What therapies are on the horizon for HER2 positive breast cancer?

ABSTRACT

Introduction: Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, HER2-positive metastatic breast cancer remains an almost invariably deadly disease, with primary or acquired resistance to HER2-directed agents developing during treatment. Many efforts are focused on identifying new agents that may more effectively inhibit HER2 signaling and on possible combination strategies.

Areas covered: This review summarizes the landscape of drugs under development for HER2-positive metastatic breast cancer, as antibody-drug conjugates, monoclonal anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors. Moreover, available data for possible combination of anti-HER2 drugs and different agents, as immunotherapy, PI3K/mTOR inhibitors, CDK4/6 inhibitors currently under evaluation are reviewed. These strategies may overcome mechanisms of resistance and further improve patient outcomes.

Expert opinion: Identification of valuable predictive biomarkers is needed to better inform choice of treatment sequence for the individual patient and limit the financial toxicity of these agents.

KEYWORDS:

• HER2 positive advanced breast cancer
• immunotherapy
• antibody drug conjugates
• new drug development
• margetuximab
• DS-8201a
• tyrosine kinase inhibitors

Article highlights

• Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, primary or acquired resistance to HER2-directed agents may develop over treatment course leading to treatment failure and tumor progression

• Many efforts are ongoing to identify new agents that may more effectively inhibit HER2 signaling, as new anti-HER2 monoclonal antibodies (including margetuximab) or novel tirosine kinase inhibitors, as tucatinib

• Antibody-drug conjugates, as DS8201a and SYD985 can be considered a new successful class of targeted agents coupling the selectivity of monoclonal antibodies and the cytotoxicity of chemotherapy agents

• Bispecific antibodies are monoclonal antibodies that target two different epitopes with the possibility to suppress multiple pathways simultaneously

• HER2-positive breast cancer is considered an immunogenic subtype. Since immunogenicity may be boosted by the action of trastuzumab, many studies investigating the combination of trastuzumab and immunotherapy are currently ongoing

• Combinations of anti-HER2 therapy with other agents including CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are possible strategies to overcome some mechanisms of acquired resistance

• Many strategies to improve treatment tailoring are currently under investigation, including functional imaging in advanced HER2+ BC and identification of predictive biomarkers of drug efficacy

Declaration of interest

G Curigliano has received personal fees from Novartis, Pfizer, and Roche for expert presentations and personal fees as a member of the advisory board for Ellipses Pharma, Lilly, Novartis, Pfizer, Roche, Samsung, and Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer of this manuscript has disclosed involvement in clinical research for Amgen, Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Celgene, and Pierre Fabre. They have also served on the advisory boards and consulted for Novartis, Pfizer, Roche/Genentech, Eisai, and Celgene. Peer reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.