The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives

• Published in: Cancer treatment reviews 2022-03, Vol.104, p.102351-102351, Article 102351
• Main Authors: Patelli, Giorgio, Zeppellini, Annalisa, Spina, Francesco, Righetti, Elena, Stabile, Stefano, Amatu, Alessio, Tosi, Federica, Ghezzi, Silvia, Siena, Salvatore, Sartore-Bianchi, Andrea
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - adverse effects; Carcinoma, Transitional Cell - drug therapy; ERBB2; HER2; Humans; Metastatic bladder cancer; Metastatic urothelial cancer; Mutation; Receptor, ErbB-2; Targeted treatment; Trastuzumab - adverse effects; Urinary Bladder Neoplasms - drug therapy
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2022.102351

Keys. ADC = antibody drug conjugate; ChT = cytotoxic chemotherapy; HER1-4 = human epidermal growth factor receptor 1–4; mUC = metastatic urothelial cancer; MoAb = monoclonal antibody; P = phosphate group; PD-L1 = programmed death ligand-1; TDM-1 = trastuzumab-emtansine; T-DXd = trastuzumab-deruxtecan; TKI = tyrosine kinase inhibitor. Created with BioRender.com. Color should be used for this figure in print. In this systematic review, 33 clinical trials were selected with respect to HER2-targeting in metastatic urothelial cancer (mUC). All studies were assigned to one of the following strategies: 1. HER2-targeting with single agents; 2. Anti-HER2 agents in combination with cytotoxic chemotherapy; 3. dual HER2 blockade; 4. HER2-targeted antibody-drug conjugates; and 5. other novel approaches. Drugs and combinations used in these trials were reported for each strategy (green-colored if trials yielded positive results, red-colored if negative, black-colored if still ongoing). [Display omitted] •HER2 alterations are potential therapeutic targets in metastatic urothelial cancer.•Anti-HER2 single agents and chemotherapy combinations failed to provide any benefit.•Dual blockade through monoclonal antibodies proved active in HER2-amplified tumors.•Antibody drug conjugates are the most promising therapeutic strategy in this field.•Targeting HER2 mutations is still at very early stage of clinical study. HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches. 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and tras