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Oncotarget. 2017 Jul 12;8(40):68123-68130. doi: 10.18632/oncotarget.19243. eCollection 2017 Sep 15.

Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naïve patients with non-small cell lung cancer harboring EGFR mutations.

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Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan.
Department of Respiratory Medicine, Japan Community Healthcare Organization Kyushu Hospital, KitaKyushu, Japan.
Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita, Japan.
Department of Respiratory Medicine, Saiseikai Fukuoka General Hospital, Fukuoka, Japan.
Department of Respiratory Medicine, Koga Hospital 21, Kurume, Japan.
Department of Respiratory Medicine, Steel Memorial Yawata Hospital, KitaKyushu, Japan.
Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, Japan.
Department of Respiratory Medicine, KitaKyushu Municipal Medical Center, KitaKyushu, Japan.


The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation-positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non-small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7-15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0-7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.


T790M; acquired resistance; afatinib; non–small cell lung cancer (NSCLC); rebiopsy

Conflict of interest statement

CONFLICTS OF INTERESTS Kentaro Tanaka has received honoraria from Nippon Boehringer Ingelheim. Kaname Nosaki has received research funding from MSD and Novartis Pharma as well as honoraria from AstraZeneca, Chugai, Eli Lilly, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, ONO, and MSD. Kohei Otsubo has received honoraria from Nippon Boehringer Ingelheim. Hiroshi Wataya has received honoraria from Nippon Boehringer Ingelheim. Taishi Harada has received honoraria from Nippon Boehringer Ingelheim. Yoichi Nakanishi has received research funding and honoraria from Nippon Boehringer Ingelheim. Isamu Okamoto has received research funding and honoraria from Nippon Boehringer Ingelheim.

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