Implementing Antibody-Drug Conjugates (ADCs) in HER2-positive Breast Cancer

State of the Art and Future Directions

Emanuela Ferraro; Joshua Z. Drago; Shanu Modi

Disclosures

Breast Cancer Res. 2021;23(84) 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

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.[1] 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.[2] 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.[3] 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.

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