Oral Toxicities of Targeted Cancer Therapies: Stomatitis Risk Across PI3K/AKT/mTOR Pathway Inhibitors

Stomatitis is a common adverse event associated with targeted therapies for hormone receptor–positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhib-iting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor–associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world settings. We performed a retrospective pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) to evaluate stomatitis reports for alpelisib, capivasertib, everolimus, and palbociclib. Events were identified using three term sets—Original Trial Terms (OTT), Comprehensive Trial Terms (CTT), and Stomatitis-Associated Main Terms (SAMT)—reflecting varying definitions. Disproportionality analyses using reporting odds ratio (ROR) and proportional reporting ratio (PRR) were calculated with 95% con-fidence intervals. All agents showed ROR and PRR >1, indicating higher odds and re-porting proportions of stomatitis compared with other drugs. Everolimus demonstrated the strongest association (ROR: 30.72 [29.61–31.88]), followed by alpelisib (ROR: 13.11 [11.79–14.58]) and palbociclib (ROR: 11.73 [11.35–12.11]). Capivasertib had the lowest risk (ROR: 3.14 [1.81–5.43]), though limited by fewer reports. Differences between CTT and SAMT were minimal (~2%), supporting SAMT as an efficient screening tool. These findings underscore the need for optimized stomatitis detection and continued moni-toring, particularly for PI3K and mTOR inhibitors, in both clinical trials and postmar-keting surveillance.