Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes.
BACKGROUND
Acquired resistance has become the bottleneck affecting the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Studies have shown that the antidiabetic drug metformin could effectively increase the sensitivity of TKI-resistant lung cancer cells to EGFR-TKI. This study aimed to evaluate the effect of metformin in combination with EGFR-TKI on the prognosis of non-small cell lung cancer (NSCLC) patients with diabetes mellitus type 2 (DM2).


METHODS
Data of NSCLC patients with DM2 who received treatment in six hospitals in China between January 2006 and January 2014 were reviewed retrospectively. They were divided into two groups: Group A, where the patients (n = 44) received EGFR-TKI plus metformin; and Group B, where the patients (n = 46) received EGFR-TKI plus hypoglycemic agents other than metformin. Prognostic differences between the two groups were assessed.


RESULTS
The median progression-free survival (PFS) and median overall survival (OS) in Group A were significantly longer than those in Group B (19.0 months vs. 8.0 months, P = .005; 32.0 months vs. 23.0 months, P = .002). The objective response rate (ORR) and disease control rate (DCR) in Group A were significantly higher than those in Group B (70.5% vs. 45.7%, P = .017; 97.7% vs. 80.4%, P = .009). Secondary data analysis showed that metformin use significantly prolonged the median PFS in subgroups using either first-line EGFR-TKI or second-line EGFR-TKI.


CONCLUSIONS
Metformin and EGFR-TKI have a synergistic effect in the treatment of DM2 NSCLC patients harboring EGFR-activating mutations. Metformin use is associated with improved survival and delayed onset of acquired resistance to EGFR-TKI.
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Hengyi
H
Chen
Department of Medical Oncology, Sichuan Cancer Hospital, Chengdu 610041, China.
Wenxiu
W
Yao
Department of Medical Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Qian
Q
Chu
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Rui
R
Han
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Yubo
Y
Wang
Department of Medical Oncology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Jianguo
J
Sun
Department of Oncology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Dong
D
Wang
Department of Medical Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Yongsheng
Y
Wang
Department of Respiratory Disease, Gulou Hospital, Nanjing University Medical School, Nanjin 210008, China.
Mengshu
M
Cao
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China. Electronic address: heyong8998@126.com.
Yong
Y
He
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D043844:Crown Ethers / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018572:Disease-Free Survival; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D016896:Treatment Outcome
D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D008687:Metformin; C531470:icotinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
Diabetes; EGFR-TKI; EGFR-activating mutations; Metformin; NSCLC