Systematic review: Targeting HER2 in bladder cancer

Abstract

Background: HER2 (ErbB2) is a receptor of the Human Epidermal Growth Factor Receptor (HER) family whose role in oncogenesis of numerous malignancies is well described. Drugs targeting HER2 are currently approved in breast and gastroesophageal cancers while pan-HER targeting agents are approved in multiple malignancies. HER2 genomic alterations are commonly described in urothelial cancer and multiple trials have assessed the efficacy of anti-HER2 agents in both muscle-invasive and metastatic urothelial carcinoma. Objective: To review prospective clinical trials of therapeutic agents with HER2-targeting activity in patients with bladder cancer. Methods: A systematic search of PubMed, ASCO abstracts and Clinicaltrials.gov was performed to identify studies of HER2-targeting agents in bladder cancer. Reported results from prospective trials were reviewed and summarized. Results: Eleven prospective clinical trials with reported results were identified that investigated activity of trastuzumab, lapatinib, neratinib, afatinib, or autologous cellular immunotherapy (DN24-02) in various bladder cancer treatment settings. Another 11 prospective trials that include bladder cancer patients and are investigating agents with anti-HER2 activity are currently ongoing or have completed enrollment but do not have published results. The reported clinical trials had variable HER2-positivity inclusion criteria and most did not meet their pre-specified benchmarks of clinical efficacy. A recent afatinib trial in an unselected patient population had promising findings in patients with HER2 and HER3 alterations. Conclusion: Trials of HER2-targeting agents generally in unselected bladder cancer patients have not shown definitive clinical efficacy. Better patient selection, such as via utilization of next-generation sequencing assays that detect specific genomic alterations, and novel therapy combinations that include HER2-targeting agents (with immunotherapy or other modalities) may lead to improved outcomes in current, ongoing or future trials.