Gender differences in adverse events related to Osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system

ABSTRACT Objective We analyze and identify the signals of gender differences in adverse events (ADEs) related to Osimertinib and provide reference for clinical implementation of individualized drug use. Methods ADE reports of Osimertinib received from FAERS database from the first quarter of 2016 to the fourth quarter of 2022 were extracted. Reporting odds ratio (ROR) data analysis strategy was used for mining of signal strength that represents gender differences in ADEs related to Osimertinib. Results The number of Osimertinib ADE reports included in the analysis was 7968 in females and 7570 in males, respectively. According to ROR, men were more likely to develop pneumonia aspiration, lung infection, interstitial lung disease, pulmonary toxicity, dyspnea, ventricular extrasystoles, and pulmonary thrombosis, while women were more likely to develop cardiac failure congestive, stomatitis, diarrhea, muscle spasms, nail disorder, onycholysis, skin disorder, dry skin, and rash. Conclusion Gender differences existed in ADE signals related to Osimertinib. The higher risk of ADEs in male patients was lung diseases that seem more serious than those nail toxicities or skin problems that occurred in female patients. In order to ensure the safety of medication, we should be alert to the differences between different genders and take corresponding preventive measures to reduce the occurrence of serious ADEs.


Introduction
Lung cancer is the malignant tumor with the highest incidence and mortality worldwide in 2022, among which non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancer [1].The incidence of NSCLC for men is higher than that for women (42.4 per 100 000 vs 33.8 per 100 000) according to the latest data in the United States (US) [2].While the NSCLC is not easy to detect in the early stages, most patients are diagnosed in the middle and late stages where there is no operating opportunity for them.Compared with systemic chemotherapy, targeted therapy can significantly prolong the survival of patients with advanced lung cancer and help improve their quality of life [3].Among the oncogenic driver genes in NSCLC patients, the mutation ratio of epidermal growth factor receptor (EGFR) gene is the highest, accounting for approximately 50.2% [4].EGFR tyrosine kinase inhibitor (EGFR-TKI), which targets the mutation of EGFR, has been widely used in clinical practice [5].In its clinical application for more than a decade, it has been found that most patients using EGFR-TKI may develop resistance and lead to disease progression after 9-13 months of progression-free survival, among which resistance caused by mutations at the exon 19 deletions or exon 21 L858R mutations or T790M mutations are the most common [6,7].
Osimertinib is a third-generation EGFR-TKI developed by AstraZeneca, which can simultaneously target the initial mutation of the EGFR gene and the mutation of T790M site [8].Osimertinib was approved and marketed by the US Food and Drug Administration (FDA) in November 2015.It is used for clinical treatment of patients with advanced local or metastatic NSCLC who have disease progression during or after EGFR-TKI treatment and have been confirmed by testing to have exon 19 deletions or exon 21 L858R mutations or positive T790M mutations on EGFR gene [8].Studies have confirmed that Osimertinib took the problem of tumor cells' resistance to the first and second generations of EGFR-TKIs, while patients could achieve significant clinical therapeutic effect and have good tolerance in early clinical studies [9].
With the increasing application of Osimertinib in clinical treatment, its adverse effects have attracted wide attention.Without the limitation of small sample size, strict admission criteria in premarketing clinical studies, the adverse events (ADEs) monitoring and analysis using a real-world pharmacovigilance study are particularly important to identify potential safety issues of Osimertinib [10][11][12][13].In view of the gender differences shown in the toxicity of chemotherapy and immunotherapy, the occurrence of ADEs related to Osimertinib may also have gender differences [14,15].
Herein, in this study, the ADEs reports related to Osimertinib in the FDA adverse events reporting system (FAERS) were extracted.Based on the reporting odds ratio (ROR) data mining algorithm and statistical test, signal mining and evaluation of gender differences in ADEs related to Osimertinib were conducted, aiming at providing decision support for Osimertinib treatment programs for patients with different genders and providing reference for clinical rational use of Osimertinib.

Study design and data sources
This retrospective pharmacovigilance study is a disproportionality analysis based on adverse drug reactions reported in the FEARS, one of typical public spontaneous reporting systems, which includes reports from more than 100 countries worldwide [16].The FEARS services as a post-marketing safety surveillance program for all the FDA-approved drug and therapeutic biologic products through the collection of spontaneous safety reports and post-marketing clinical studies related to drug use within and outside the United States.The FAERS database was encoded based on the Medical Dictionary for Regulatory Activities (MedDRA).In this study, the system organ class (SOC) and preferred terms (PTs) from the MedDRA were applied for the international standardization of ADEs [17].

Data extraction
In this study, the adverse event information of 28 quarters from the first quarter of 2016 to the fourth quarter of 2022 was collected and imported into the local database.The dataset contains seven data subsets, including DRUG (drug information), DEMO (patient demographic information), REAC (reaction and adverse event information), OUTC (patient outcome information), INDI (drug indication information), THER (therapy duration information), and RPSR (Report Source information) along with their detailed description of terminologies.The SAS software (version 9.4) was used to correlate these seven subsets of the database, and duplicate information was deleted based on the CASEID, FDA_DT, and PRIMARYID according to the FDA recommendations: When CASEID (the number that identifies FAERS cases) is the same, we select the latest FDA_DT (the date when the FDA received the case), and when CASEID and FDA_DT are the same, we select a higher PRIMARYID (the unique number that identifies FAERS reports).On this basis, with 'Osimertinib,' 'Tagrisso' and 'AZD9291' as keywords, the database was further defined with 'PS (primary suspect drug)' to exclude non-primary suspected drugs.Finally, 13771 reports of Osimertinib-related adverse reactions were obtained for subsequent analysis.

Statistical analysis
Three tables ('DEMO,' 'DRUG,' and 'REAC') were used for data mining and analysis.'DEMO' displays demographic characteristics: patient's medical history, gender, reporting country, event date, etc. 'DRUG' records the details of the drug used, while 'REAC' lists ADEs that were identified by the PTs.Currently, the ADE mining strategies commonly used were based on the disproportionality analysis, which mainly include frequency methods and Bayesian methods [18,19].The former includes reporting odds ratio (ROR) method and proportional reporting ratio (PRR) method, while the latter methods include Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) method.In this study, all four of these algorithms were used for ADE signal mining.Detailed strategies were provided in the Supplementary file 1.The signals that met the three criteria out of the four above methods were considered as the potential ADE signals related to Osimertinib.
In order to identify the gender difference in ADEs related to Osimertinib, the obtained potential signals were further analyzed at the PT levels and classified into different SOCs to better outline the signals.The gender data in the 2 × 2 contingency table along with a modified ROR signal mining method was employed as shown in Table 1.When the ROR was greater than 1 and the p value tested by chi-square was less than 0.05, it suggests male patients are more likely to report a specific ADE than female patients.On the contrary, when the ROR was less than 1 and the p-value tested by chisquare was less than 0.05, it suggests female patients are more likely to report a specific ADE than male patients.All statistical analyses were performed using SAS software, GraphPad Prism 9, and Microsoft Excel software.

Results
As of December 2022, a total of 19,494,698 ADE reports were retrieved from the FAERS database.Through a deduplication process based on the comparison of CASEID, FDA_DT, and PRIMARYID, 10091,518 unique ADE reports remained during the period between the first quarter of 2016 to the fourth quarter of 2022, among which 13,771 reports on Osimertinib were finally extracted as the primary suspect drug.In this study, 29010 Osimertinib-related PTs were obtained for the following ADE mining, including ROR, PRR, BCPNN, and MGPS strategies (Figure 1).

General characteristics
Data extraction obtained 13,771 ADE reports of Osimertinib, 8,126 of which were female, 4,036 of which were male, and 1,609 of whose gender was unknown.The clinical characteristics of reports associated with Osimertinib, including clinical outcomes of reported patient, age distribution of reported patient, reporter's type of occupation, and the country of the reporter are shown in Table 2.For both male and female patients, the majority of reports (41.1% and 38.6%, respectively) were from elderly patients aged over 65 years.The top three countries of origin for reporters were America (44.7% and 47.3%), Japan (15.1% and 12.8%), and China (6.0% and 4.3%).With the exception of one-third of the reports submitted by consumers, most reporters were health professionals, including physicians (26.0% and 25.0%), pharmacists (10.2% and 10.4%), and other health professionals (2.8% and 2.6%).Almost half of the patients (58.0% and 47.6%) reported a clinical outcome of death, likely due to disease progression in advanced lung cancer cases.With more extensive indications for Osimertinib, such as for NSCLC with EGFR/T790M mutation, NSCLC with EGFR/19-del

Identification of potential ADR/ADE signals related to Osimertinib
After disproportionality analysis using both frequency methods and Bayesian methods, a total of 296 PT signals were met the thresholds of three out of four statistical methods.

Gender difference in ADEs related to Osimertinib
Next, we investigate whether there exist gender differences in the above obtained 196 significant ADE signals related to Osimertinib.Through extraction the number of targeted PTs, a total of 168 PTs that reported both in men and women were submitted for statistical analysis.According to the modified ROR method, male patients are more likely to report a specific ADE than female patients when the lower limit of 95% CI of ROR was greater than one and vice versa.As shown in Table 4, the higher risk of ADE signals related to Osimertinib in men with significant differences included pneumonia aspiration, lung infection, interstitial lung disease, pulmonary toxicity, dyspnea, ventricular extrasystoles, and pulmonary thrombosis.On the contrary, signs of a higher risk of ADE in the male population included cardiac failure congestive, stomatitis, diarrhea, muscle spasms, nail disorder, onycholysis, skin disorder, dry skin, and rash.
In order to better demonstrate the gender difference in the ADEs related to Osimertinib, a volcano plot was employed to visualize the significant signals.With the statistical test by Chisquare (χ 2 ), the value of -Log 10 (p-value) was used as scale on the vertical axis of the volcano plot, while Log 2 (ROR) value was taken as scale on the horizontal axis.The results are shown in Figure 2.Each dot represents a PT signal related to Osimertinib, with red dots representing higher-risk ADE signals in men and blue dots representing higher-risk ADE signals in women.Those ADE signals with significant difference are labeled in the figure.

Discussion
At present, the 'gold standard' of ADEs signal detection has not been established worldwide, and the commonly used signal mining method is disproportionality analysis [18,20].Among them, the frequency method is simple and sensitive, but it is easy to produce false-positive signals when the number of reports is small.Although the Bayes method has good stability, the calculation is complicated and the signal detection time is relatively delayed.Different signal mining methods can effectively improve the sensitivity and specificity of ADEs signal detection and help to reduce the false-positive rate [21].Therefore, in this study, the frequency method and Bayes method were simultaneously used for data mining of FAERS database to improve the reliability of signal detection results.
Through a comprehensive pharmacovigilance analysis, it was found that there were 196 positive PT signals related to Osimertinib, which involved in 15 system organs, almost covering the information provided by the instructions of Osimertinib.Among the significant pharmacovigilance signals (Supplementary Table S1), the most frequent adverse reactions were interstitial lung disease (373 reports), pneumonitis (197 reports), hepatic function abnormal (137 reports), nail disorder (86 reports), and cardiac dysfunction (83 reports).The results were consistent with the common adverse reactions reported in the drug instructions, suggesting that the data mining strategies used in this study are feasible to identify the potential ADE signals [22][23][24].Moreover, this study also found that some important ADEs have not been mentioned in the instructions of Osimertinib, including Trousseau's syndrome, thrombophlebitis migrants, infectious pleural effusion, acute glomerulonephritis, lymphangitis, pulmonary artery thrombosis, venous thrombosis limb, superior vena cava syndrome, and jugular vein thrombosis.These ADEs were represented with highly positive signals according to four algorithms in our analysis, suggesting that these signals might also be important and frequent.
Although randomized controlled trials are the gold standard for determining the efficacy of a drug, there are shortcomings in the evaluation of ADE, especially in detecting gender differences in ADE.Gender differences in ADE can be fully explored through post-marketing safety monitoring of drugs to provide decision support for individualized medication guidance, which is of great significance for improving clinical rational drug use [25].The study found that men are more prone to pneumonia aspiration, lung infection, interstitial lung disease, pulmonary toxicity, dyspnea, and pulmonary thrombosis, while women are more prone to suffer from cardiac failure congestive, stomatitis, diarrhea, muscle spasms, nail disorder, onycholysis, skin disorder, dry skin, and rash.Of note, the higher risk of ADEs in male patients was lung diseases that seemed more serious than those nail toxicities or skin problems that occurred in the female patients.Although the exact mechanism for Osimertinib related pulmonary toxicity remains unclear, one possible mechanism involves immune mediated facilitation of inflammatory signals [26].As for the Osimertinibassociated cardiotoxicity, it may attribute to the HER2 inhibition, a similar mechanism underlying trastuzumab-caused cardiotoxicity [27].Given the known role of Osimertinib as an EGFR-TKI, it is plausible that EGFR signaling pathways inhibition underlies nail or skin toxicities from Osimertinib.It prevents keratinocytes from maturing and migrating to the stratum corneum, resulting in a thinning of the outermost layers of the epidermis and corneal layers [28].Similarly, because the EGFR is highly expressed by gastrointestinal epithelial cells, Osimertinib may cause mucosal atrophy and excess chloride secretion through the dysregulated EGFR signaling [29,30].Since the existence of sex differences in pharmacokinetics and pharmacodynamics, gut microbiota composition, and endogenous sex hormone exposure, it always demonstrated the significant difference between male and female patients [14].However, for the patients who received Osimertinib with advanced NSCLC, the mechanisms behind the difference probably attributed to the smoking history in male patients.The smoking history is associated with the efficacy of EGFR-TKIs treatment [31].Therefore, we need to pay more attention to develop individualized treatment plans for the male patients and adopt corresponding measures to reduce the occurrence of serious lung diseases.Pharmacovigilance analysis in the real world based on the FAERS database can improve the defects such as small sample size and short observation time in clinical trials, but there are still some limitations in this study.First of all, FEARS database reports mostly come from developed countries in Europe and the United States, and reports will inevitably be inaccurate, or even under-reported or omitted, which may lead to bias in research results.Secondly, the actual incidence of interested ADEs could not be achieved because the FAERS database collects ADEs in the form of self-reporting and lacks information on the number of druguser population.Thirdly, in this study, the study on the safety of gender differences in ADE did not consider the effects of drug combination, underlying diseases, and age differences of patients on signals.It was hence difficult to clearly distinguish whether the signal comes from Osimertinib or is the result of combination drug.

Conclusion
In summary, a pharmacovigilance analysis was conducted based on the FAERS database to explore the gender differences in Osimertinib-related ADEs, which shows significant ADRs difference between male and female patients.Male patients are more prone to serious lung diseases, while women are more prone to suffer from mild ADEs.The results would be helpful for medical personnel to better develop individualized treatment plans based on gender differences and adopt corresponding measures to reduce the occurrence of serious ADEs.Although the gender differences in ADE Note: a, the number of targeted PTs in men; b, the number of the other PTs in men; c, the number of targeted PTs in women; d, the number of the other PTs in women; CI, confidence interval; Direction: M represents the higher risk in men with significant difference; F represents the higher risk in women with significant difference.

Figure 1 .
Figure 1.The flow diagram of selecting Osimertinib-related ADEs from the FAERS database.

Figure 2 .
Figure 2. Volcano plot of gender difference in the ADE signals related to Osimertinib.

Table 1 .
The 2 × 2 contingency table for disproportionality analysis of the gender difference in ADEs related to Osimertinib.

Table 3 .
With exclusion of the signals unrelated to drugs or disease progression, such as product issues, social environment, investigations, injury poisoning and procedural complications, and neoplasms benign, malignant, and unspecified (including cysts and polyps), 196 PT signals were finally obtained.As shown in Supplementary TableS1, these significant PT signals were mapped to 15 system organ classes (SOCs).The top five lines in terms of ADE report numbers are respiratory, thoracic, and mediastinal disorders (2036 reports), skin and subcutaneous tissue disorders (1071 reports), gastrointestinal disorders (985 reports), cardiac disorders (691 reports), and metabolism and nutrition disorders (618 reports).At the PT level, nail toxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, keratitis, cutaneous vasculitis, diarrhea, stomatitis, dry skin, and dizziness were present, which is consistent with the warnings and precautions in the medicine instructions.It is worth noting that some unexpected significant AEs were also identified in this study but without any mention in the drug label.For example, the infection-induced diseases including the Trousseau's syndrome, thrombophlebitis migrants, infectious pleural effusion, acute glomerulonephritis, and lymphangitis; the thromboembolism diseases including pulmonary artery thrombosis, venous thrombosis limb, superior vena cava syndrome, and jugular vein thrombosis were represented with high positive signals according to four algorithms in our analysis.The top 50 PTs of ADEs related to Osimertinib in the ROR values are demonstrated in

Table 3 .
Top 50 Preferred Terms of ADEs related to Osimertinib in the ROR values.

Table 4 .
Identification of the gender differences in ADEs related to Osimertinib.