Safety, Tolerability, and Management of Toxic Effects of Phosphatidylinositol 3-Kinase Inhibitor Treatment in Patients with Cancer: A Review

Importance: The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, which regulates multiple cellular processes, including metabolism, proliferation, motility, growth, and survival, is one of the most frequently dysregulated pathways in human cancers. The PI3K/AKT/mTOR cascade can be aberrantly activated by multiple factors, including diverse oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, MTOR, and other critical genes, which can be used as targets for anticancer therapy. Limited single-agent activity, high levels of toxic effects, and a lack of predictive biomarkers for treatment selection have all been major barriers to the clinical development of these compounds. Many adverse effects are uncommon and have poorly understood mechanisms. An understanding of these toxic effects, as well as a better definition of management guidelines, will be important because more PI3K inhibitors are under development and may soon be incorporated into routine practice. Observations: A search of PubMed, draft prescribing information of currently approved PI3K inhibitors, European Medical Association and US Food and Drug Administration product information, and expert panel opinion on the management of the prominent toxic effects of this class of agents was conducted on August 29, 2018. This article provides an overview of the main toxic effects of PI3K inhibitors reported in clinical trials and a summary of recommendations for identification and management of treatment-emergent toxic effects, including hypoglycemia, cutaneous reactions, pneumonitis, neuropsychiatric effects, hepatotoxic effects, diarrhea, and colitis. Overall, the clinical development of most PI3K inhibitors has been discontinued owing to insufficient activity, problematic toxic effects, and the absence of biomarkers correlated with clinical activity. Knowledge of the isoforms and their distribution in tissue can help clinicians anticipate toxic effects. Notably, novel, more specific inhibitors for individual isoforms of PI3K showed therapeutic activity with improved toxic effect profiles compared with non-isoform-selective agents. Conclusions and Relevance: An improved understanding of the complexities of the main toxic-effect mechanisms and their management might open viable paths to advancing PI3K inhibitors from clinical studies to new standard-of-care treatments.