Original Research

Retrospective Evaluation of Drug-Drug Interactions With Erlotinib and Gefitinib Use in the Military Health System

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Background: Erlotinib and gefitinib are epidermal growth factor receptor–tyrosine kinase inhibitors approved for non–small cell lung cancer treatment by the US Food and Drug Administration. Drug-drug interactions (DDIs) with these agents are vague and poorly understood. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with erlotinib or gefitinib and describe their clinical manifestations.

Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved September 2021), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved May 2022). Patients’ medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients’ diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with erlotinib or gefitinib, and evaluate DDIs with antidepressants.

Results: Of 387 patients using erlotinib, 264 completed treatments; 28 of 33 patients using gefitinib completed treatment. The P value for erlotinib discontinuation when used alone vs concomitantly was < .001, and the P value for gefitinib discontinuation was .06. Patients who took erlotinib or gefitinib concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 1 to 75 prescription drugs, and those in the completed group were prescribed 3 to 103. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment.

Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in erlotinib or gefitinib discontinuation. There were no significant DDIs determined between erlotinib or gefitinib and antidepressants.



Most cancer treatment regimens include the administration of several chemotherapeutic agents. Drug-drug interactions (DDIs) can increase the risk of fatal adverse events and reduce therapeutic efficacy.1,2 Erlotinib, gefitinib, afatinib, osimertinib, and icotinib are epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) that have proven efficacy for treating advanced non–small cell lung cancer (NSCLC). Erlotinib strongly inhibits cytochrome P450 (CYP) isoenzymes CYP 1A1, moderately inhibits CYP 3A4 and 2C8, and induces CYP 1A1 and 1A2.2 Gefitinib weakly inhibits CYP 2C19 and 2D6.2 CYP 3A4 inducers and inhibitors affect metabolism of both erlotinib and gefitinib.3,4

Erlotinib and gefitinib are first-generation EGFR-TKIs and have been approved for NSCLC treatment by the US Food and Drug Administration (FDA). These agents have been used since the early 2000s and increase the possibility of long-term response and survival.2,5,6 EGFR-TKIs have a range of potential DDIs, including interactions with CYP-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins.2 Few retrospective studies have focused on the therapeutic efficacy of erlotinib, gefitinib, or the combination of these agents.7-14

DDIs from cancer and noncancer therapies could lead to treatment discontinuation and affect patient outcomes. The goals for this study were to perform a broad-scale retrospective analysis focused on investigating prescribed drugs used with erlotinib and gefitinib and determine patient outcomes as obtained through several Military Health System (MHS) databases. Our investigation focused on (1) the functions of these drugs; (2) identifying adverse effects (AEs) that patients experienced; (3) evaluating differences when these drugs are used alone vs concomitantly, and between the completed vs discontinued treatment groups; (4) identifying all drugs used during erlotinib or gefitinib treatment; and (5) evaluating DDIs with antidepressants.

This retrospective study was performed at the Department of Research Programs at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. The WRNMMC Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center of the US Department of Defense (DoD) Cancer Registry and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.


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