STANDARD TREATMENT — HER2, a transmembrane receptor protein involved in normal cell growth, is overexpressed in about 20% of breast cancers. Amplification and/or overexpression of HER2 is associated with more aggressive disease and reduced survival. Standard first-line treatment of HER2-positive advanced or metastatic breast cancer has been a taxane plus the anti-HER2 monoclonal antibodies trastuzumab (Herceptin) and pertuzumab. Fam-trastuzumab deruxtecan monotherapy has been a preferred second-line option.2,3

CLINICAL STUDIES — FDA approval of fam-trastuzumab deruxtecan for first-line treatment was based on the results of a randomized trial (DESTINY-Breast09) in 1157 patients with HER2-positive advanced or metastatic breast cancer who had not received chemotherapy or HER2-targeted therapy (or had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before the diagnosis of advanced or metastatic disease). Patients were randomized to receive fam-trastuzumab deruxtecan alone, fam-trastuzumab deruxtecan plus pertuzumab, or standard treatment (a taxane, trastuzumab, and pertuzumab) until disease progression or unacceptable toxicity occurred. In the prespecified interim analysis, median progression-free survival (PFS) was significantly longer with fam-trastuzumab deruxtecan plus pertuzumab than with standard treatment (40.7 vs 26.9 months). Compared to standard treatment, patients receiving fam-trastuzumab plus pertuzumab also had a higher response rate (85.1% vs 78.6%) and a longer median duration of response (39.2 vs 26.4 months).4

DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of Enhertu for first-line treatment of HER2-positive unresectable or metastatic breast cancer is 5.4 mg/kg administered intravenously once every 3 weeks in addition to pertuzumab until disease progression or unacceptable toxicity occurs. The label recommends dosage adjustments that should be made if adverse effects occur. One dose of Enhertu for a 70-kg patient costs about $13,000.5

CONCLUSION — In one clinical trial in adults with HER2-positive unresectable or metastatic breast cancer who had not received chemotherapy or HER2-targeted therapy for advanced or metastatic disease, progression-free survival was significantly longer with fam-trastuzumab deruxtecan (Enhertu) plus pertuzumab (Perjeta) than with the current standard of care. Fam-trastuzumab deruxtecan plus pertuzumab will likely become the standard first-line treatment for HER2-positive unresectable or metastatic breast cancer.