Jain S, et al. - In the present study, researchers tested the safety and activity of alpelisib (a phosphoinositide 3-kinase [PI3K] α isoform-specific inhibitor) in combination with T-DM1 for trastuzumab- and taxane-resistant HER2-positive metastatic breast cancer (MBC). For this investigation, patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. They found that alpelisib in combination with T-DM1 was tolerable and displayed activity in trastuzumab-resistant HER2-positive MBC. In addition, activity was noted in T-DM1-resistant disease. They suggested that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy. Fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia were the most frequent toxicities seen.