Retrospective Evaluation of Drug-Drug Interactions With Erlotinib and Gefitinib Use in the Military Health System
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.
Discussion
The difference between erlotinib and gefitinib data can be attributed to the FDA approval date and gefitinib’s association with a higher frequency of hepatotoxicity.18-20 The FDA designated gefitinib as an orphan drug for EGFR mutation–positive NSCLC treatment. Gefitinib first received accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC. Gefitinib then was voluntarily withdrawn from the market following confirmatory clinical trials that did not verify clinical benefit.
The current approval is for a different patient population—previously untreated, metastatic EGFR exon 19 or 21 L858R mutation—than the 2003 approval.4,6 There was no record of gefitinib use after 2017 in our study.
Erlotinib is a reversible EGFR-TKI that is approved by the FDA as first-line (maintenance) or second-line treatment (after progression following at least 1 earlier chemotherapy regimen) for patients with metastatic NSCLC who harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.3 Since 2005, the FDA also approved erlotinib for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.3 Without FDA indication, erlotinib is used for colorectal, head and neck, ovarian carcinoma, pancreatic carcinoma, and breast cancer.21
Erlotinib and gefitinib are not considered first-line treatments in EGFR exon 19 or 21–mutated NSCLC because osimertinib was approved in 2018. Targeted therapies for EGFR mutation continue to advance at a fast pace, with amivantamab and mobocertinib now FDA approved for EGFR exon 20 insertion–mutated NSCLC.
Erlotinib Use
Thirty-nine patients (10%) in this study were prescribed erlotinib for off-label indications. Erlotinib was used alone or in combination with bevacizumab, capecitabine, cisplatin, denosumab, docetaxel, gemcitabine, and the MEK-inhibitor selumetinib. Erlotinib combined with cisplatin, denosumab, docetaxel, and gemcitabine had no recorded AEs, with 10 data entries for gemcitabine and 1 for other drugs. Three patients received bevacizumab and erlotinib, and 1 patient (diagnosed with kidney NOS) showed rash or facial swelling/erythema and diffuse body itching then stable disease after 2 cycles.
One patient (diagnosed with cancer located at the pancreas head) was bridged with capecitabine and erlotinib when going on a vacation, then received FOLFIRINOX (a combination chemotherapy regimen containing folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin), which led to significant fatigue, blurry vision, and constipation. One patient was treated for lung NOS with the MEK-inhibitor selumetinib plus erlotinib and developed pneumonitis following treatment.
Because oncologists followed guidelines and protocols in systemic treatment, DDIs of erlotinib concurrently (before or after) and in combination with cancer drugs were unlikely. Further investigation is needed for several 1:1:1 DDIs with noncancer drugs. A retrospective overview is not a randomized clinical study; therefore, analysis is limited. Data from the MHS were obtained solely from notes from physicians who treated the patients; therefore, exact information explaining whether a patient completed treatment or had to withdraw could not be extrapolated (ie, blood/plasma samples were not obtained to confirm).
Discontinued Treatment
The reasons for treatment discontinuation with erlotinib or gefitinib varied among patients, with no consistent AE or cause. Most data were for switching treatments after discontinuing treatment with erlotinib (101 of 123 patients) and gefitinib (2 of 5 patients). This is not surprising given the widely recognized pillars of therapy for NSCLC: chemotherapy, target therapy, and immunotherapy.22 From the MHS records, the reasons patients switched treatment of erlotinib or gefitinib were not listed or listed as due to negative EGFR testing, lack of responsiveness, or enrollment in a different treatment.
