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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

Author Affiliations
  • 1The Medical Department, 3D Medicines Inc, Shanghai, China
  • 2Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
JAMA Oncol. Published online March 12, 2020. doi:10.1001/jamaoncol.2020.0059

To the Editor Arrieta and colleagues1 recently published an open-label randomized clinical trial (RCT) evaluating the addition of metformin to tyrosine kinase inhibitor (TKI) treatment in nondiabetic patients with non–small cell lung cancer carrying epidermal growth factor receptor (EGFR) variants. The authors reported significantly improved survival benefits without additional toxic effects. However, there are some major issues about this work that need to be addressed, especially considering that our larger-scale placebo-controlled double-blind RCT2 attempting to answer the same question had negative results.

According to their article1 and a poster that Arrieta et al submitted to the 2018 American Society of Clinical Oncology annual meeting, 139 patients were randomly assigned in a 1:1 ratio to metformin plus a TKI (n = 69) or a TKI alone (n = 70). However, in their original abstract submitted approximately 2 months earlier,3 only 49 patients were enrolled in the combination arm and 67 in the TKI arm. Therefore, 23 patients were recruited between the 2 submissions, but oddly, 20 of them ended up in the metformin group while only 3 were placed in the control arm, so obviously allocation randomization/concealment, the cornerstone of RCTs, was disrupted.

Patient enrollment also seemed biased because loss of LKB1 was extraordinarily enriched (33.3%) in the subset evaluated,1 while LKB1 variants, which predominantly predict protein loss, are mutually exclusive with EGFR variants as confirmed by the 1.45% rate of LKB1-EGFR covariants in The Cancer Genome Atlas non–small cell lung cancer cohort.4 Baseline characteristics were not balanced, either, because all 5 patients with exon 18 G719X variants, who are supposedly less sensitive to first-generation TKIs than to afatinib, were allocated to the combination group.5 The heterogeneous selection of TKIs represents another source of bias, with more than 40% of the patients choosing afatinib over gefitinib/erlotinib, for which the rationale was never provided. The uneven distribution of TKIs between treatment arms further complicated the picture, especially without stratification by types of variants and TKIs.

Indeed, the monotherapy arm exhibited remarkably lower overall survival and objective response rate1 than historical data on first-line TKIs, which they unconvincingly attributed to a high incidence of brain metastases and adoption of chemotherapy beyond progression; however, the control group’s progression-free survival looked reasonable, and switching to chemotherapy on dropout/completion was common in pivotal studies. Moreover, the intolerable toxic effects of metformin, as inferred from discontinuation occurring in 16 of 69 patients (23.2%) and dosage reduction occurring in 24 of 69 patients (34.8%),1 also contradict their claim that the 2 groups had similar safety profiles. Metformin plus gefitinib was shown to cause a higher frequency of diarrhea than gefitinib alone.2 Given the issues enumerated above, we advise extra caution before any conclusions are drawn.

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Article Information

Corresponding Author: Yong He, MD, Department of Respiratory Medicine, Daping Hospital, Army Medical University, No. 10 Changjiang Branch Rd, Chongqing 400042, China (heyong8998@126.com).

Published Online: March 12, 2020. doi:10.1001/jamaoncol.2020.0059

Conflict of Interest Disclosures: None reported.

References
1.
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
2.
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
3.
Rodriguez  OGA, Barron  FB, Padilla  M-ÁS,  et al.  Combination of metformin plus TKI vs TKI alone in EGFR(+) LUNG adenocarcinoma: a randomized phase II study  [abstract].  J Clin Oncol. 2018;36(15)(suppl):9013. doi:10.1200/JCO.2018.36.15_suppl.9013Google ScholarCrossref
4.
Sanchez-Cespedes  M.  The role of LKB1 in lung cancer.  Fam Cancer. 2011;10(3):447-453. doi:10.1007/s10689-011-9443-0PubMedGoogle ScholarCrossref
5.
Yang  JC, Sequist  LV, Geater  SL,  et al.  Clinical activity of afatinib in patients with advanced non–small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.  Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1PubMedGoogle ScholarCrossref
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