Elsevier

Lung Cancer

Volume 88, Issue 1, April 2015, Pages 74-79
Lung Cancer

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2015.01.026Get rights and content

Highlights

Abstract

Objectives

Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – afatinib, erlotinib, and gefitinib – are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs.

Materials and methods

We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations.

Results

Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6–2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity.

Conclusion

Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.

Introduction

Targeted therapies are under active development as a means to improve treatment efficacy in selected patient populations. Small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR), including the reversible inhibitors gefitinib and erlotinib, were the first targeted drugs to enter clinical use for the treatment of unselected patients with non-small cell lung cancer (NSCLC). Somatic mutations in the EGFR gene (EGFR) are associated with the therapeutic response to EGFR-TKIs in individuals with advanced NSCLC [1], [2]. Indeed, randomized phase III studies revealed that first-line EGFR-TKI treatment resulted in an improved progression-free survival compared with standard chemotherapy in patients with advanced NSCLC who were selected on the basis of the presence of EGFR mutations [3], [4], [5], [6]. Afatinib is an orally available drug that binds irreversibly to members of the ErbB family of proteins and thereby blocks signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2, or ErbB2), ErbB4, and other relevant ErbB family dimers. The pivotal phase III studies, LUX-Lung 3 and 6 trials, showed that afatinib was superior to platinum doublets for the treatment of EGFR mutation-positive NSCLC [7], [8]. The United States, European Union, and Japan recently approved afatinib for the treatment of NSCLC patients harboring EGFR mutations. Three EGFR-TKIs (afatinib, erlotinib, and gefitinib) are thus now available for first-line treatment of patients with EGFR mutation-positive NSCLC. Given the possible long-term exposure of EGFR mutation-positive patients to EGFR-TKIs, the toxicological properties of these drugs in such individuals may differ from those observed in unselected patients including those with or without EGFR mutations. Moreover, there have been no fully published clinical trials that have prospectively evaluated the effects of one EGFR-TKI in comparison with another in EGFR mutation-positive NSCLC patients. We have therefore now performed a pooled analysis of the occurrence of severe (grade ≥3) toxicity according to type of EGFR-TKI based on data extracted from phase II or III trials with advanced NSCLC patients positive for EGFR mutations.

Section snippets

Search method

Trials were identified from a previous meta-analysis [9], a previous pooled analysis [10], and systematic computerized searches of the PubMed database encompassing the period from 1 June 2004 to 31 July 2014 with the key words “gefitinib,” “erlotinib,” “afatinib,” “non-small cell lung cancer,” “clinical trial,” and “EGFR mutation.” We chose to start with 2004 because this year marked the identification of EGFR mutations in NSCLC and their association with the response to EGFR-TKI treatment [1],

Selected trials

On the basis of our search criteria, we identified 22 phase II or III trials of EGFR-TKIs for the treatment of patients with advanced NSCLC positive for EGFR mutations (Fig. 1). One of these trials was subsequently excluded because of a lack of information about AEs [14]. The remaining 21 trials [3], [4], [5], [6], [7], [8], [11], [12], [13], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], including a total of 1468 EGFR mutation-positive patients and published between

Discussion

Given the long-term exposure of EGFR mutation-positive patients to EGFR-TKIs, the toxicological properties of these agents in such patients may differ from those observed in unselected patients. The INTEREST phase III trial [27], which enrolled unselected patients and randomly assigned them to receive gefitinib or docetaxel, as well as the ZEST phase III trial [28], which compared vandetanib with erlotinib also in unselected patients, found that all-grade hepatotoxicity related to gefitinib or

Conflict of interest statement

I.O. and K.N. have received honoraria from Chugai Pharmaceuticals, AstraZeneca, and Boehringer Ingelheim.

Acknowledgments

This study was supported in part by The National Cancer Center Research and Development Fund 26-A-4, Uehara Memorial Foundation, and Takeda Science Foundation.

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