TY - JOUR
T1 - 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
AU - Tanaka, Kentaro
AU - Nosaki, Kaname
AU - Otsubo, Kohei
AU - Azuma, Koichi
AU - Sakata, Shinya
AU - Ouchi, Hiroshi
AU - Morinaga, Ryotaro
AU - Wataya, Hiroshi
AU - Fujii, Akiko
AU - Nakagaki, Noriaki
AU - Tsuruta, Nobuko
AU - Takeshita, Masafumi
AU - Iwama, Eiji
AU - Harada, Taishi
AU - Nakanishi, Yoichi
AU - Okamoto, Isamu
N1 - Funding Information:
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.
Funding Information:
This study was supported by Nippon Boehringer Ingelheim.
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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, secondgeneration 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.
AB - 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, secondgeneration 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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UR - http://www.scopus.com/inward/citedby.url?scp=85038917952&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.19243
DO - 10.18632/oncotarget.19243
M3 - Article
AN - SCOPUS:85038917952
VL - 8
SP - 68123
EP - 68130
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 40
ER -