Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation

Tatsuro Fukuhara; Makoto Maemondo; Akira Inoue; Kunihiko Kobayashi; Shunichi Sugawara; Satoshi Oizumi; Hiroshi Isobe; Akihiko Gemma; Masao Harada; Hirohisa Yoshizawa; Ichiro Kinoshita; Yuka Fujita; Yasuo Saijo; Koichi Hagiwara; Satoshi Morita; Toshihiro Nukiwa

doi:10.1016/j.lungcan.2015.02.004

Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation

Lung Cancer. 2015 May;88(2):181-6. doi: 10.1016/j.lungcan.2015.02.004. Epub 2015 Feb 9.

Authors

Tatsuro Fukuhara¹, Makoto Maemondo², Akira Inoue³, Kunihiko Kobayashi⁴, Shunichi Sugawara⁵, Satoshi Oizumi⁶, Hiroshi Isobe⁷, Akihiko Gemma⁸, Masao Harada⁹, Hirohisa Yoshizawa¹⁰, Ichiro Kinoshita¹¹, Yuka Fujita¹², Yasuo Saijo¹³, Koichi Hagiwara¹⁴, Satoshi Morita¹⁵, Toshihiro Nukiwa¹⁶

Affiliations

¹ Department of Respiratory Medicine, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan. Electronic address: fukuhara-tatsuro@miyagi-pho.jp.
² Department of Respiratory Medicine, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan.
³ Department of Respiratory Medicine, Tohoku University, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
⁴ Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama 350-1298, Japan.
⁵ Department of Pulmonary Medicine, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai 980-0873, Japan.
⁶ First Department of Medicine, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
⁷ Department of Medical Oncology, KKR Sapporo Medical Center, 6-3-40 Hiragishi 1-jo, Toyohira-ku, Sapporo 062-0931, Japan.
⁸ Department of Internal Medicine, Division of Pulmonary Medicine, Infections Disease and Oncology, Nipppon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
⁹ Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, 4-jo-2-3-54 Kikusui, Shiroishi-ku, Sapporo 003-0804, Japan.
¹⁰ Bioscience Medical Research Center, Niigata University Medical & Dental Hospital, 8050, Ikarashi 2-no-cho, Nishi-ku, Niigata 950-2181, Japan.
¹¹ Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
¹² Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, 7-4048 Hanasakicho, Asahikawa 070-0901, Japan.
¹³ Department of Medical Oncology, Niigata University Medical & Dental Hospital, 8050, Ikarashi 2-no-cho, Nishi-ku, Niigata 950-2181, Japan.
¹⁴ Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
¹⁵ Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
¹⁶ Japan Anti-Tuberculosis Association, Misaki-cho 1-3-12, Chiyoda-ku, Tokyo 101-0061, Japan.

PMID: 25726043
DOI: 10.1016/j.lungcan.2015.02.004

Abstract

Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non-responders.

Methods: Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin-paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders.

Results: Five (4.9%) and 9 (8.2%) cases in the carboplatin-paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin-paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) (P=0.044 and P=0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (OS). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation.

Conclusions: NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment.

Keywords: Carboplatin–paclitaxel; EGFR; Gefitinib; L858R mutation; NEJ002; Smoking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Carboplatin / administration & dosage
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics
Clinical Trials, Phase III as Topic
Disease-Free Survival
ErbB Receptors / antagonists & inhibitors
Exons / drug effects
Exons / genetics
Female
Gefitinib
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Male
Middle Aged
Mutation / drug effects
Mutation / genetics
Paclitaxel / administration & dosage
Protein Kinase Inhibitors / therapeutic use*
Quinazolines / therapeutic use*
Retrospective Studies
Sequence Deletion / drug effects
Sequence Deletion / genetics
Smoking / adverse effects*
Treatment Outcome

Substances

Protein Kinase Inhibitors
Quinazolines
Carboplatin
ErbB Receptors
Paclitaxel
Gefitinib