Disproportionality Analysis of Oral Toxicities Associated with PI3K/AKT/mTOR Pathway Inhibitors Using the FAERS...

Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, particularly those inhibiting 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 pharmacovigilance disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) to evaluate stomatitis reports for alpelisib, capivasertib, everolimus, and palbociclib. Methods: Events were identified using four term sets-Stomatitis, Original Trial Terms (OTT), Comprehensive Trial Terms (CTT), and Stomatitis-Associated Main Terms (SAMT)-which reflect varying definitions and medical terminologies. Disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Information Component (IC) were calculated with 95% confidence intervals. Results: All agents showed ROR and PRR >1, indicating higher odds and reporting proportions of stomatitis compared with other drugs. These findings were confirmed by IC analysis. 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 reporting odds (ROR: 3.14 [1.81-5.43]), though limited by fewer reports. Differences between CTT and SAMT were minimal (~2%). Conclusions: These results support the use of the SAMT as an efficient screening tool. Furthermore, these findings underscore the need for optimized stomatitis detection and continued monitoring, particularly for PI3K and mTOR inhibitors, in both clinical trials and postmarketing surveillance.