alpelisib + fulvestrant + trastuzumab

This is a combination therapy consisting of three agents: alpelisib, fulvestrant, and trastuzumab. Alpelisib is an oral, alpha-specific phosphatidylinositol 3-kinase (PI3K) inhibitor that targets the p110α isoform encoded by the PIK3CA gene. Fulvestrant is a selective estrogen receptor degrader (SERD) that binds to and accelerates degradation of the estrogen receptor, blocking its signaling. Trastuzumab is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), inhibiting HER2-mediated signaling pathways. This combination is being investigated for use in patients with advanced or metastatic breast cancer that is HER2-positive and harbors PIK3CA mutations, particularly in those who have previously received anti-HER2 therapies. The rationale for this regimen stems from evidence that PIK3CA mutations can confer resistance to HER2-targeted therapy; thus, dual inhibition of PI3K and HER2—plus hormonal blockade in hormone receptor–positive disease—may overcome resistance mechanisms[1][4][9].