(312) Gastrointestinal Adverse Events Associated with PI3K Inhibitors: A Disproportionality Analysis of FDA Adverse Event Reporting System

Publication Number: 986

Background: Phosphoinositide 3- Kinase (PI3K) inhibitors are a class of drugs that work by inhibiting PI3K enzymes. They are mainly used to treat breast cancer, chronic lymphocytic leukaemia (CLL), B-cell non-Hodgkin’s lymphoma and marginal zone lymphoma (MZL), but the incidence of gastrointestinal adverse events associated with these are not well established.

Objectives: The research was done to establish the safety profile of PI3K inhibitors using the FDA Adverse Event Reporting System (FAERS).

Methods: We generated safety signals using disproportionality analysis in US Food and Drug Administration (FDA) adverse event reporting system database (FAERS) using Open Vigil 2.1(2004Q1-2021Q3). The drugs under study were Umbralisib, Idelalisib, Duvelisib and Alpelisib. All the Gastrointestinal Adverse Events (GIAEs) that fall under the system organ classification of “Gastrointestinal disorders” “infection and infestation” as per MedDRA v-24 were used as the events of interest. Proportional reporting ratio (PRR) and Reporting odds ratio (ROR) were used as the main parameters for generating safety signals. Value of ROR-1.96SE>1 and PRR≥2 with an associated χ2 value of 4 was considered as the threshold for a signal.

Results: FAERS reported a total of 1757 reports associated with GIAEs related to PI3K inhibitors. Most significant signals were obtained for taste disorder [ROR 40.5 (95 % CI=30.4;54)] for alpelisib, gastrointestinal fungal infection [ROR 41.037 (13.1;128.6)] for idelalisib, colitis [ROR 29.4(14.5;59.5)] for duvelisib and upper abdominal pain [ROR 8.4(2.6, 27.2)] for umbralisib related GIAEs. Most deaths were reported with Alpelisib and Idelalisib (n=61,117) respectively. Most life-threatening manifestations (n=38) were reported with Idelalisib. Gastrointestinal adverse events associated with Alpelisib were mainly reported in females (n=1855) with breast cancer whereas, the majority of adverse events with Idelalisib were seen in male (n=557) and females (n=342) with CLL. In the case of Duvelisib and Umbralisib, an equal number of adverse events were seen in both males and females with CLL and B-cell lymphoma respectively.

Conclusions: While analysing spontaneous reporting data we identified gastrointestinal adverse events with Umbralisib, Idelalisib, Duvelisib, Alpelisib and established that the maximum number of these adverse events were associated with Alpelisib. To validate these findings, more research with a superior epidemiological study design of a defined population is required.