Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation.
BACKGROUND
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.
Department of Respiratory Medicine, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan. Electronic address: fukuhara-tatsuro@miyagi-pho.jp.
Tatsuro
T
Fukuhara
Department of Respiratory Medicine, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan.
Makoto
M
Maemondo
Department of Respiratory Medicine, Tohoku University, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
Akira
A
Inoue
Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama 350-1298, Japan.
Kunihiko
K
Kobayashi
Department of Pulmonary Medicine, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai 980-0873, Japan.
Shunichi
S
Sugawara
First Department of Medicine, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Satoshi
S
Oizumi
Department of Medical Oncology, KKR Sapporo Medical Center, 6-3-40 Hiragishi 1-jo, Toyohira-ku, Sapporo 062-0931, Japan.
Hiroshi
H
Isobe
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.
Akihiko
A
Gemma
Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, 4-jo-2-3-54 Kikusui, Shiroishi-ku, Sapporo 003-0804, Japan.
Masao
M
Harada
Bioscience Medical Research Center, Niigata University Medical & Dental Hospital, 8050, Ikarashi 2-no-cho, Nishi-ku, Niigata 950-2181, Japan.
Hirohisa
H
Yoshizawa
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Ichiro
I
Kinoshita
Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, 7-4048 Hanasakicho, Asahikawa 070-0901, Japan.
Yuka
Y
Fujita
Department of Medical Oncology, Niigata University Medical & Dental Hospital, 8050, Ikarashi 2-no-cho, Nishi-ku, Niigata 950-2181, Japan.
Yasuo
Y
Saijo
Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
Koichi
K
Hagiwara
Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Satoshi
S
Morita
Japan Anti-Tuberculosis Association, Misaki-cho 1-3-12, Chiyoda-ku, Tokyo 101-0061, Japan.
Toshihiro
T
Nukiwa
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005091:Exons / Q000187:drug effects / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D012189:Retrospective Studies; D017384:Sequence Deletion / Q000187:drug effects / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D016896:Treatment Outcome
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016190:Carboplatin; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib
Carboplatin–paclitaxel; EGFR; Gefitinib; L858R mutation; NEJ002; Smoking