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Adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis.

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Affiliations

  • 1. Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
      Authors
    • Yin X 1
    • Zhao Z 1
    • Yin Y 1
    • Shen C 1
    • Chen X 1
    • Cai Z 1
    • Wang J 1
    • Chen Z 1
    • Yin Y 1
    • Zhang B 1
    (10 authors)

ORCIDs linked to this article

Clinical and Translational Science, 25 Jan 2021, 14(3):919-933
https://doi.org/10.1111/cts.12957 PMID: 33382906 PMCID: PMC8212741

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Abstract 

The efficacy of agents targeting epidermal growth factor receptor (EGFR) in patients with various cancers was well elucidated. However, the safety profile of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has not been systematically investigated. This meta-analysis aimed to evaluate the safety profile of EGFR-TKIs in patients with cancer. A systematic search of PubMed, EMBASE, Cochrane Library databases, ASCO, and ESMO abstracts were conducted. Randomized controlled trials (RCTs) that compared safety profile of EGFR-TKIs with placebo were included. The end points included treatment-related adverse events (AEs), treatment discontinuation, and toxic death. Twenty-eight RCTs containing 17,800 patients were included. The analyses showed that the most frequently observed all-grade AEs in patients treated with EGFR-TKIs were diarrhea (53.7%), rash (48.6%), mucositis (46.5%), alanine aminotransferase (ALT) increased (38.9%), and skin reaction (35.2%). The most common high-grade (grade ≥3) AEs were mucositis (14.8%), pain (8.2%,), metabolism and nutrition disorders (7.4%), diarrhea (6.2%), dyspnea (6.1%), and hypertension (6.1%). The incidence of serious AEs, treatment discontinuation, and toxic death due to AEs were 18.2%, 12.36%, and 3.0%, respectively. Pooled risk ratio (RR) showed that the use of EGFR-TKIs was associated with an increased risk of developing AEs. Subgroup analysis indicated that the risk of AEs varied significantly according to tumor type, generation line, and drug type. Our meta-analysis indicates EGFR-TKIs was associated with a significant increased risk of a series of unique AEs. Early detection and proper management of AEs are important to reduce morbidity, avoid treatment discontinuation, and improve patient quality of life. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? The safety profile of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) varied in different trials, and has not been systemically investigated. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted this meta-analysis of randomized control trials (RCTs) to provide a comprehensive evaluation of adverse event in patients with cancer receiving EGFR-TKIs. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our meta-analysis indicates EGFR-TKIs was associated with a significant increased risk of a series of unique adverse events (AEs). HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The integrated understanding of safety profile of EGFR-TKIs will help in the future design of new EGFR-TKIs with a better safety profile.

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Clin Transl Sci. 2021 May; 14(3): 919–933.
Published online 2021 Jan 25. https://doi.org/10.1111/cts.12957
PMCID: PMC8212741
PMID: 33382906

Adverse event profiles of epidermal growth factor receptor‐tyrosine kinase inhibitors in cancer patients: A systematic review and meta‐analysis

Xiaonan Yin, 1 Zhou Zhao, 1 Yuan Yin, 1 Chaoyong Shen, 1 Xin Chen, 1 Zhaolun Cai, 1 Jian Wang, 1 Zhixin Chen, 1 Yiqiong Yin,corresponding author 1 and Bo Zhangcorresponding author 1
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Abstract

Abstract

The efficacy of agents targeting epidermal growth factor receptor (EGFR) in patients with various cancers was well elucidated. However, the safety profile of EGFR tyrosine kinase inhibitors (EGFR‐TKIs) has not been systematically investigated. This meta‐analysis aimed to evaluate the safety profile of EGFR‐TKIs in patients with cancer. A systematic search of PubMed, EMBASE, Cochrane Library databases, ASCO, and ESMO abstracts were conducted. Randomized controlled trials (RCTs) that compared safety profile of EGFR‐TKIs with placebo were included. The end points included treatment‐related adverse events (AEs), treatment discontinuation, and toxic death. Twenty‐eight RCTs containing 17,800 patients were included. The analyses showed that the most frequently observed all‐grade AEs in patients treated with EGFR‐TKIs were diarrhea (53.7%), rash (48.6%), mucositis (46.5%), alanine aminotransferase (ALT) increased (38.9%), and skin reaction (35.2%). The most common high‐grade (grade ≥3) AEs were mucositis (14.8%), pain (8.2%,), metabolism and nutrition disorders (7.4%), diarrhea (6.2%), dyspnea (6.1%), and hypertension (6.1%). The incidence of serious AEs, treatment discontinuation, and toxic death due to AEs were 18.2%, 12.36%, and 3.0%, respectively. Pooled risk ratio (RR) showed that the use of EGFR‐TKIs was associated with an increased risk of developing AEs. Subgroup analysis indicated that the risk of AEs varied significantly according to tumor type, generation line, and drug type. Our meta‐analysis indicates EGFR‐TKIs was associated with a significant increased risk of a series of unique AEs. Early detection and proper management of AEs are important to reduce morbidity, avoid treatment discontinuation, and improve patient quality of life.

Study Highlights

  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The safety profile of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) varied in different trials, and has not been systemically investigated.

  • WHAT QUESTION DID THIS STUDY ADDRESS?

We conducted this meta‐analysis of randomized control trials (RCTs) to provide a comprehensive evaluation of adverse event in patients with cancer receiving EGFR‐TKIs.

  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our meta‐analysis indicates EGFR‐TKIs was associated with a significant increased risk of a series of unique adverse events (AEs).

  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The integrated understanding of safety profile of EGFR‐TKIs will help in the future design of new EGFR‐TKIs with a better safety profile.

INTRODUCTION

Epidermal growth factor receptor (EGFR) pathway is an important therapeutic target for the treatment of cancer, which plays a critical role in regulating tumor angiogenesis, cell survival, differentiation, and migration through its downstream signaling pathways including phosphatidylinositol‐3‐kinase (PI3 K)/AKT pathway, mitogen‐activated protein kinase (MAPK) pathway, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. 1 , 2 , 3 Indeed, many small molecule tyrosine kinase inhibitors (TKIs) that target the EGFR, such as erlotinib and gefitinib, have been approved for the treatment of a range of solid tumors including non‐small cell lung cancer (NSCLC), head and neck cancer, pancreatic carcinoma, and esophageal cancer. 4 , 5 , 6 , 7

In contrast with traditional chemotherapy agents, EGFR‐TKIs are associated with a new set of toxicity profile, such as diarrhea, rash, mucositis, and fatigue. 8 , 9 Although most EGFR‐TKIs‐related adverse events (AEs) are manageable and not life‐threatening, they can significantly affect patients’ physical function and quality of life, leading to the nonadherence and the increase of treatment costs. In addition, the toxicity profiles of EGFR‐TKIs varied in different trials. However, to the best of our knowledge, comprehensive meta‐analysis focusing on the AE profile of EGFR‐TKIs has not been investigated. Therefore, we conducted a comprehensive search and meta‐analysis of randomized control trials (RCTs) to fully investigate the AE profile of EGFR‐TKIs in patients with cancer.

METHODS

Search strategy and selection of the studies

The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. A systematic search of PubMed, EMBASE, and Cochrane Library databases was conducted until October 1, 2020. Search terms included “afatinib,” “erlotinib,” “gefitinib,” “osimertinib,” “dacomitinib,” “lapatinib,” “neratinib,” “vandetanib,” “icotinib,” “tumor,” “cancer,” “controlled clinical trial,” and “randomized controlled trial.” The searches were limited to human RCTs and the language was restricted to English. Additionally, abstracts from the American Society of Clinical Oncology (ASCO) annual meetings and European Society of Medical Oncology (EMSO) were also searched to retrieve additional trials that may not have been published. Only the most complete, recent report of a trial was included when multiple publications of the same clinical trials were identified.

Trials that met the following criteria were included: (a) randomized controlled phase 2 and 3 trials in patients with cancer, (b) EGFR‐TKIs (afatinib or erlotinib or gefitinib or osimertinib or dacomitinib or lapatinib or neratinib or vandetanib or icotinib) were applied as the only therapy in the experimental arm, and the control arm includes placebo, best supportive care, no therapy, or observation, and (c) available data on AEs.

Data extraction and clinical outcomes

For each study that met inclusion criteria, the following information was extracted: the first author’s name, year of publication, trial phase, underlying malignancy, sample size, treatment and number of patients in the experimental and control arms, median age, name and dosage of the EGFR‐TKIs, median treatment duration, types and numbers of all‐grade and high‐grade (grade ≥3) AEs assessed by the National Cancer Institute Common Terminology for Adverse Events (NCI‐CTCAE) in the experimental and control arms, numbers of serious AEs, treatment discontinuation, and toxic death due to AE in the experimental and control arms. AEs reported in no more than two studies were excluded. Data extraction was conducted independently by two reviewers (Y.X.N. and Z.Z.), and any disagreements were resolved by consensus.

Quality assessment

The quality of the included trials was independently assessed by two reviewers (Y.X.N. and Z.Z.) using the revised Cochrane Risk of Bias Tool for Randomized Trials (RoB version 2.0). 10 Discrepancies between authors were resolved by consensus. We assessed the following five major domains of bias: (a) bias arising from the randomization process, (b) bias due to deviations from intended interventions, (c) bias due to missing outcome data, (d) bias in measurement of the outcome, and (e) bias in selection of the reported result. Finally, the overall risk‐of‐bias in each study was classified into three types: (1) low risk of bias, (2) some concerns, or (3) high risk of bias.

Statistical analysis

The primary end point of this meta‐analysis was the incidence and risk ratio (RR) of all‐grade and high‐grade (grade ≥3) AEs, serious AEs, treatment discontinuation, and toxic death associated with EGFR‐TKIs treatment. For calculation of incidence, the number of all‐grade and high‐grade AEs, serious AEs, treatment discontinuations, and toxic deaths were extracted from the EGFR‐TKI group from each trial. For calculation of RR, end point events of patients assigned to the EGFR‐TKI group were compared with those assigned to the control group in the same trial. The pooled incidence or RR and the corresponding 95% confidence interval (CI) were calculated using a fixed or random effects model, depending on heterogeneity. Heterogeneity was quantified with the I 2 statistic. I 2 values less than 30% was considered low, values between 30 and 50% were considered low to moderate, values between 50 and 75% were considered moderate to high, and values greater than 75% were considered high. Significance heterogeneity was set at I 2 value greater than 50%. A random‐effect model was used when I 2 greater than 50%, otherwise, a fixed‐effect model was used. Subgroup analysis was conducted to examine whether the RRs of AE varied by type of drug, type of cancer (NSCLC vs. non‐NSCLC), and generation line of EGFR‐TKI (first‐generation, second‐generation, or third‐generation). The χ2 statistic was used to assess the subgroup analysis. A p value of less than 0.05 was considered statistically significant. Potential publication bias was conducted using funnel plots (plots of study results against precision). All analyses were performed using the comprehensive meta‐analysis program (version 2.0; Biostat, Englewood, NJ).

RESULTS

The initial search yielded 767 potentially relevant studies. At the initial screening, studies were excluded for at least one of the following reasons: reviews, letters, commentaries, case reports, non‐randomized trials, and RCTs with combination therapies in the treatment arm. Full‐text review was performed at the remaining 121 trials, 93 trials were excluded for overlapping data, not Phase 2 or 3 trials, or containing chemotherapy or hormonal therapy in control arm. In total, 28 trials with 17,800 patients were included in our analysis. 4 , 5 , 6 , 7 , 34 Figure 1 displays the selection process.

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The flow chart of study selection. RCT, randomized controlled trial

Characteristics of included studies

The characteristics of the included studies were summarized in Table 1. A total of 28 trials with 17,800 patients were identified for this meta‐analysis. The underlying malignancies included were NSCLC (14 trials), breast cancer (4 trials), head and neck cancer (4 trials), thyroid cancer (2 trials), bladder cancer (1 trial), hepatocellular carcinoma (1 trial), esophageal cancer (1 trial), and pancreatic carcinoma (1 trial). Among these trials, lapatinib was investigated in 7 trials, vandetanib in 6 trials, erlotinib in 5 trials, gefitinib in 5 trials, afatinib in 2 trial, dacomitinib in 1 trial, neratinib in 1 trial, and osimertinib in 1 trial, and median treatment duration ranged from 2 weeks to 19.5 months. All trials were open‐label, randomized trials, including 10 Phase 2 and 18 Phase 3 trials. In 28 trials, the AEs were recorded and graded according to the CTCAE version 2.0, 3.0, or 4.0.

Table 1

Characteristics of the included studies

Author(year)Trial phaseJadad scaleTumor typeLine of therapyNCI‐CTCAE versionNo. of patientsTreatment comparisonPatients per armMedian ageTreatment duration median (range)
Miller, V. A. (2012) 12 Phase 2b/35NSCLC≥Second line3585Afatinib 50 mg/day3905810.5 months
Placebo1955911 months
Burtness, B. (2019) 13 Phase 35Head and neck cancerAdjuvant3617Afatinib 50 mg/day41158300 days
Placebo20657455.5 days
Ellis, P. M. (2014) 15 Phase 35NSCLC≥Second line4720Dacomitinib 45 mg/day47763.5NR
Placebo23966.5NR
Shepherd, F. A. (2005) 19 Phase 33NSCLC≥Second line2731Erlotinib 150 mg/day485627.9 months
Placebo24259NR
Propper, D. (2014) 6 Phase 23Pancreatic carcinomaSecond line3207Erlotinib 150 mg/day104626.95 months
Placebo103578.77 months
Lee, S. M. (2012) 20 Phase 35NSCLCFirst‐line3670Erlotinib 150 mg/day33477NR
Placebo31377
Kelly, K. (2015) 4 Phase 35NSCLCAdjuvant3973Erlotinib 150 mg/day61162NR
Placebo34362
Cappuzzo, F. (2010) 18 Phase 34NSCLCMaintenance3889Erlotinib 150 mg/day43360NR
Placebo44560
Zhang, L. (2012) 22 Phase 35NSCLCMaintenance3296Gefitinib 250 mg/day14755148 days
Placebo1485573 days
Thatcher, N. (2005) 21 Phase 35NSCLC≥Second line21682Gefitinib 250 mg/day1126622.9 months
Placebo562612.7 months
Goss, G. (2009) 29 Phase 25NSCLCFirst‐line3201Gefitinib 250 mg/day10074NR
Placebo10176NR
Gaafar, R. M. (2011) 16 Phase 33NSCLCSecond‐line2173Gefitinib 250 mg/day8561115 days
Placebo866285 days
Dutton, S. J. (2014) 5 Phase 35Esophageal cancerSecond‐line4450Gefitinib 500 mg/day22464.744 days
Placebo22564.935 days
Powles, T. (2017) 27 Phase 34Bladder CancerMaintenance3232Lapatinib 1500 mg/day11670.76 months
Placebo11671.16 months
Leary, A. (2015) 14 Phase 24Breast cancerNeoadjuvant3121Lapatinib 1500 mg/day94532 weeks
Placebo27572 weeks
Harrington, K. (2015) 7 Phase 35Head and neck cancerMaintenance3688Lapatinib 1500 mg/day3465462.9 weeks
Placebo3425562.9 weeks
Harrington, K. (2013) 28 Phase 24Head and neck cancerMaintenanceNR67Lapatinib 1500 mg/day3556392 days
Placebo3157241 days
Goss, P. E. (2014) 11 Phase 35Breast cancerMaintenance33147Lapatinib 1500 mg/day157151NR
Placebo157652NR
Del Campo, J. M. (2012) 17 Phase 23Head and neck cancerFirst‐line3108Lapatinib 1500 mg/day71584 weeks
Placebo36554 weeks
Decensi, A. (2011) 23 Phase 2b3Breast cancerNeoadjuvant358Lapatinib 1500 mg/day2753.63 weeks
Placebo3152.63 weeks
Martin, M. (2017) 24 Phase 35Breast cancerAdjuvant32840Neratinib 240 mg/day142052353 days
Placebo142052360 days
Thornton, K. (2012) 31 Phase 33Thyroid CancerFirst‐line3330Vandetanib 300 mg/day23150.790.1 weeks
Placebo9953.439.9 weeks
Lee, J. S. (2012) 34 Phase 34NSCLCSecond‐line3922Vandetanib 300 mg/day61960165 days
Placebo30350152 days
Hsu, C. (2012) 33 Phase 24Hepatocellular carcinomaFirst‐line342Vandetanib 300 mg/day195439 days
Placebo235630 days
Leboulleux, S. (2012) 32 Phase 25Thyroid CancerFirst‐line3145Vandetanib 300 mg/day736318.9 months
Placebo726419.5 months
Ahn, J. S. (2014) 30 Phase 24NSCLCMaintenance3117Vandetanib 300 mg/day756159 days
Placebo4260.554 days
Arnold, A. M. (2007) 26 Phase 23NSCLCMaintenance2107Vandetanib 300 mg/day5356.97 weeks
Placebo5462.412 weeks
Wu, Y. L. (2020) 25 Phase 35NSCLCAdjuvant3682Osimertinib 80 mg/day3396422.5 months
Placebo3436218.7 months

Abbreviations: NCI‐CTCAE, National Cancer Institute Common Terminology for Adverse Events; NSCLC, non‐small cell lung cancer.

Incidence of adverse event

A pooled incidence of all‐grade and high‐grade (grade ≥3) AEs were performed on the 28 RCTs (Table 2). In the analysis of all‐grade AEs of EGFR‐TKIs treatment, diarrhea (53.7%, 95% CI: 45.5–61.6), rash (48.6%, 95% CI: 40.2–57.0), mucositis (46.5%, 95% CI: 27.8–66.2), alanine aminotransferase (ALT) increased (38.9%, 95% CI: 19.9–62.0), and skin reactions (35.2%, 95% CI: 13.8–64.7) were most common. The most common high‐grade AEs were mucositis (14.8%, 95% CI: 4.6–38.7), pain (8.2%, 95% CI: 4.9–13.4), metabolism and nutrition disorders (7.4%, 95% CI: 7.4%, 95% CI: 5.8–9.3), diarrhea (6.2%, 95% CI: 3.8–9.9), dyspnea (6.1%, 95% CI: 2.9–12.3), and hypertension (6.1%, 95% CI: 4.7–7.8). Toxic outcomes, such as serious AEs, treatment discontinuation, and toxic death due to AE, are also important aspects of the drug’s safety profile. Seventeen trials (7527 patients) reported serious AEs and 1130 cases were identified. The risk of serious AEs was 18.2% (95% CI: 12.7–25.5). Eighteen trials (8626 patients) reported treatment discontinuation due to AEs, and 1339 patients were identified. The risk of treatment discontinuation was 12.36% (95% CI: 8.4–17.9). Sixteen trials (5752 patients) reported toxic death and 239 cases were identified. The risk of toxic death was 3.0% (95% CI: 1.8–4.9).

Table 2

Top 20 all‐ and high‐grade AEs for EGFR‐TKIs group

AEsModelStudiesEvent rate (%)Lower limitUpper limit Z value p value
Toxicity outcome
Serious AERandom1718.2412.7125.47−6.894<0.001
Treatment discontinuationRandom1612.368.3717.90−8.825<0.001
Toxic deathRandom183.011.844.90−13.450<0.001
All grade
DiarrheaRandom2553.745.561.60.8840.377
RashRandom2348.640.257.0−0.3280.743
MucositisRandom446.527.866.2−0.3430.732
ALT increasedRandom338.919.962.0−0.9410.347
Skin reactionRandom235.213.864.7−0.9840.325
AcneRandom528.513.251.2−1.8600.063
PainRandom227.310.355.2−1.6170.106
HypertensionRandom624.013.638.7−3.2530.001
FatigueRandom1523.716.932.0−5.492<0.001
NauseaRandom2023.617.730.7−6.341<0.001
Prolonged QTCFixed220.314.128.4−6.086<0.001
Decreased appetiteRandom1917.614.720.9−14.280<0.001
NeutropeniaRandom417.18.332.0−3.741<0.001
Radiation skin injuryFixed216.112.819.9−12.394<0.001
Dry skinRandom1116.110.523.8−6.638<0.001
Dry mouthRandom415.97.829.9−4.012<0.001
StomatitisRandom815.49.424.3−5.891<0.001
AstheniaRandom915.19.323.5−6.180<0.001
VomitingRandom1614.910.420.9−8.323<0.001
CoughRandom914.48.922.5−6.430<0.001
High grade (grade ≥3)
MucositisRandom314.84.638.7−2.6570.008
PainFixed28.24.913.4−8.635<0.001
Metabolism and nutrition disordersFixed27.45.89.3−19.199<0.001
DiarrheaRandom216.23.89.9−10.532<0.001
DyspneaRandom96.12.912.3−6.965<0.001
HypertensionFixed46.14.77.8−19.969<0.001
Vascular disordersFixed26.04.67.8−18.860<0.001
RashRandom184.92.98.1−10.678<0.001
NeutropeniaRandom34.71.217.2−4.102<0.001
ECG QT prolongedRandom24.51.018.8−3.770<0.001
Gastrointestinal disordersRandom24.30.722.6−3.2480.001
Aminotransferases increasedRandom24.00.720.1−3.4660.001
FatigueRandom163.72.16.4−11.062<0.001
ALT increasedRandom33.30.912.2−4.735<0.001
Alkaline phosphatase increasedFixed22.60.87.7−6.194<0.001
Bilirubin increasedFixed22.60.87.7−6.194<0.001
AstheniaRandom62.61.06.3−7.584<0.001
Photosensitivity reactionFixed22.51.25.2−9.557<0.001
InfectionRandom62.40.96.1−7.347<0.001
HypocalcemiaFixed32.21.14.5−10.499<0.001

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; ECG, electrocardiogram; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Risk ratio of adverse event

To determine the specific contribution of EGFR‐TKIs and exclude confounding factors, we calculate the RRs of AEs in patients assigned to EGFR‐TKIs versus controls (Table 3). A meta‐analysis of the RRs of top 20 all‐grade AEs was performed. The results indicated that patients treated with EGFR‐TKIs had a significant increased risk of prolonged QTC (RR = 24.56, 95% CI: 3.37–179.05, p = 0.002), hypertension (RR = 5.99, 95% CI: 3.98–9.02, p < 0.001), acne (RR = 3.58, 95% CI: 1.94–6.60, p < 0.001), diarrhea (RR = 3.32, 95% CI: 2.82–3.92, p < 0.001), dry skin (RR = 3.19, 95% CI: 2.41–4.23, p < 0.001), stomatitis (RR = 3.19, 95% CI: 2.33–4.37, p < 0.001), rash (RR = 3.18, 95% CI: 2.68–3.77, p < 0.001), ALT increased (RR = 2.74, 95% CI: 2.01–3.75, p < 0.001), mucositis (RR = 1.71, 95% CI: 1.10–2.65, p = 0.017), vomiting (RR = 1.37, 95% CI: 1.11–1.69, p = 0.003), and nausea (RR = 1.31, 95% CI: 1.10–1.58, p = 0.003). However, patients treated with EGFR‐TKI had a significant decreased risk of radiation skin injury (RR = 0.69, 95% CI: 0.52–0.92, p = 0.012). A meta‐analysis of the RR of high‐grade AEs showed that patients treated with EGFR‐TKIs had a significant increased risk of electrocardiogram (ECG) QT prolonged (RR = 9.90, 95% CI: 1.94–50.48, p = 0.006), rash (RR = 7.34, 95% CI: 4.34–12.16, p < 0.001), diarrhea (RR = 7.32, 95% CI: 5.05–10.61, p < 0.001), hypertension (RR = 6.69, 95% CI: 1.91–23.51, p = 0.003), gastrointestinal disorders (RR = 1.85, 95% CI: 1.06–3.25, p = 0.031), and mucositis (RR = 1.42, 95% CI: 1.08–1.85, p = 0.012). In addition, patients treated with EGFR‐TKI had a significant increased risk of serious AEs (RR = 1.20, 95% CI: 1.05–1.37, p = 0.008) and treatment discontinuation (RR = 3.68, 95% CI: 3.25–4.17, p < 0.001).

Table 3

Summary RR of AEs with EGFR‐TKIs

OutcomeModelNumber of studiesRRLower limitUpper limit Z value p value
Toxic outcomes
Serious AERandom171.201.051.372.6530.008
Treatment discontinuationFixed163.683.254.1720.468<0.001
Toxic deathFixed181.180.961.461.5800.114
All grade
Prolonged QTCFixed224.563.37179.053.1580.002
HypertensionFixed65.993.989.028.569<0.001
AcneRandom53.581.946.604.088<0.001
DiarrheaRandom253.322.823.9214.312<0.001
Dry skinRandom113.192.414.238.067<0.001
StomatitisRandom83.192.334.377.234<0.001
RashRandom233.182.683.7713.334<0.001
ALT increasedFixed32.742.013.756.312<0.001
Skin reactionRandom21.910.834.381.5320.125
MucositisRandom41.711.102.652.3870.017
Dry mouthRandom41.590.992.581.9060.057
VomitingRandom161.371.111.692.9470.003
NauseaRandom201.311.101.582.9660.003
FatigueRandom151.100.901.350.9730.330
AstheniaFixed91.060.911.240.7940.427
PainFixed20.990.751.31−0.0760.939
NeutropeniaFixed40.910.721.16−0.7390.460
CoughFixed90.910.811.04−1.4080.159
Radiation skin injuryFixed20.690.520.92−2.5130.012
High grade
ECG QT prolongedFixed29.901.9450.482.7570.006
RashRandom187.344.4312.167.748<0.001
DiarrheaRandom217.325.0510.6110.516<0.001
HypertensionFixed46.691.9123.512.9670.003
Aminotransferases increasedFixed26.170.7550.531.6970.090
Photosensitivity reactionFixed25.160.6540.921.5530.120
ALT increasedFixed33.320.9411.761.8620.063
HypocalcemiaFixed32.870.5515.001.2460.213
Bilirubin increasedFixed22.110.2816.140.7210.471
Gastrointestinal disordersFixed21.851.063.252.1600.031
Vascular disordersRandom21.550.683.561.0430.297
AstheniaFixed61.510.982.341.8550.064
Metabolism and nutrition disordersFixed21.420.902.231.5240.127
MucositisFixed31.421.081.852.5270.012
FatigueRandom161.240.891.721.2650.206
NeutropeniaFixed31.230.841.811.0570.290
PainFixed21.190.562.550.4500.653
InfectionFixed61.050.711.550.2350.814
DyspneaFixed90.920.821.04−1.3540.176

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; ECG, electrocardiogram; EGFR, epidermal growth factor receptor; RR, risk ratio; TKI, tyrosine kinase inhibitor.

Subgroup analysis

Subgroup analysis according to the tumor type

In order to explore the relationship between EGFR‐TKIs associated AEs and tumor types, we further analyzed the RRs of AEs in patients with NSCLC and non‐NSCLC (Table 4). For all‐grade mucositis (p < 0.001), nausea (p = 0.016), and high‐grade vascular disorders (p = 0.002), there were significant differences in the RRs by type of cancer. All‐grade mucositis and high‐grade vascular disorders were more likely to occur in patients with NSCLC than with non‐NSCLC, whereas all‐grade nausea was more likely to occur in patients with non‐NSCLC than with NSCLC.

Table 4

Summary RR of AEs with EGFR‐TKIs in the subgroup analysis according to the tumor type

OutcomesRR [95% CI] p value for group difference
Non‐NSCLCNSCLC
Toxicity outcome
Serious AE1.15 [0.97, 1.37]1.28 [1.03, 1.58]0.470
Treatment discontinuation3.95 [3.40, 4.60]3.16 [2.54, 3.94]0.102
Toxic death1.27 [0.81, 2.00]1.16 [0.92, 1.47]0.719
All‐grade
Diarrhea3.23 [2.56, 4.07]3.40 [2.74, 4.23]0.745
Rash2.91 [2.18, 3.88]3.47 [2.63, 4.58]0.384
Mucositis1.04 [0.94, 1.15]24.30 [9.14, 64.60]<0.001
ALT increased2.66 [1.74, 4.07]2.85 [1.79, 4.54]0.834
Acne2.95 [1.16, 7.52]4.32 [1.59, 11.77]0.586
Hypertension5.67 [2.43, 13.26]5.52 [2.46, 12.38]0.965
Fatigue1.34 [0.97, 1.84]0.91 [0.66, 1.26]0.099
Nausea1.56 [1.28, 1.91]1.10 [0.90, 1.35]0.016
Prolonged QTC34.53 [2.12, 563.53]17.32 [1.03, 292.59]0.734
Decreased appetite1.63 [1.05, 2.52]1.70 [1.15, 2.50]0.894
Neutropenia0.88 [0.68, 1.13]1.36 [0.63, 2.95]0.292
Dry skin3.84 [2.08, 7.08]3.02 [2.01, 4.55]0.523
Dry mouth1.42 [0.70, 2.88]4.01 [1.05, 15.30]0.180
Stomatitis2.36 [0.82, 6.81]5.14 [2.12, 12.47]0.269
Asthenia1.13 [0.90, 1.42]1.02 [0.83, 1.25]0.508
Vomiting1.31 [0.89, 1.94]1.44 [0.94, 2.21]0.756
Cough0.97 [0.56, 1.67]0.91 [0.80, 1.04]0.836
High‐grade
Mucositis1.39 [1.06, 1.82]14.56 [0.87, 243.05]0.103
Pain1.70 [0.64, 4.50]0.68 [0.20, 2.31]0.247
Metabolism and nutrition disorders1.07 [0.55, 2.06]1.84 [0.99, 3.42]0.240
Diarrhea5.94 [2.44, 14.67]7.77 [3.28, 18.41]0.671
Dyspnea0.66 [0.11, 3.82]0.93 [0.83, 1.04]0.704
Hypertension8.57 [1.17, 62.99]5.69 [1.13, 28.66]0.754
Vascular disorders0.67 [0.31, 1.46]4.90 [1.77, 13.56]0.002
Rash6.58 [2.19, 19.75]13.66 [4.72, 39.51]0.349
Neutropenia1.25 [0.84, 1.86]1.02 [0.22, 4.82]0.806
ECG QT prolonged7.71 [1.04, 56.99]16.18 [0.97, 268.80]0.674
Aminotransferases increased7.47 [0.40, 138.58]5.03 [0.24, 103.96]0.854
Fatigue2.03 [1.01, 4.07]1.09 [0.66, 1.79]0.153
ALT increased3.88 [0.21, 71.38]3.21 [0.79, 13.04]0.908
Asthenia1.59 [0.70, 3.58]1.48 [0.88, 2.49]0.888
Infection1.15 [0.57, 2.33]1.01 [0.63, 1.61]0.760
Hypocalcemia5.16 [0.65, 40.92]1.01 [0.06, 15.92]0.354

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; CI, confidence interval; ECG, electrocardiogram; EGFR, epidermal growth factor receptor; NSCLC, non‐small cell lung cancer; RR, risk ratio; TKI, tyrosine kinase inhibitor.

Subgroup analysis according to the generation line

Studies were further stratified according to the generation line of EGFR‐TKIs (first‐, second‐, or third‐generation; Table 5). Erlotinib and gefitinib were first‐generation EGFR‐TKIs, afatinib, dacomitinib, lapatinib, neratinib, and vandetanib were second‐generation EGFR‐TKIs, and osimertinib was third‐generation EGFR‐TKI. There were significant differences in the RRs by generation line of EGFR‐TKIs for all‐grade fatigue (p = 0.020), nausea (p = 0.030), and high‐grade diarrhea (p = 0.029), vascular disorders (p = 0.002), and fatigue (p = 0.001). Patients treated with second‐generation EGFR‐TKIs were more likely to occur all‐grade fatigue, nausea, and high‐grade vascular disorders and fatigue when compared with patients treated with first‐generation EGFR‐TKIs. Furthermore, second‐generation EGFR‐TKIs were associated with the highest risk of high‐grade diarrhea compared with first‐ or third‐generation EGFR‐TKIs.

Table 5

Summary RR of AEs with EGFR‐TKI in the subgroup analysis according to the generation line

OutcomesRR [95% CI] p value for group difference
First‐generationSecond‐generationThird‐generation
Toxicity outcome
Serious AE1.29 [0.99, 1.68]1.16 [0.98, 1.38]1.30 [0.75, 2.24]0.779
Treatment discontinuation3.24 [2.50, 4.20]3.82 [3.31, 4.42]3.74 [1.89, 7.41]0.548
Toxic death1.70 [1.15, 2.51]1.03 [0.81, 1.32]0.34 [0.01, 8.25]0.078
All‐grade
Diarrhea2.73 [2.04, 3.65]3.74 [3.07, 4.55]2.34 [1.20, 4.55]0.120
Rash3.96 [2.80, 5.61]2.87 [2.25, 3.65]−0.133
ALT increased2.60 [1.39, 4.86]2.79 [1.95, 4.01]−0.847
Acne3.96 [2.80, 5.61]2.87 [2.25, 3.65]−0.133
Fatigue0.70 [0.46, 1.09]1.27 [1.00, 1.62]−0.020
Nausea1.01 [0.76, 1.33]1.44 [1.22, 1.71]−0.030
Decreased appetite1.32 [0.81, 2.14]1.78 [1.25, 2.53]3.45 [1.01, 11.75]0.304
Dry skin2.52 [1.45, 4.36]3.65 [2.38, 5.59]3.66 [1.49, 8.97]0.554
Stomatitis3.31 [0.93, 11.84]3.97 [1.41, 11.21]4.29 [0.53, 34.45]0.969
Asthenia1.06 [0.82, 1.39]1.08 [0.87, 1.34]−0.946
Vomiting1.06 [0.64, 1.74]1.55 [1.10, 2.18]−0.217
Cough0.88 [0.72, 1.08]0.89 [0.74, 1.07]1.11 [0.80, 1.54]0.457
High‐grade
Pain0.68 [0.20, 2.31]1.70 [0.64, 4.50]−0.247
Metabolism and nutrition disorders1.07 [0.55, 2.06]1.84 [0.99, 3.42]−0.240
Diarrhea2.65 [1.12, 6.26]11.47 [5.97, 22.05]8.14 [0.61, 108.04]0.029
Dyspnea0.92 [0.82, 1.04]0.93 [0.59, 1.48]−0.975
Vascular disorders0.67 [0.31, 1.46]4.90 [1.77, 13.56]−0.002
Rash20.73 [4.68, 91.77]7.34 [3.08, 17.50]−0.237
Gastrointestinal disorders0.34 [0.01, 8.16]1.96 [1.11, 3.46]−0.287
Aminotransferases increased5.03 [0.24, 103.96]7.47 [0.40, 138.58]−0.854
Fatigue0.73 [0.48, 1.11]2.17 [1.37, 3.42]−0.001
ALT increased7.05 [0.37, 135.25]2.81 [0.69, 11.37]−0.581
Alkaline phosphatase increased3.04 [0.13, 73.47]5.09 [0.25, 103.62]−0.817
Bilirubin increased1.01 [0.06, 15.92]5.09 [0.25, 103.62]−0.438
Asthenia1.27 [0.72, 2.26]1.92 [0.98, 3.78]−0.362
Infection0.89 [0.42, 1.89]1.11 [0.70, 1.76]−0.626
Hypocalcemia1.01 [0.06, 15.92]5.16 [0.65, 40.92]−0.354

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; CI, confidence interval; EGFR, epidermal growth factor receptor; RR, risk ratio; TKI, tyrosine kinase inhibitor.

Subgroup analysis according to the agent used

In order to explore the impact of individual agents on the RRs of AEs, we calculated RRs based on the type of agent used (Table 6). For all‐grade AEs, there were significant differences in the RRs by type of drug for diarrhea (p < 0.001), mucositis (p < 0.001), acne (p < 0.001), nausea (p = 0.004), decreased appetite (p = 0.035), dry skin (p < 0.001), dry mouth (p = 0.003), and vomiting (p < 0.001). Afatinib was associated with the highest risk of all‐grade diarrhea (RR = 38.88) and dry mouth (RR = 6.89), dacomitinib was associated with the highest risk of all‐grade mucositis (RR = 40.27), acne (RR = 16.72), dry skin (RR = 5.97), and vomiting (RR = 14.61), whereas neratinib was associated with the highest risk of all‐grade nausea (RR = 2.75) and decreased appetite (RR = 4.67). Erlotinib was associated with the lowest risk of all‐grade diarrhea (RR = 3.43), nausea (RR = 0.99), dry skin (RR = 1.54), and vomiting (RR = 0.86), lapatinib was associated with the lowest risk of all‐grade mucositis (RR = 1.13), decreased appetite (RR = 0.94), and dry mouth (RR = 1.15), osimertinib was associated with the lowest risk of all‐grade acne (RR = 2.52). For high‐grade AEs, there were significant differences in the RRs by type of drug for diarrhea (p < 0.001), vascular disorders (p = 0.002), rash (p = 0.002), and fatigue (p = 0.001). Dacomitinib was associated with the highest risk of high‐grade diarrhea (RR = 68.10), vandetanib was associated with the highest risk of high‐grade vascular disorders (RR = 5.16), erlotinib was associated with the highest risk of rash (RR = 54.09), and neratinib was associated with the highest risk of fatigue (RR = 3.88). In addition, gefitinib was associated with the lowest risk of high‐grade diarrhea (RR = 1.12), vascular disorders (RR = 0.65), and fatigue (RR = 3.09), lapatinib was associated with the lowest risk of high‐grade rash (RR = 0.66).

Table 6

Summary RR of AEs with EGFR‐TKI in the subgroup analysis according to the drug type

OutcomesRR [95% CI] p value for group difference
VandetanibAfatinibDacomitinibErlotinibGefitinibLapatinibNeratinibOsimertinib
Toxicity outcome
Serious AE1.83 [0.98, 3.43]1.16 [0.53, 2.54]1.13 [0.50, 2.53]1.70 [0.93, 3.09]1.24 [0.70, 2.19]1.11 [0.70, 1.78]1.23 [0.55, 2.73]1.36 [0.58, 3.21]0.922
Treatment discontinuation3.80 [1.96, 7.37]2.77 [1.09, 7.06]11.74 [2.38, 57.99]4.25 [2.43, 7.44]2.36 [1.21, 4.60]2.62 [1.43, 4.79]6.65 [3.10, 14.27]4.08 [1.48, 11.25]0.341
Toxic death1.04 [0.56, 1.95]0.75 [0.26, 2.13]0.95 [0.64, 1.41]1.98 [0.76, 5.10]1.69 [1.08, 2.64]1.50 [0.80, 2.81]−0.34 [0.01, 8.28]0.348
All‐grade
Diarrhea6.12 [3.82, 9.82]38.88 [19.21, 78.69]19.74 [7.65, 50.92]3.43 [2.07, 5.69]3.79 [2.12, 6.79]7.62 [4.80, 12.10]37.64 [15.39, 92.07]3.49 [1.39, 8.73]<0.001
Rash5.52 [2.96, 10.30]16.60 [6.50, 42.39]3.81 [0.93, 15.65]8.91 [4.53, 17.53]6.13 [2.76, 13.62]4.11 [2.25, 7.51]2.29 [0.64, 8.23]−0.125
Mucositis−−40.27 [14.74, 110.03]−−1.13 [0.84, 1.51]−−<0.001
ALT increased4.60 [2.84, 7.45]−−−3.03 [1.49, 6.17]−−−0.340
Acne4.61 [2.58, 8.23]−16.72 [10.00, 27.94]−−−−2.52 [1.37, 4.63]<0.001
Fatigue1.02 [0.44, 2.35]1.93 [0.63, 5.97]2.10 [0.43, 10.26]0.70 [0.27, 1.79]0.63 [0.12, 3.42]1.25 [0.49, 3.21]1.49 [0.32, 6.87]−0.792
Nausea1.57 [1.12, 2.20]1.33 [0.83, 2.11]2.58 [1.37, 4.88]0.99 [0.68, 1.45]1.01 [0.68, 1.50]1.46 [1.11, 1.93]2.75 [1.79, 4.21]−0.004
Decreased appetite1.66 [0.97, 2.86]3.58 [1.63, 7.83]3.34 [1.16, 9.61]1.37 [0.79, 2.37]1.28 [0.61, 2.67]0.94 [0.48, 1.85]4.67 [1.75, 12.45]3.81 [1.25, 11.64]0.035
Neutropenia1.65 [0.82, 3.31]−−−−0.79 [0.56, 1.10]−−0.061
Dry skin3.88 [1.55, 9.71]2.92 [1.85, 4.60]5.97 [3.46, 10.28]1.54 [1.08, 2.20]3.76 [2.42, 5.86]5.53 [3.98, 7.68]−4.47 [2.71, 7.37]<0.001
Dry mouth−6.89 [1.62, 29.31]4.28 [1.67, 11.00]−−1.15 [0.86, 1.54]−−0.003
Stomatitis−20.17 [4.55, 89.52]−5.66 [1.13, 28.37]1.58 [0.20, 12.18]1.75 [0.42, 7.33]−4.99 [0.63, 39.67]0.156
Asthenia1.16 [0.83, 1.64]−−1.26 [0.77, 2.05]0.99 [0.73, 1.34]1.09 [0.76, 1.58]−−0.841
Vomiting1.24 [0.75, 2.05]1.46 [0.86, 2.49]14.61 [4.80, 44.50]0.86 [0.55, 1.33]1.48 [0.92, 2.37]1.29 [0.92, 1.81]4.11 [2.46, 6.87]−<0.001
Cough0.96 [0.71, 1.30]0.64 [0.40, 1.02]−0.98 [0.71, 1.37]0.73 [0.51, 1.03]0.80 [0.30, 2.12]−1.13 [0.76, 1.68]0.387
High‐grade
Mucositis−−14.99 [0.89, 252.28]−−1.53 [1.08, 2.16]−−0.115
Pain−−−−0.66 [0.18, 2.42]1.78 [0.62, 5.11]−−0.244
Metabolism and nutrition disorders1.90 [0.99, 3.65]−−−1.07 [0.53, 2.18]−−−0.244
Diarrhea8.94 [3.18, 25.13]30.04 [5.16, 175.05]68.10 [3.61, 1286.19]10.59 [3.51, 31.91]1.12 [0.46, 2.72]7.74 [3.44, 17.42]40.00 [14.41, 111.07]8.32 [0.85, 81.45]<0.001
Dyspnea0.95 [0.52, 1.75]0.90 [0.41, 1.98]−0.81 [0.60, 1.10]0.95 [0.60, 1.50]−−−0.935
Vascular disorders5.16 [1.83, 14.57]−−−0.65 [0.29, 1.49]−−−0.002
Rash5.96 [1.87, 18.93]43.92 [8.72, 221.13]11.81 [0.69, 201.24]54.09 [13.31, 219.84]7.68 [1.43, 41.27]3.09 [1.76, 5.40]11.04 [0.61, 199.83]−0.002
Neutropenia0.62 [0.16, 2.41]−−−−1.36 [0.86, 2.15]−−0.281
Gastrointestinal disorders2.05 [1.12, 3.75]−−−0.33 [0.01, 8.30]−−−0.276
Aminotransferases increased−−−−5.10 [0.24, 107.21]8.32 [0.41, 168.45]−−0.823
Fatigue1.36 [0.74, 2.51]3.03 [1.02, 8.96]1.65 [0.53, 5.10]0.79 [0.58, 1.07]0.66 [0.37, 1.16]3.02 [1.09, 8.36]3.88 [1.58, 9.56]−0.001
ALT increased2.98 [0.69, 12.84]−−−7.19 [0.37, 140.51]−−−0.601
Alkaline phosphatase increased5.30 [0.25, 113.04]−−−3.07 [0.12, 76.45]−−−0.810
Bilirubin increased5.30 [0.25, 113.04]−−−1.01 [0.06, 16.45]−−−0.433
Asthenia2.41 [1.02, 5.70]−−2.82 [0.33, 24.25]1.20 [0.65, 2.22]1.36 [0.43, 4.31]−−0.572
Infection1.10 [0.65, 1.88]−−0.50 [0.12, 2.10]1.12 [0.45, 2.82]1.22 [0.35, 4.23]−−0.769
Hypocalcemia5.30 [0.66, 42.82]−−−1.01 [0.06, 16.45]−−−0.352

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; CI, confidence interval; EGFR, epidermal growth factor receptor; RR, risk ratio; TKI, tyrosine kinase inhibitor.

Quality of the studies and publication bias

The trials included in this study were assessed using the Jadad scoring system. Overall, the Jadad scores for each trial are listed in Table 1, and the median score was 4, indicating that the quality of the studies was satisfactory. Furthermore, the funnel plots of AEs profile identified in the current meta‐analysis were relatively symmetrical, indicating that there is no significant publication bias.

DISCUSSION

With the discovery of EGFR pathway, a new set of effective and relatively safe EGFR‐TKIs have been introduced for the treatment of patients with NSCLC, breast cancer, thyroid cancer, head and neck cancer, and other types of cancers. In recent years, EGFR‐TKIs have been extensively studied in patients with various cancer and approved as first line, greater than or equal to second line, maintenance, or adjuvant therapy. 18 , 35 , 36 , 37 , 38 Drug‐related AEs are an essential problem for patients treated with EGFR‐TKIs in clinical practice, which may lead to treatment discontinuation and poor patient adherence. To the best of our knowledge, accurate analysis of EGFR‐TKIs‐related AEs has not yet been fully investigated. Hence, in this systematic review, we summarize the safety profile of EGFR‐TKIs in patients with cancer.

Our results suggested a significantly increased risk of a variety of AEs with the use of EGFR‐TKIs compared with placebo. Among EGFR‐TKI‐related AEs of all grades, diarrhea (53.7%), rash (48.6%), mucositis (46.5%), ALT increase (38.9%), and skin reaction (35.2%) were the most common. The most common grade 3 or more AEs were mucositis (14.8%), pain (8.2%), metabolism and nutrition disorders (7.4%), diarrhea (6.2%), dyspnea (6.1%), and hypertension (6.1%). For all‐grade AEs, EGFR‐TKIs significantly increased the risk of prolonged QTC, hypertension, acne, diarrhea, dry skin, stomatitis, rash, and ALT. For high‐grade AEs, ECG QT prolonged, rash, diarrhea, and hypertension had a higher occurrence in patients receiving EGFR‐TKIs versus placebo. EGFR is a receptor tyrosine kinase that is expressed on almost all normal cell surfaces, especially on those of epithelial origin, such as digestive tract, skin, and liver, which might be the reasons that EGFR‐TKIs are commonly associated with rash, diarrhea, mucositis, and ALT increase. 39 , 40

In order to identify the potential risk factors, we performed subgroup analysis according to tumor types. Patients with NSCLC showed a significantly increased risk of all‐grade mucositis and high‐grade vascular disorders compared with patients with non‐NSCLC, whereas all‐grade nausea was more likely to occur in patients with non‐NSCLC than with NSCLC. This could be attributed to the reason that different tumors have distinct pathogeneses and different responses for EGFR‐TKIs treatment. However, the RRs of some common AEs, such as all‐grade diarrhea, rash, high‐grade mucositis, and pain did not vary differently according to tumor types. These results were inconsistent with the findings from previous meta‐analysis conducted by Li et al. 40 In their study, all‐grade diarrhea was more likely to occur in patients with NSCLC (RR = 4.01) than with non‐NSCLC (RR = 2.81). The discrepancy can be explained by the differences in the numbers of patients enrolled. Our study included more patients than previous meta‐analysis, and could provide more precisive information for the risk of EGFR‐TKIs related AEs. When stratified by generation line, our results showed that second‐generation EGFR‐TKIs were associated with the highest risk of all‐grade fatigue, nausea, and high‐grade diarrhea, vascular disorders, and fatigue. The possible explanation was that first‐generation EGFR‐TKIs were reversible inhibitors, whereas second‐generation EGFR‐TKIs were irreversible inhibitors that had higher affinity for the kinase domain of EGFR, which may lead to the higher risk of AEs.

In addition, subgroup analysis was performed to examine whether the RRs of AEs varied by the type of drug. The risk of AEs varied significantly according to drug types. It was noteworthy that afatinib was associated with the highest risk of all‐grade diarrhea and dry mouth, dacomitinib was associated with the highest risk of all‐grade mucositis, acne, dry skin, vomiting, and high‐grade diarrhea, neratinib was associated with the highest risk of all‐grade nausea, decreased appetite, and high‐grade fatigue, vandetanib was associated with the highest risk of vascular disorders, and erlotinib was associated with the highest risk of high‐grade rash. One proposed theory is that different EGFR‐TKIs have different structure and pharmacokinetics, and target different receptors, which may lead to different risk of AEs. The differences in the safety profile of different EGFR‐TKIs may have an impact on the clinical decision making, and clinicians must pay attention when using these EGFR‐TKIs.

This study has several limitations. First, the data analyzed in this study were extracted from published clinical trials and were not on the patient level. Second, CTCAE versions for recording AEs from the incorporated trials were different, which may contribute to the change in some AEs grading, such as hypertension and rash, leading to the heterogeneity among different studies. Third, the top 20 all‐grade and high‐grade AEs determined by our meta‐analysis were not reported by all included trials, which may lead to reduced power of subgroup analysis to reach a definitive conclusion. Fourth, the present study mainly included RCTs concerning lapatinib, vandetanib, erlotinib, gefitinib, with only two trials concerning afatinib, one trial concerning dacomitinib, one trial concerning neratinib, and one trial concerning osimertinib. Hence, afatinib‐, dacomitinib‐, neratinib‐, and osimertinib‐related AEs may not be fully reviewed in our study.

CONCLUSION

In conclusion, our study showed a unique safety profile of EGFR‐TKIs, which is characterized mainly by diarrhea, rash, and mucositis. This finding will provide clinicians and patients a comprehensive recognition of the risk of EGFR‐TKI‐related AEs. Early detection and proper management of AEs are important to reduce morbidity, avoid treatment discontinuation, and improve patient quality of life. In addition, the integrated understanding of toxicity profile of EGFR‐TKIs will help in the future design of new EGFR‐TKIs with a better safety profile.

CONFLICTS OF INTERESTS

The other authors declared no competing interests for this work.

AUTHOR CONTRIBUTION

X.Y. and Z.Z. wrote the manuscript. Y.Y. and B.Z. designed the research. Z.Z., Z. Cai, J.W., and Z. Chen performed the research. X.Y., Y.Y., C.S., and X.C. analyzed the data.

Notes

Xiaonan Yin and Zhou Zhao contributed equally to this work.

Funding information

This study was supported by the National Natural Science Foundation of China Program grant (grant agreement number 81572931) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC18034).

Contributor Information

Yiqiong Yin, moc.qq@2479032931.

Bo Zhang, moc.621@kwcwxh.

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