Gender Differences in EGFR-TKI-Related Adverse Events: A Pharmacovigilance Study Based on the FAERS Database

Abstract

Introduction

Based on the FAERS database, this retrospective pharmacovigilance study analyzed gender-based reporting signals for adverse events associated with three EGFR-TKIs.

Methods

Adverse drug reaction (ADR) data were collected from the FAERS database for three drugs: gefitinib (Q4 2003–Q4 2024), afatinib (Q4 2013–Q4 2024), and osimertinib (Q4 2015–Q4 2024). Reporting odds ratio (ROR) was used to detect the disproportionality signals and to assess the presence of gender differences in reporting.

Results

A total of 6,618 adverse events were reported for gefitinib (3,917 in females and 2,701 in males), 5,073 for afatinib (3,110 in females and 1,963 in males), and 18,415 for osimertinib (12,007 in females and 6,408 in males). For all three medications, the annual number of adverse drug event (ADE) reports was higher in females than in males. The ROR value and number of ADE reports under the SOC distribution indicated predominant reporting signals of skin and gastrointestinal adverse reactions. Gender-specific analysis of skin and gastrointestinal ADEs revealed that: (i) Gefitinib showed higher reporting signals for intestinal pneumatosis and skin ulcers in females; (ii) Afatinib showed higher reporting signals for acneiform dermatitis and oral pain in females, while males showed a higher reporting frequency of stomatitis and glossitis; (iii) Osimertinib showed higher reporting signals for diarrhea in females. These observed reporting disparities generate hypotheses regarding potential contributing factors, such as gender-based differences in hormone levels, gastrointestinal tract anatomy, and skin barrier function.

Conclusions

This pharmacovigilance analysis suggests the presence of sex-based reporting disparities in adverse event reports for three EGFR-TKIs. Females showed overall stronger reporting signals, with notable differences observed in specific skin and gastrointestinal events. Although the analysis has certain limitations, these findings generate hypotheses to inform future focused investigations.

Keywords

EGFR-TKIs FAERS adverse events gender differences

1. Introduction

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) serve as the first-line agents in the treatment of non-small cell lung cancer, providing favorable treatment outcomes for patients.¹ EGFR-TKIs function by specifically binding to the tyrosine kinase structural domains of EGFR.² Currently, three main generations of EGFR-TKIs have been developed.³ The first-generation EGFR-TKIs are reversible and inhibit EGFR autophosphorylation through binding to the catalytic ATP pocket.⁴ Nevertheless, due to the reversible nature, patients usually develop drug resistance frequently after 9-15 months of progression-free survival.⁵ Subsequently, the second-generation irreversible inhibitors were developed,⁶ but they exhibit poor selectivity for wild-type EGFR, leading to a narrow therapeutic window.^4,7 Therefore, the third generation of EGFR-TKIs was developed for T790M-positive mutations. Despite potent therapeutic efficacy, adverse drug reactions (ADRs) associated with EGFR-TKIs remain a persistent concern for both patients and physicians.

The emergence of ADRs associated with EGFR-TKIs has attracted significant attention. For example, diarrhea, rash, and fatigue are commonly regarded as the most frequently reported adverse reactions.^8,9 Currently, several analyses have summarized the ADRs associated with various EGFR-TKIs. These analyses have focused on different aspects. For instance, some have examined the cardiotoxicity of different EGFR-TKIs,¹⁰ while others have concentrated on the safety profile of interstitial lung disease.¹¹ Among the various factors influencing ADRs, gender differences exert a significant influence on drug pharmacokinetics and pharmacodynamics. Notably, physiological distinctions exist between females and males regarding body size and composition, metabolism, elimination, and oral absorption.¹² Estrogen, for example, may regulate lung cancer growth and survival by promoting extranuclear receptor transduction.¹³ However, only a limited number of studies have specifically addressed gender differences in the context of EGFR-TKIs,¹⁴ thus warranting further investigation in this area.

The FDA Adverse Event Reporting System (FAERS) serves as the primary data source of ADRs. The FAERS database has been collecting adverse reactions to FDA-approved drugs since their introduction to the market, and can be used to monitor the post-marketing safety of drugs and therapeutic products.¹⁵ Therefore, in this study, three classic EGFR-TKIs (gefitinib, afatinib and osimertinib) were selected from the FAERS database. By applying the disproportionality analysis to analyze the adverse events of these three drugs and the associated gender differences, we aim to investigate whether male and female patients exhibit distinct patterns of ADRs when using EGFR-TKIs. This signal-detection study aims to identify gender-based reporting differences in adverse events associated with three EGFR-TKIs, and thereby establish a foundation for further hypothesis-driven research.

2. Materials and Methods

2.1. Study Design

This retrospective pharmacovigilance study was a disproportionality analysis based on adverse drug reactions reported in the FAERS database. The study was conducted in accordance with the Reporting of Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in Pharmacovigilance (READUS-PV) guidelines.^16,17The reporting of this study conforms to the RECORD statement.¹⁸ Importantly, this is a hypothesis-generating signal detection study and does not estimate incidence, risk, or causal relationships.

2.2. Data Acquisition and Preprocessing

Adverse drug event (ADE) reports were collected from FAERS for three drugs from the date of market approval to Q4 of 2024, including gefitinib (Q4 2003- Q4 2024), afatinib (Q4 2013- Q4 2024), and osimertinib (Q4 2015- Q4 2024). The search terms for gefitinib were ‘gefitinib’ and its trade name ‘Iressa’, for afatinib, the search terms were ‘afatinib’, trade name ‘Gilotrif’, for osimertinib, they were ‘osimertinib’ and ‘Tagrisso’. To ensure data integrity and prevent duplicate entries, a deduplication process suggested by the FDA was implemented based on the unique PRIMARYID, CASEID and FDA receipt date (FDA_DT). When the PRIMARYIDs were identical, we retained the most recent FDA_DT. When both FDA_DT and CASEID were the same, we chose the higher PRIMARYID. Also, for the suspected pharmaceutical, we only included “primarily suspect”. Gender information was obtained from “SEX” in the FAERS database, which documents biological sex of patients. For this analysis, reports coded as “M” (male) and “F” (female) were included, while those with missing, blank, or unknown entries were excluded. The basic information of the reports included gender, age, ADE reporter and country, year of reporting, drug, severity and type of ADE, etc. The adverse events data were coded according to the preferred terminology from the International Medical Dictionary for Regulatory Activities (MedDRA).¹⁹

2.3. Statistical Analysis

The study employed the disproportionality analysis²⁰ to calculate the reporting odds ratio (ROR) and its 95% confidence interval (CI) for adverse events. The gender-specific RORs were calculated based on the two-by-two contingency table (Table 1) and Formula 1. Signal validity criteria were: a≥3, lower limit of 95% CI>1. In the subsequent identification and ranking of key safety signals (Preferred Terms, PTs), those clearly reflecting underlying disease progression (e.g., “Death”, “Disease progression”, and “Drug resistance”) were systematically excluded to minimize confounding by the primary malignancy. The larger the ROR value, the greater the statistical association in reporting between the target drug and the suspected ADE.

Table 1.

The Two-By-Two Contingency Table of Disproportionality Methods

Item	Number of target adverse events	Number of other adverse events
Target drug	a	b
Other drug	c	d

Formula1:

R O R = (\frac{a}{c}) / (\frac{b}{d})

95 % CI = e^{\ln (ROR) \pm 1.96 \sqrt (1 / a + 1 / b + 1 / c + 1 / d)}

Data processing and statistical analyses were performed using R (version 4.3.3) and Excel (version 2021, Microsoft). Volcano diagrams were generated by GraphPad Prism (version 10, GraphPad Software).

3. Results

3.1. Characteristics of ADE for Osimertinib, Afatinib, and Gefitinib

In total, 6,618, 5,073, and 18,415 adverse events were reported for gefitinib, afatinib, and osimertinib, respectively. Across all three drugs, reports from females consistently outnumbered those from males (gefitinib: 59.2% vs. 40.8%; afatinib: 61.3% vs. 38.7%; osimertinib: 65.2% vs. 34.8%).Patient characteristics including gender, median age, reporter type, country, reporting year, route of drug administration, and outcomes were summarized in Table 2.

Table 2.

Characteristics of Adverse Event Reports Submitted for Osimertinib, Afatinib and Gefitinib in the FAERS Database

Type of adverse event	Osimertinib	Afatinib	Gefitinib
Characteristics	Case Number (Proportion, %)
Number of cases	18415	5073	6618
Gender
Male	6408(34.8)	1963(38.7)	2701(40.8)
Female	12007(65.2)	3110(61.3)	3917(59.2)
Median Age (Year)	69.52	67	67
Reporter
Consumer	8212(44.59)	1193(23.52)	1038(15.68)
Physician	4757(25.83)	3110(61.30)	2411(36.43)
Unknown	3004(16.31)	31(0.61)	1942(29.34)
Pharmacist	2122(11.52)	410(8.08)	520(7.86)
Other health-professional	320(1.74)	329(6.49)	707(10.68)
Reported countries
United States	9002(48.88)	1406(27.72)	653(9.86)
Japan	1889(10.26)	824(16.24)	1041(15.73)
China	1368(7.43)	215(4.24)	2386(36.05)
other	6156(33.43)	2628(51.8)	2538(38.36)
Route
Oral	18310(99.43)	3206(63.20)	6071(91.73)
Other	105(0.57)	1867(36.80)	547(8.27)
Outcomes
Death	9185(44.44)	1190(20.24)	1410(17.73)
Other serious	7044(34.08)	2403(40.88)	3513(44.18)
Hospitalization	3625(17.54)	1968(33.48)	2037(25.62)
Life threatening	575(2.78)	207(3.52)	404(5.08)
Disability	222(1.07)	109(1.85)	243(3.06)
Required intervention to prevent permanent impairment/damage	9(0.04)	1(0.02)	340(4.28)
Congenital anomaly	8(0.04)	0(0.00)	4(0.05)
Time to event onset	65.00	14.00	35.00

Time to event onset, the time difference between the start of drug administration and the occurrence of adverse reactions.

3.2. Distribution of the Number of ADE-Related Reports and Year of Reporting for the Three Drugs

The annual number of ADE reports was higher in women than in men for all three drugs (Figure 1). The number of drug ADE reports varied over time, and since the launch of osimertinib in 2015, the number of adverse events reported for osimertinib has been on an overall upward trend, while afatinib and gefitinib have been on an overall downward trend, which may be related to the gradual substitution of the first- and second-generation EGFR-TKIs by new drugs after their launch.

Figure 1.

The annual number of ADE reports of EGFR-TKIs. (A) Distribution of adverse events of osimertinib, afatinib, and gefitinib in each year. (B–D) Adverse event reports by gender for osimertinib (B), afatinib (C) and gefitinib (D) over time

3.3. Analysis of the Number of SOC Adverse Events and Signal Strength Based on Gender

The number of reports and signal intensity of most female system organ classes (SOCs) were higher than those of male SOCs (Table 3). Signal intensity of the SOCs showed that the sites with higher signal intensities were the same for both sexes in the SOCs of the three drugs, but the ordering was different. The signals of benign, malignant and unknown tumors and various congenital familial hereditary diseases were located in the first and second places for osimertinib and gefitinib, respectively. In contrast, the signals of benign, malignant and unknown tumors were located in the first place and the signals of congenital familial hereditary diseases were located in the fifth place for afatinib. Adverse reactions in these two SOCs were more focused on adverse reactions not related to the drug application.

Table 3.

Signal Strength of Reports of Gefitinib, Afatinib and Osimertinib at the SOC Level in the FAERS Database

Drug		Gefitinib		Afatinib		Osimertinib
System organ class (SOC)	Gender	Case reports	ROR (95%CI)	Case reports	ROR (95%CI)	Case reports	ROR (95%CI)
General disorders and administration site conditions	Female	2167	0.97(0.92, 1.01)	1380	0.49(0.47, 0.52)	7577	1.67(1.63, 1.72)*
General disorders and administration site conditions	Male	1402	0.91(0.86, 0.96)	835	0.62(0.57, 0.66)	4200	2.29(2.2, 2.37)*
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Female	1777	7.5(7.13,7.89)*	1295	4.56(4.3, 4.83)*	2570	4.21(4.04, 4.39)*
	Male	1146	4.13(3.88,4.39)*	961	3.94(3.68, 4.21)*	1386	2.9(2.74, 3.06)*
Gastrointestinal disorders	Female	1400	1.27(1.2, 1.34)*	3240	3.16(3.04, 3.29)*	2374	0.96(0.92, 1)
Gastrointestinal disorders	Male	941	1.3(1.21, 1.39)*	1471	2.91(2.75, 3.08)*	790	0.75(0.7, 0.8)
Skin and subcutaneous tissue disorders	Female	1201	1.68(1.58, 1.78)*	1831	2.3(2.18, 2.41)*	1927	1.07(1.02, 1.12)*
Skin and subcutaneous tissue disorders	Male	676	1.58(1.46, 1.71)*	827	2.48(2.31, 2.67)*	540	0.83(0.76, 0.9)
Respiratory, thoracic and mediastinal disorders	Female	1060	1.84(1.73, 1.96)*	923	1.44(1.35, 1.54)*	2071	1.63(1.56, 1.7)*
Respiratory, thoracic and mediastinal disorders	Male	1173	2.76(2.59, 2.93)*	560	1.6(1.47, 1.74)*	1147	1.87(1.76, 1.99)*
Investigations	Female	775	1.05(0.98, 1.13)	549	0.7(0.65, 0.77)	1536	0.99(0.94, 1.04)
Investigations	Male	738	1.15(1.07, 1.24)*	264	0.54(0.48, 0.61)	704	0.83(0.77, 0.9)
Infections and infestations	Female	618	0.92(0.85, 1)	929	1.24(1.16, 1.32) *	945	0.59(0.55, 0.63)
Infections and infestations	Male	508	1.02(0.93, 1.11)	496	1.23(1.12, 1.35)*	512	0.68(0.62, 0.74)
Nervous system disorders	Female	610	0.53(0.49, 0.57)	566	0.47(0.43, 0.51)	1405	0.59(0.56, 0.63)
Nervous system disorders	Male	430	0.53(0.48, 0.59)	298	0.49(0.44, 0.55)	616	0.58(0.54, 0.63)
Hepatobiliary disorders	Female	333	3.24(2.91, 3.62)*	97	0.95(0.78, 1.16)	396	1.94(1.75, 2.14)*
Hepatobiliary disorders	Male	200	2.07(1.8, 2.38)*	72	1(0.79, 1.26)	226	1.76(1.55, 2.01)*
Injury, poisoning and procedural complications	Female	296	0.23(0.21, 0.26)	357	0.22(0.2, 0.25)	1151	0.34(0.32, 0.36)
Injury, poisoning and procedural complications	Male	187	0.21(0.18, 0.24)	178	0.21(0.18, 0.25)	397	0.25(0.23, 0.28)
Metabolism and nutrition disorders	Female	276	1.11(0.99, 1.25)	711	2.8(2.59, 3.02)*	723	1.39(1.29, 1.49)*
Metabolism and nutrition disorders	Male	246	1.06(0.93, 1.2)	383	2.2(1.99, 2.44)*	341	1.08(0.97, 1.2)
Blood and lymphatic system disorders	Female	226	1.26(1.11, 1.44)*	143	0.74(0.63, 0.88)	699	1.8(1.67, 1.94)*
Blood and lymphatic system disorders	Male	194	1.03(0.9, 1.19)	93	0.64(0.53, 0.79)	326	1.28(1.14, 1.42)*
Musculoskeletal and connective tissue disorders	Female	217	0.27(0.24, 0.31)	269	0.3(0.27, 0.34)	788	0.45(0.42, 0.48)
Musculoskeletal and connective tissue disorders	Male	161	0.38(0.32, 0.44)	122	0.36(0.3, 0.43)	238	0.4(0.35, 0.45)
Cardiac disorders	Female	190	0.68(0.58, 0.78)	129	0.49(0.41, 0.59)	962	1.97(1.85, 2.1)*
Cardiac disorders	Male	216	0.67(0.58, 0.77)	92	0.43(0.35, 0.53)	479	1.4(1.28, 1.54)*
Eye disorders	Female	188	0.68(0.59, 0.79)	255	0.84(0.74, 0.95)	435	0.71(0.64, 0.78)
Eye disorders	Male	111	0.67(0.55, 0.8)	90	0.7(0.56, 0.86)	117	0.5(0.42, 0.61)
Renal and urinary disorders	Female	175	0.97(0.84, 1.13)	202	1.01(0.88, 1.16)	282	0.67(0.6, 0.76)
Renal and urinary disorders	Male	194	0.87(0.75, 1)	123	0.67(0.56, 0.8)	160	0.47(0.4, 0.55)
Psychiatric disorders	Female	159	0.22(0.19, 0.26)	166	0.23(0.2, 0.27)	325	0.22(0.2, 0.25)
Psychiatric disorders	Male	124	0.2(0.16, 0.23)	99	0.21(0.17, 0.25)	121	0.14(0.12, 0.17)
Congenital, familial and genetic disorders	Female	151	5.49(4.68, 6.45)*	44	2.01(1.49, 2.7)*	229	3.9(3.43, 4.45)
Congenital, familial and genetic disorders	Male	110	3.63(3.01, 4.39)*	57	1.94(1.5, 2.52)*	119	3.16(2.64, 3.78)
Vascular disorders	Female	135	0.53(0.45, 0.63)	130	0.5(0.42, 0.59)	457	0.91(0.83, 1)
Vascular disorders	Male	136	0.6(0.51, 0.71)	79	0.47(0.38, 0.59)	286	0.99(0.88, 1.12)
Reproductive system and breast disorders	Female	40	0.34(0.25, 0.46)	47	0.39(0.29, 0.51)	39	0.17(0.13, 0.24)
Reproductive system and breast disorders	Male	16	0.24(0.15, 0.4)	11	0.21(0.12, 0.38)	16	0.18(0.11, 0.29)
Immune system disorders	Female	31	0.2(0.14, 0.29)	30	0.16(0.12, 0.24)	103	0.27(0.22, 0.33)
Immune system disorders	Male	17	0.2(0.12, 0.32)	14	0.2(0.12, 0.34)	25	0.19(0.13, 0.29)
Ear and labyrinth disorders	Female	31	0.52(0.37, 0.75)	31	0.47(0.33, 0.68)	79	0.59(0.47, 0.74)
Ear and labyrinth disorders	Male	10	0.27(0.14, 0.5)	13	0.43(0.25, 0.74)	23	0.43(0.28, 0.64)
Endocrine disorders	Female	14	0.43(0.26, 0.73)	13	0.37(0.21, 0.63)	48	0.66(0.5, 0.88)
Endocrine disorders	Male	7	0.29(0.14, 0.6)	4	0.2(0.07, 0.52)	14	0.37(0.22, 0.63)

SOC, system organ class.

*Indicates statistically significant signals.

In addition to these two types of SOC adverse reactions, the signal strength for cardiac diseases was stronger in women and for systemic diseases and various reactions at the site of administration in men for osimertinib. The signal strength for gastrointestinal diseases was the second strongest for both women and men for afatinib. And the signal strength for hepatic and biliary disorders was stronger for women and respiratory, thoracic, and mediastinal disorders for men for gefitinib. In the adverse events of gefitinib, the signals of the hepatobiliary system were stronger in women, and the signals of the respiratory system, thoracic and mediastinal systems were stronger in men. Also, it may not be reasonable to determine whether tumor metastasis and tumor progression are caused by osimertinib based on ADR signals alone.⁸ These signals reflect the underlying disease progression in lung cancer patients receiving therapy, rather than adverse drug reactions attributable to the treatment itself. Therefore, PTs related to tumor progression, metastasis, and other non-drug-related disease outcomes under SOCs were excluded from subsequent gender analysis, such as the “neoplasms benign, malignant and unspecified” and “congenital, familial and genetic disorders”, etc.

3.4. Comparative Gender Analysis and Visualization of Signal Results

Relying solely on the number of ADE reports and the ROR signal to determine whether tumor metastasis and progression were associated with osimertinib reporting signals may not be justified.⁸ Consequently, specific preferred terms (PTs) were excluded during subsequent analyses. To mitigate the influence of the inherent probability of adverse drug reaction occurrence on gender differences, the ROR value was calculated using a gender stratified analysis, and the SOCs and corresponding PTs that were not related to the adverse reactions of the drug itself were excluded. The calculation method follows Formula 1 and Table 1, with the distinction that the variables a, b, c, and d were defined as follows:

a: Number of reports for the target adverse event in females.

b: Number of reports for other adverse events in females.

c: Number of reports for the target adverse event in males.

d: Number of reports for other adverse events in males.

For gefitinib, ADE signals were identified in 698 PTs, with 204 valid signals (lower 95% CI of ROR > 1) in males and 240 valid ADEs in females. For afatinib, ADE signals were identified in 645 PTs, with 156 valid ADEs in males (the lower limit of the 95% CI of the ROR was >1), and 254 in females. For osimertinib, ADE signals were identified in 546 PTs, with 165 valid ADE in males and 126 valid ADEs in females. The results of ADE signal mining for gender differences were analyzed and visualized using volcano plots (Figure 2). The PTs for gender difference significance (p<0.05) were marked in Figure 2. According to the volcano diagram results, some notable reporting signals were identified. For example, gefitinib showed higher reporting signals for hair texture abnormalities and nausea in males, and for hepatic function abnormalities in both genders. Patients taking afatinib showed higher reporting signals for rash, acne, and hair texture abnormalities in males, and decreased weight and epistaxis in females. Also, patients treated with osimertinib showed higher reporting signals for increased blood creatine phosphokinase in females. Meanwhile, the top 10 adverse events for the three drugs are summarized (Supplementary Table 1), ranked by the number of adverse reaction reports. Notably, adverse events such as diarrhea and rash exhibited strong reporting frequencies across all three agents, underscoring their prominence as major safety signals.

Figure 2.

Volcano map of gender differences of risk signals for gefitinib (A), afatinib (B) and osimertinib (C)

3.5. Analysis of Gender Differences in Gastrointestinal Disorders and Skin and Subcutaneous Tissue Disorders of Adverse Reactions

Skin and subcutaneous tissue disorders, as well as gastrointestinal disorders, are the most common adverse events associated with EGFR-TKIs.²¹ The number of gastrointestinal and skin adverse events, along with the signal intensities for these three drugs under the current SOC distribution were higher, which is consistent with previous studies.⁸ However, little attention has been paid to the effect of gender differences. Therefore, the top ten PTs with signal intensities common to both sexes in gastrointestinal and cutaneous adverse reactions were compiled and analyzed.

In the gastrointestinal adverse reactions of gefitinib (Table 4), a total of 15 effective signals were identified in males and 26 effective signals were identified in females. Among the top ten signal PTs, only the pneumatosis intestinalis (PI) showed a significant gender difference in reporting signals, with an ROR signal value of 27.64 (14.81, 51.56) in females and 7.56 (3.14, 18.2) in males. For skin adverse reactions, a total of 21 valid signals were found in males and 35 in females, the ROR value for skin ulcer was 5.78 (4.04, 8.27) in females and 1.75 (0.87, 3.5) in males.

Table 4.

Signal Strength of Reports of Gefitinib at the PT Level in the FAERS Database

Drug	Gefitinib
SOC	PT	Gender	Case reports	ROR	(95% CI)
Gastrointestinal disorders	Pneumatosis intestinalis#	Female	10	27.64	(14.81, 51.56)
	Pneumatosis intestinalis#	Male	5	7.56	(3.14, 18.2)
	Subileus	Female	3	7.9	(2.54, 24.56)
	Subileus	Male	3	6.9	(2.22, 21.44)
	Enterocolitis	Female	6	6.98	(3.13, 15.57)
	Enterocolitis	Male	6	5.65	(2.53, 12.59)
	Intestinal ischemia	Female	5	5.17	(2.15, 12.44)
	Intestinal ischemia	Male	6	5.64	(2.53, 12.57)
	Hematemesis	Female	19	4.22	(2.69, 6.63)
	Hematemesis	Male	14	2.72	(1.61, 4.6)
	Duodenal ulcer	Female	4	4.19	(1.57, 11.17)
	Duodenal ulcer	Male	5	2.92	(1.21, 7.02)
	Mouth ulceration	Female	18	3.75	(2.36, 5.95)
	Mouth ulceration	Male	5	1.98	(0.83, 4.77)
	Esophagitis	Female	7	3.41	(1.63, 7.16)
	Esophagitis	Male	9	4.57	(2.37, 8.79)
	Diarrhea	Female	440	3.27	(2.97, 3.6)
	Diarrhea	Male	259	2.8	(2.47, 3.16)
	Stomatitis	Female	44	3.2	(2.38, 4.3)
	Stomatitis	Male	25	3.27	(2.2, 4.84)
Skin and subcutaneous tissue disorders	Eczema asteatotic	Female	3	40.2	(12.84, 125.87)
	Eczema asteatotic	Male	3	33.34	(10.64, 104.4)
	Dermatitis acneiform	Female	32	35.05	(24.71, 49.71)
	Dermatitis acneiform	Male	32	26	(18.33, 36.87)
	Skin toxicity	Female	17	21.88	(13.57, 35.29)
	Skin toxicity	Male	13	14.54	(8.42, 25.11)
	Dermatitis exfoliative	Female	11	13.22	(7.31, 23.92)
	Dermatitis exfoliative	Male	6	5	(2.24, 11.15)
	Ingrowing nail	Female	6	11.13	(4.99, 24.83)
	Ingrowing nail	Male	4	11.24	(4.21, 30.05)
	Seborrheic dermatitis	Female	3	10.89	(3.5, 33.86)
	Seborrheic dermatitis	Male	3	9.87	(3.17, 30.69)
	Nail disorder	Female	20	9.42	(6.07, 14.62)
	Nail disorder	Male	10	14.01	(7.52, 26.11)
	Onychoclasis	Female	17	9.33	(5.79, 15.03)
	Onychoclasis	Male	3	5.04	(1.62, 15.66)
	Purpura	Female	11	6.88	(3.8, 12.43)
	Purpura	Male	6	3.24	(1.45, 7.21)
	Skin ulcer#	Female	30	5.78	(4.04, 8.27)
	Skin ulcer#	Male	8	1.75	(0.87, 3.5)

#Indicates PT with significant gender-based differences in reporting signals.

With regard to gastrointestinal adverse reactions of afatinib (Table 5), a total of 29 valid signals were identified in males and 49 valid signals were identified in females, and two of the top ten signal strengths were found to be significantly different. The ROR value for stomatitis was 19.78 (17.66, 22.16) in females and 25.14 (21.38, 29.55) in males, while for glossitis, the ROR was 7.74 (3.47, 17.26) in females, 26.09 (13.51, 50.38) in males. For oral pain, the ROR values were higher in females: 10.28 (8, 13.2) in females and 4.43 (2.38, 8.25) in males. For skin adverse reactions with afatinib, 25 valid signals were identified in males and 42 in females, among which dermatitis acneiform showed a significant gender difference. The ROR for dermatitis acneiform was 90.14 (72.71, 111.76) in females and 50.1 (37.36, 67.2) in males, indicating greater signal intensity in females.

Table 5.

Signal Strength of Reports of Afatinib at the PT Level in FAERS Database

Drug	Afatinib
SOC	PT	Gender	Case reports	ROR	(95% CI)
Gastrointestinal disorders	Stomatitis#	Female	308	19.78	(17.66, 22.16)
	Stomatitis#	Male	152	25.14	(21.38, 29.55)
	Gastrointestinal toxicity	Female	14	18.4	(10.87, 31.17)
	Gastrointestinal toxicity	Male	10	22.88	(12.26, 42.7)
	Cheilitis	Female	16	13.97	(8.54, 22.85)
	Cheilitis	Male	7	14.24	(6.77, 29.96)
	Chapped lips	Female	11	10.63	(5.87, 19.23)
	Chapped lips	Male	4	9.91	(3.71, 26.47)
	Oral pain#	Female	62	10.28	(8, 13.2)
	Oral pain#	Male	10	4.43	(2.38, 8.25)
	Diarrhea	Female	1277	8.75	(8.25, 9.27)
	Diarrhea	Male	654	9.01	(8.31, 9.76)
	Glossitis#	Female	6	7.74	(3.47, 17.26)
	Glossitis#	Male	9	26.09	(13.51, 50.38)
	Enterocolitis	Female	7	7.2	(3.43, 15.14)
	Enterocolitis	Male	4	4.53	(1.7, 12.08)
	Pneumatosis intestinalis	Female	3	7.59	(2.44, 23.6)
	Pneumatosis intestinalis	Male	3	5.65	(1.82, 17.54)
	Esophageal stenosis	Female	3	5.92	(1.91, 18.4)
	Esophageal stenosis	Male	3	9.56	(3.07, 29.74)
	Dermatitis acneiform#	Female	88	90.14	(72.71, 111.76)
	Dermatitis acneiform#	Male	46	50.1	(37.36, 67.2)
	Nail bed inflammation	Female	5	63.83	(26.14, 155.88)
	Nail bed inflammation	Male	3	113.63	(35.46, 364.15)
	Cutaneous symptom	Female	8	51.65	(25.56, 104.38)
	Cutaneous symptom	Male	3	28.27	(9.04, 88.4)
Skin and subcutaneous tissue disorders	Skin toxicity	Female	39	44.1	(32.08, 60.63)
	Skin toxicity	Male	24	31.27	(20.87, 46.83)
	Nail disorder	Female	58	24.21	(18.67, 31.39)
	Nail disorder	Male	20	35.14	(22.57, 54.71)
	Onychalgia	Female	6	19.59	(8.76, 43.8)
	Onychalgia	Male	3	36.22	(11.56, 113.52)
	Onychoclasis	Female	33	15.02	(10.66, 21.16)
	Onychoclasis	Male	14	25.92	(15.29, 43.94)
	Seborrheic dermatitis	Female	4	12.89	(4.82, 34.46)
	Seborrheic dermatitis	Male	3	13.54	(4.35, 42.16)
	Skin fissures	Female	52	10.9	(8.29, 14.32)
	Skin fissures	Male	17	7.04	(4.37, 11.34)
	Skin disorder	Female	56	6.9	(5.3, 8.98)
	Skin disorder	Male	16	3.97	(2.43, 6.49)

#Indicates PT with significant gender-based differences in reporting signals.

The gastrointestinal adverse reactions of osimertinib revealed 6 valid signals in males and 6 in females (Table 6). The results of the study on gender differences in PTs of males and females showed that only diarrhea was significantly different between genders in the top 10 PTs of the gastrointestinal system of osimertinib, with an ROR of 1.39 (1.21, 1.6) in males and 2.16 (2.01, 2.33) in females. In skin adverse reactions, a total of 12 valid signals were found in men and 14 in women, with no significant gender difference.

Table 6.

Signal Strength of Reports of Osimertinib at the PT Level in FAERS Database

Drug	Osimertinib
SOC	PT	Gender	Case reports	ROR	(95% CI)
Gastrointestinal disorders	Stomatitis	Female	137	4.12	(3.48, 4.87)
	Stomatitis	Male	35	3.13	(2.25, 4.37)
	Mouth ulceration	Female	31	2.97	(2.09, 4.22)
	Mouth ulceration	Male	13	3.82	(2.22, 6.59)
	Oral pain	Female	32	2.63	(1.86, 3.72)
	Oral pain	Male	6	1.54	(0.69, 3.44)
	Diarrhea#	Female	700	2.16	(2.01, 2.33)
	Diarrhea#	Male	198	1.39	(1.21, 1.6)
	Dysphagia	Female	59	1.56	(1.21, 2.02)
	Dysphagia	Male	31	1.47	(1.03, 2.09)
	Pancreatitis	Female	32	1.95	(1.38, 2.76)
	Pancreatitis	Male	7	0.71	(0.34, 1.5)
	Dry mouth	Female	51	1.31	(0.99, 1.72)
	Dry mouth	Male	9	0.71	(0.37, 1.37)
	Constipation	Female	99	0.98	(0.8, 1.19)
	Constipation	Male	38	0.82	(0.6, 1.13)
	Vomiting	Female	189	0.83	(0.72, 0.96)
	Vomiting	Male	70	0.92	(0.73, 1.17)
	Gastrointestinal disorder	Female	34	0.76	(0.54, 1.07)
	Gastrointestinal disorder	Male	9	0.55	(0.28, 1.05)
Skin and subcutaneous tissue disorders	Onychoclasis	Female	90	19.63	(15.92, 24.21)
	Onychoclasis	Male	17	16.72	(10.35, 27.01)
	Dermatitis acneiform	Female	39	18.69	(13.6, 25.69)
	Dermatitis acneiform	Male	22	12.96	(8.5, 19.74)
	Ingrowing nail	Female	20	17.35	(11.14, 27.04)
	Ingrowing nail	Male	3	5.92	(1.9, 18.44)
	Nail disorder	Female	80	16.24	(13.01, 20.28)
	Nail disorder	Male	17	16.8	(10.4, 27.16)
	Skin toxicity	Female	16	8.46	(5.17, 13.85)
	Skin toxicity	Male	4	2.69	(1.01, 7.19)
	Erythema multiforme	Female	26	8.29	(5.63, 12.21)
	Erythema multiforme	Male	13	6.65	(3.85, 11.47)
	Skin fissures	Female	33	3.17	(2.25, 4.46)
	Skin fissures	Male	5	1.08	(0.45, 2.6)
	Drug eruption	Female	17	2.61	(1.62, 4.2)
	Drug eruption	Male	5	1.23	(0.51, 2.97)
	Skin disorder	Female	50	3.02	(2.29, 3.99)
	Skin disorder	Male	12	1.65	(0.94, 2.91)
	Dry skin	Female	174	1.97	(1.7, 2.29)
	Dry skin	Male	39	1.47	(1.08, 2.02)

#Indicates PT with significant gender-based differences in reporting signals.

4. Discussion

This study analyzed adverse event reporting signals for three EGFR-TKIs through a gender-stratified analysis based on the FAERS database. The annual overall number of ADE reporter was consistently higher in females than in males for all three drugs. Additionally, the number of reports and signal intensity across most SOC distributions were higher in females than in males, indicating a critical focus area for further analysis. Among the ADEs of EGFR-TKIs, skin and gastrointestinal adverse reactions were the most prevalent.²¹ Previous studies have indicated that physiological disparities, such as body fat percentage and hormonal regulation, have been implicated as potential hypotheses underlying gender-related variations in drug responses.²²

Among skin disorders, skin ulcer reporting signals associated with gefitinib were significantly more frequent in females than in males. Additionally, pneumatosis intestinalis, a gastrointestinal adverse event, was also more frequent in females with afatinib use. However, no gender difference in reporting was observed in the skin-related adverse events associated with osimertinib. The most frequently reported adverse event associated with EGFR-TKIs was acneiform rash.^23,24 Acneiform rash remains the most common EGFR-TKI adverse event,^23,24 which could be attributed to EGFR expression in the basal layer of the skin, including epidermal keratinocytes, follicular keratinocytes, and sebocytes.²⁵ EGFR-TKI inhibition disrupts normal skin physiology, leading to rash, and in severe cases, skin ulcers.^26,27 Hormones play a significant role in the development of acne, with studies demonstrating that androgens encourage sebum production.²⁸Women are known to have a weaker skin barrier and experience fluctuating hormone levels during menstruation, which may enhance susceptibility to skin reactions. Speculatively, these factors could contribute to the observed gender differences in reporting signals for skin adverse reactions, but this hypothesis requires independent validation. Skin disorders such as rashes and dermatitis could be treated with antibiotics. Oral tetracycline is a common treatment modality, and azithromycin may be considered in patients who are resistant to tetracycline.²⁹

The observed differences in gastrointestinal reporting signals may speculatively relate to gender-specific drug metabolism and hormone levels on the gastrointestinal tissue. The reporting frequency of gefitinib-associated PI and osimertinib-associated diarrhea was higher in females than in males. PI is defined as the presence of gas in the intestinal wall.^21,30 EGF maintains mucosal integrity, and EGFR-TKI may disrupt this by depleting EGF, thereby triggering PI and diarrhea.^21,31 Studies¹⁴ have reported that osimertinib is associated with more frequent diarrhea in women in previous studies, aligning with the findings in this study. Both PI and diarrhea are associated with the intestinal tract. Considering the structure of the intestinal tract, females have longer intestinal tracts than males.³² In addition, the effect of estrogen leads to slower intestinal peristalsis in females. This means that the drugs act for a longer time in the female intestinal tract.³³ Additionally, males have higher levels of stomach acid, potentially altering EGFR-TKI bioavailability and gastrointestinal toxicity.³⁴ As a hypothesis, we speculate that the occurrence of adverse events may also be influenced by differences in intestinal EGFR expression levels between genders, which needs independent testing.

Reporting signals for stomatitis and glossitis associated with afatinib were higher in males than in females. Both of these adverse events involve inflammation of the oral cavity. Androgens are more likely to cause inflammation by polarizing macrophages towards the M1 pro-inflammatory phenotype and increasing the release of inflammatory factors.³⁵ Males generate less saliva in the oral cavity than females, and elevated androgen levels in males may diminish oral tight junction protein expression, weaken the physical barrier of the oral mucosa, and influence the occurrence of oral adverse reactions. Meanwhile, sociological factors such as oral hygiene and smoking habits may also contribute to oral adverse reactions. The above factors may serve as hypotheses and require further research for verification. Mouthwash can effectively control stomatitis induced by EGFR-TKIs.³⁶ As for oral pain adverse reactions, differences in pain threshold between genders could be a speculative hypothesis.

Nevertheless, this study still has several important limitations that should be considered. A primary limitation stems from the nature of the FAERS database itself. As a spontaneous reporting system, it inherently suffers from underreporting, misreporting, duplicate entries, and incomplete clinical data (e.g., comorbidities, concomitant medications), which may have affected the results. Crucially, the FAERS lacks denominator data (the total number of patients exposed to each drug), which means we cannot calculate incidence rates or any measure of causal effect. Consequently, the ROR values reported here represent only reporting associations, not definitive causal relationships.³⁷

Furthermore, reporting bias may differ by gender: females may be more inclined to report cosmetic or mild events, while males may underreport such events, potentially inflating apparent gender differences. Importantly, because our analysis relied on basic disproportionality methods, we could not adjust for potential confounding factors (e.g., age, cancer stage, or combination therapies), which is an inherent limitation of FAERS analyses. Moreover, the interpretation of PTs is constrained by the nature of FAERS data, including variability in reporting detail and potential misclassification of events. In addition, multiple statistical comparisons across hundreds of PTs increase the risk of false-positive signals; we did not apply multiple testing corrections (e.g., Bonferroni) because signal detection typically prioritizes sensitivity over specificity.

Another limitation is that FAERS does not provide reliable information on the duration of drug exposure or the time from drug initiation to event onset for most reports, limiting our ability to assess temporal relationships or to distinguish acute from cumulative toxicity. Lastly, some low-event ADRs may exhibit inflated signal strength due to normalization of the total event count. Since signal detection relied solely on the ROR method, the robustness of the identified signals may be limited. Future studies employing multi-method validation are highly encouraged.

Given these limitations, all findings should be interpreted as hypothesis-generating signals,³⁸ not as evidence of causal relationships or definitive biological differences.

5. Conclusion

This pharmacovigilance study, utilizing the FAERS database for signal detection analysis, identified gender-based differences in adverse event reporting associated with three EGFR-TKIs. Overall, females showed gender-specific differences in reporting signals across all three agents, with notable differences in skin and gastrointestinal adverse event reporting. Potential hypotheses for these reporting signal differences are preliminarily discussed. While these exploratory findings are subject to limitations inherent to spontaneous reporting systems and require prospective validation, they provide a hypothesis-generating foundation for future epidemiological research and suggest considerations for gender-aware monitoring in clinical practice.

Supplemental Material

Supplemental material - Gender Differences in EGFR-TKI-Related Adverse Events: A Pharmacovigilance Study Based on the FAERS Database

Supplemental material for Gender Differences in EGFR-TKI-Related Adverse Events: A Pharmacovigilance Study Based on the FAERS Database by Shuman Wang, Tingting Wu, Yajing Liu,Chen Shi and Zhiwen Fu in Cancer Control.

Footnotes

ORCID iD

Shuman Wang

Author Contributions

Z.W. Fu and C. Shi contributed to the conceptualization of the study, development of methodology, and data analysis. CS provided funding and support for this study. S.M. Wang, T.T. Wu, Y.J. Liu and Z.W. Fu performed the database searches and data analysis. S.M. Wang and Y.J. Liu contributed to figures preparation and data interpretation. S.M. Wang, T.T. Wu and Z.W. Fu wrote the original draft of the manuscript. Z.W. Fu and C. Shi helped to review and write the final report.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The National Natural Science Foundation of China (Grant No. 82474007) funded this study.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The FAERS database undergoes regular quarterly updates and can be accessed online at .

Supplemental Material

Supplemental material for this article is available online.

Appendix

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