Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents a particularly aggressive form of the disease, characterized by the overexpression of the HER2 receptor, which drives tumor development and progression. Accounting for approximately 14% of breast cancer cases in the United States, HER2+ breast cancer is associated with a high risk of mortality and poor prognosis, with 5-year survival rates of 45.6% and 39.5% for HER2+/HR+ and HER2+/HR- metastatic breast cancer, respectively.
The introduction of trastuzumab, a monoclonal antibody targeting HER2, marked a significant advancement in the treatment of HER2+ breast cancer. However, despite the benefits of trastuzumab and pertuzumab in the neoadjuvant and adjuvant settings, approximately 30% of patients still experience recurrence or metastasis. This has led to the exploration of new treatment options, including margetuximab, a monoclonal antibody developed using Fc-engineering strategies to enhance its antitumor potency.
Results from the phase 3 SOPHIA trial demonstrated that margetuximab, in combination with chemotherapy, significantly extended progression-free survival compared to trastuzumab plus chemotherapy in patients with HER2+ unresectable or metastatic breast cancer who had previously received HER2-directed therapies. The trial also suggested that patients with the CD16A-158FF genotype may particularly benefit from margetuximab, highlighting the potential of pharmacogenomic targeting in improving treatment outcomes.
Despite these advancements, the sequencing of treatments for HER2+ metastatic breast cancer remains a challenge, with a lack of evidence-based recommendations for later lines of therapy. Real-world case studies have shown that margetuximab can be an effective option for patients who have progressed on multiple lines of treatment, with progression-free survival times consistent with those observed in clinical trials. However, the management of adverse events and the optimization of treatment sequencing continue to be areas of active research and discussion.
The ongoing MARGOT trial aims to further evaluate the role of personalized treatment based on CD16A genotype, potentially paving the way for more targeted and effective therapeutic strategies for HER2+ breast cancer patients. As the landscape of HER2+ breast cancer treatment continues to evolve, the integration of real-world evidence with data from controlled clinical trials will be crucial in optimizing patient care and outcomes.
