Abstract 7169: A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions

Abstract

Abstract Purpose: Combination-therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in an real-world setting. Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Complex adverse-event frequencies of drugs or their combinations were visualized as heatmaps onto a 2D UMAP grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heatmaps. Additionally, statistical synergy analyses were performed based on BLISS independence or Chi-square testing. Results: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse-event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. Conclusion: Our study provides a framework for analyzing adverse events and suggest that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice. Citation Format: Asli Küçükosmanoglu, Silvia I. Scoarta, Bart Westerman. A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7169.