Research Papers:

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

Kentaro Tanaka, Kaname Nosaki, Kohei Otsubo, Koichi Azuma, Shinya Sakata, Hiroshi Ouchi, Ryotaro Morinaga, Hiroshi Wataya, Akiko Fujii, Noriaki Nakagaki, Nobuko Tsuruta, Masafumi Takeshita, Eiji Iwama, Taishi Harada, Yoichi Nakanishi and Isamu Okamoto _

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Oncotarget. 2017; 8:68123-68130. https://doi.org/10.18632/oncotarget.19243

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Kentaro Tanaka1,2, Kaname Nosaki3, Kohei Otsubo1, Koichi Azuma4, Shinya Sakata5, Hiroshi Ouchi6, Ryotaro Morinaga7, Hiroshi Wataya8, Akiko Fujii9, Noriaki Nakagaki10, Nobuko Tsuruta11, Masafumi Takeshita12, Eiji Iwama1, Taishi Harada1, Yoichi Nakanishi1 and Isamu Okamoto1

1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

3Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

4Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

5Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan

6Department of Respiratory Medicine, Japan Community Healthcare Organization Kyushu Hospital, KitaKyushu, Japan

7Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita, Japan

8Department of Respiratory Medicine, Saiseikai Fukuoka General Hospital, Fukuoka, Japan

9Department of Respiratory Medicine, Koga Hospital 21, Kurume, Japan

10Department of Respiratory Medicine, Steel Memorial Yawata Hospital, KitaKyushu, Japan

11Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, Japan

12Department of Respiratory Medicine, KitaKyushu Municipal Medical Center, KitaKyushu, Japan

Correspondence to:

Isamu Okamoto, email: [email protected]

Keywords: non–small cell lung cancer (NSCLC), afatinib, acquired resistance, T790M, rebiopsy

Received: February 15, 2017    Accepted: June 04, 2017    Published: July 12, 2017


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.

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