Abstract and Introduction
The development of anti-HER2 agents has been one of the most meaningful advancements in the management of metastatic breast cancer, significantly improving survival outcomes. Despite the efficacy of anti-HER2 monoclonal antibodies, concurrent chemotherapy is still needed to maximize response. Antibody-drug conjugates (ADCs) are a class of therapeutics that combines an antigen-specific antibody backbone with a potent cytotoxic payload, resulting in an improved therapeutic index. Two anti-HER2 ADCs have been approved by the FDA with different indications in HER2-positive breast cancer. Ado-trastuzumab emtansine (T-DM1) was the first-in-class HER2-targeting ADC, initially approved in 2013 for metastatic patients who previously received trastuzumab and a taxane, and the label was expanded in 2019 to include adjuvant treatment of high-risk patients with residual disease after neoadjuvant taxane and trastuzumab-based therapy. In 2020, trastuzumab deruxtecan (T-DXd) was the second approved ADC for patients who had received at least 2 lines of anti-HER2-based therapy in the metastatic setting. The success of these two agents has transformed the treatment of HER2-positive breast cancer and has re-energized the field of ADC development. Given their advanced pharmaceutical properties, next-generation HER2-targeted ADCs have the potential to be active beyond traditional HER2-positive breast cancer and may be effective in cells with low expression of HER2 or ERBB2 mutations, opening a spectrum of new possible clinical applications. Ongoing challenges include improving target-specificity, optimizing the toxicity profile, and identifying biomarkers for patient selection. The aim of this review is to summarize the principal molecular, clinical, and safety characteristics of approved and experimental anti-HER2 ADCs, contextualizing the current and future landscape of drug development.
Historically, HER2-positive breast cancer (BC) has been recognized to have a poor prognosis, with a median overall survival of 15 months with traditional chemotherapy treatments in the metastatic setting. Trastuzumab, the first HER2-targeting monoclonal antibody (mAB) developed, represents one of the most significant advancements in the management of solid tumors. Today, there are 8 approved HER2 targeted agents and the median survival is over 5 years for patients with advanced-stage disease, though it may be even longer for patients who receive novel therapies. The maximal antitumoral activity of anti-HER2 agents is achieved in combination with chemotherapy, and this effect may be related to the heterogeneity of HER2 expression among other mechanisms of primary resistance. Additionally, HER2 overexpressing cells have high proliferation rates, resulting in higher responsiveness to cytotoxic therapies.
Based on the synergistic effects of HER2-inhibition and chemotherapy, a new clas of drug have been developed. ADCs combine the antitumoral properties of both of these approches in a single pharmacological entity. The aim of this review is to provide a summary of the clinical data on ADCs approved by the US Food and Drug Administration (FDA), as well as novel ADCs under development for the treatment of HER2-positive breast cancer.
Breast Cancer Res. 2021;23(84) © 2021 BioMed Central, Ltd.
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