HER2-targeted ADCs with immunotherapy because of the synergistic action of the two drugs: HER2-directed ADCs, with their cytotoxic effect, lead to the release of cancer antigens, enhancing the anti-tumour immune response, which is boosted by the immune checkpoint inhibitor. Moreover, this combination strategy may also offer some advantages in rewiring the tumour microenvironment, favouring an anti-cancer immune response. ADC and immune checkpoint inhibitor combinations are supported by solid preclinical evidence and are emerging as novel and promising tailored therapeutic approaches for advanced UC.
Insights
Targeting human epidermal growth factor receptor 2 (HER2) with antibody-drug conjugates (ADCs) and immunotherapy shows promise for advanced urothelial cancer (UC). Combining HER2-targeted ADCs with immune checkpoint inhibitors may improve survival rates in HER2-positive UC patients.
Area of Science:
- Oncology
- Translational Medicine
- Pharmacology
Background:
- Advanced urothelial cancer (UC) has poor 5-year survival rates despite current treatments like immunotherapy and antibody-drug conjugates (ADCs).
- Targeting actionable mutations, particularly human epidermal growth factor receptor 2 (HER2) proto-oncogene, is a promising strategy for tailored therapy.
- HER2-positive UC, found in 13-25% of cases, often presents late and is associated with a poorer prognosis.
Purpose of the Study:
- To review clinical trials investigating HER2-targeting strategies in HER2-positive metastatic UC.
- To evaluate the efficacy of different HER2-targeting agents, including monoclonal antibodies, tyrosine kinase inhibitors, and ADCs.
- To explore the potential of combining HER2-targeted ADCs with immunotherapy for advanced UC.
Main Methods:
- Comprehensive literature review of clinical trials involving HER2-targeting therapies in metastatic UC.
- Analysis of data from trials using anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors, and ADCs (trastuzumab deruxtecan, disitamab vedotin).
- Examination of preclinical and clinical evidence for combination strategies involving HER2-targeted ADCs and immune checkpoint inhibitors.
Main Results:
- Anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors showed limited efficacy in UC clinical trials.
- HER2-targeted ADCs demonstrated encouraging results in HER2-positive metastatic UC.
- Combination therapy of HER2-targeted ADCs with immunotherapy exhibited synergistic anti-tumour effects, enhancing immune response and potentially modifying the tumor microenvironment.
Conclusions:
- HER2-targeted ADCs represent a promising therapeutic avenue for advanced UC.
- Combining HER2-targeted ADCs with immune checkpoint inhibitors offers a novel and potentially synergistic approach for treating HER2-positive advanced UC.
- This combination strategy warrants further investigation due to its potential to improve outcomes in advanced urothelial cancer.
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