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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.
Oncotarget 2017; 8(40):68123-68130O

Abstract

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28978102

Citation

Tanaka, Kentaro, et al. "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." Oncotarget, vol. 8, no. 40, 2017, pp. 68123-68130.
Tanaka K, Nosaki K, Otsubo K, et al. 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. Oncotarget. 2017;8(40):68123-68130.
Tanaka, K., Nosaki, K., Otsubo, K., Azuma, K., Sakata, S., Ouchi, H., ... Okamoto, I. (2017). 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. Oncotarget, 8(40), pp. 68123-68130. doi:10.18632/oncotarget.19243.
Tanaka K, et al. 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. Oncotarget. 2017 Sep 15;8(40):68123-68130. PubMed PMID: 28978102.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2017/07/12/ PY - 2017/02/15/received PY - 2017/06/04/accepted PY - 2017/10/6/entrez PY - 2017/10/6/pubmed PY - 2017/10/6/medline KW - T790M KW - acquired resistance KW - afatinib KW - non–small cell lung cancer (NSCLC) KW - rebiopsy SP - 68123 EP - 68130 JF - Oncotarget JO - Oncotarget VL - 8 IS - 40 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, 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/28978102/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_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=19243 DB - PRIME DP - Unbound Medicine ER -