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