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Comment & Response
March 12, 2020

Metformin Plus Tyrosine Kinase Inhibitors in Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer—Reply

Author Affiliations
  • 1Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México
JAMA Oncol. Published online March 12, 2020. doi:10.1001/jamaoncol.2020.0062

In Reply We read with great interest the letter by Gao et al in which several issues are raised regarding our randomized clinical trial (RCT),1 particularly considering the negative results of a double-blind RCT, the Combined Gefitinib and Metformin Therapy study.2 Importantly, all patients were randomized as per protocol. Nonetheless, at the time of the submission deadline for abstracts for the 2018 American Society of Clinical Oncology annual meeting, the data capture in the database was incomplete, and the analysis was performed with the information captured to that date, though all patients had been recruited at this point. In the following weeks, all data were captured in time to be analyzed and presented in a publicly available poster during the meeting. The information regarding allocation presented in the poster and the published article is exactly the same.

Another concern is a biased patient enrollment based on the exploratory analysis results for LKB1 loss of expression (33.3%).1 The immunohistochemistry results are from a very small, nonrepresentative population subset (24 of 139 patients),1 which does not evidence a biased enrollment. The authors cite data regarding LKB1 variants from The Cancer Genome Atlas. This reference cannot be used to contrast our results because both cohorts are considerably different. Moreover, it is important to highlight that an LKB1 variation is different from the loss of LKB1 protein expression, the latter of which being the alteration we tested. Interestingly, a study in Italy previously identified negative LKB1 expression by immunohistochemistry in 66% (65 of 98) of patients with non–small cell lung cancer (NSCLC),3 and similarly, a study performed in our population identified this result in 65 of 87 patients (75%) with NSCLC.4

Baseline characteristics are well balanced between treatment arms. Indeed, 5 patients with exon 18 G719X-bearing variants were allocated to the combination group, but randomization was not stratified by variant type. We had a heterogeneous selection of tyrosine kinase inhibitors as therapeutic options for patients included in this trial; nonetheless, tyrosine kinase inhibitor distribution across study arms was balanced. Regarding the frequency of afatinib use, tyrosine kinase inhibitor choice was determined by the attending physician and individually based on patient characteristics (eg, performance status, variant subtype).

Regarding overall survival data, Gao et al mention that we unconvincingly attribute the lower overall survival to a high frequency of brain metastases. Interestingly, data from their study show that, though not an exclusion criterion, none of the patients with NSCLC with EGFR variants had brain metastases. This unlikely event is completely counter to historical data and is never discussed.5 Therefore, it is unlikely that the results from both trials would be comparable given the considerable differences in patient demographics.

Regarding the safety questions raised, it is important to note that the patients in our study1 received 1000 mg/d of extended-release metformin (vs 2000 mg used in the Combined Gefitinib and Metformin Therapy trial2,6). Data from the METAL study have shown that metformin dosages greater than 1500 mg/d considerably increase toxic effects. Nonetheless, we do advise close monitoring and reporting of adverse events throughout.

We emphatically stress that our data do not support systematic inclusion of metformin in the clinical setting. Rather, we now have a phase 3, blinded trial under way to strengthen conclusions.

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Article Information

Corresponding Author: Oscar Arrieta, MD, MSc, Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Ave San Fernando, Sección XVI, Tlalpan Bldg 22, México City 14080, México (ogar@unam.mx).

Published Online: March 12, 2020. doi:10.1001/jamaoncol.2020.0062

Conflict of Interest Disclosures: Dr Arrieta reported receiving grants from Consejo Nacional de Ciencia y Tecnología; grants and personal fees from AstraZeneca, Boehringer Ingelheim, Merck & Co, and Roche; and personal fees from Bristol-Myers Squibb, Lilly, and Pfizer. No other disclosures were reported.

Arrieta  O, Barrón  F, Padilla  MS,  et al.  Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor–mutated lung adenocarcinoma: a phase 2 randomized clinical trial.  JAMA Oncol. 2019;5(11):e192553. doi:10.1001/jamaoncol.2019.2553PubMedGoogle Scholar
Li  L, Jiang  L, Wang  Y,  et al.  Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced NSCLC patients with EGFR mutations: a randomized, double-blind phase II trial.  Clin Cancer Res. 2019;25(23):6967-6975. doi:10.1158/1078-0432.CCR-19-0437PubMedGoogle ScholarCrossref
Bonanno  L, De Paoli  A, Zulato  E,  et al.  LKB1 expression correlates with increased survival in patients with advanced non-small cell lung cancer treated with chemotherapy and bevacizumab.  Clin Cancer Res. 2017;23(13):3316-3324. doi:10.1158/1078-0432.CCR-16-2410PubMedGoogle ScholarCrossref
Diaz-Garcia  DA, Ramírez Tirado  LA, Aviles-Salas  A,  et al.  Prognostic impact of LKB1 expression in advanced non–small-cell lung cancer.  J Thorac Oncol. 2019;14(10)(suppl):S780-S781. doi:10.1016/j.jtho.2019.08.1677Google ScholarCrossref
Tan  L, Wu  Y, Ma  X,  et al.  A comprehensive meta-analysis of association between EGFR mutation status and brain metastases in NSCLC.  Pathol Oncol Res. 2019;25(2):791-799. doi:10.1007/s12253-019-00598-0PubMedGoogle ScholarCrossref
Li  KL, Li  L, Zhang  P,  et al.  A multicenter double-blind phase II study of metformin with gefitinib as first-line therapy of locally advanced non–small-cell lung cancer.  Clin Lung Cancer. 2017;18(3):340-343. doi:10.1016/j.cllc.2016.12.003PubMedGoogle ScholarCrossref
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