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      Epidermal growth factor receptor tyrosine kinase inhibitors for non‐small cell lung cancer harboring uncommon EGFR mutations: Real‐world data from Taiwan

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          Abstract

          Background

          Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR‐TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations.

          Methods

          A total of 230 treatment‐naive patients with NSCLC harboring uncommon EGFR mutations treated with first‐line EGFR‐TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS.

          Results

          Overall, patients who received afatinib ( n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib ( n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR‐TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS.

          Conclusion

          Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations.

          Abstract

          NSCLC patients with uncommon mutations treated with afatinib demonstrated higher survival than those given gefitinib/erlotinib. The independent predictors of progression‐free survival include dose reduction, metastases to the liver and pleura. The severity of paronychia is associated with progression‐free survival, particularly in patients with uncommon mutations.

          Afatinib is superior to gefitinib/erlotinib in terms of progression‐free survival and overall survival of NSCLC patients with uncommon mutations. Afatinib may represent one possible option for treatment of patients with exon 20 insertions, particularly if specific inhibitors are unavailable in daily practice.

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          Most cited references28

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          Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

          Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).
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            Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC

            Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported.
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              Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

              Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.) 2009 Massachusetts Medical Society
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                Author and article information

                Contributors
                jiaoen@gmail.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                24 November 2022
                January 2023
                : 14
                : 1 ( doiID: 10.1111/tca.v14.1 )
                : 12-23
                Affiliations
                [ 1 ] Division of Hematology‐Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan Taiwan
                [ 2 ] Division of Thoracic Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan Taiwan
                Author notes
                [*] [* ] Correspondence

                Chiao‐En Wu, Division of Haematology‐Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, 5, Fu‐Hsing Street, Guishan District, Taoyuan City, Taiwan.

                Email: jiaoen@ 123456gmail.com

                Author information
                https://orcid.org/0000-0002-1900-2984
                Article
                TCA14537
                10.1111/1759-7714.14537
                9807449
                36424878
                cbc04bce-74a7-47a6-aba0-0bbc54c15e3d
                © 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 23 May 2022
                : 28 March 2022
                : 25 May 2022
                Page count
                Figures: 5, Tables: 4, Pages: 12, Words: 6093
                Funding
                Funded by: Chang Gung Memorial Hospital, Linkou , doi 10.13039/501100005795;
                Award ID: CIRPG3H0061~2
                Award ID: CORPG3J0151~2
                Award ID: CMRPG3J0971~3
                Award ID: CRRPG3K0021~2
                Award ID: NMRPG3K6201~3
                Award ID: CMRPG
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                January 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:02.01.2023

                afatinib,erlotinib,gefitinib,lung cancer,uncommon mutation
                afatinib, erlotinib, gefitinib, lung cancer, uncommon mutation

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