Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer

Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated in oncogenesis, treatment resistance, and disease progression, making it an attractive target for anticancer drug development. Early experiences with PI3K/AKT/mTOR inhibitors have highlighted challenges associated with their modest efficacy, as well as safety and tolerability issues; however, several effective next-generation PI3K/AKT/mTOR inhibitors have now been approved for patients with breast cancer. As a result, there is a growing need to understand the presentation, characteristics, and management of common toxicities (hyperglycemia, rash, stomatitis, and diarrhea). This review summarizes available safety data from phase III randomized clinical trials for approved PI3K/AKT/mTOR pathway-targeted therapies (everolimus, alpelisib, capivasertib, and inavolisib), including incidence, severity, adverse event-related dose modifications, and time to onset. We also provide guidance for preparation, monitoring, and management strategies for integrating these therapies into clinical practice, with the hope that appropriate support will allow patients to tolerate higher PI3K/AKT/mTOR inhibitor dose intensities, which has the potential to translate to improved patient outcomes.