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Original Investigation
September 5, 2019

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

Author Affiliations
  • 1Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
  • 2Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia
  • 3Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia
  • 4Clinical Research and Biology Systems Department, Universidad el Bosque, Bogotá, Colombia
  • 5Department of Radiology and Imaging, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
  • 6Catalan Institute of Oncology, Germans Trias i Pujol Research Institute and Hospital Campus Can Ruti, Barcelona, Spain
JAMA Oncol. 2019;5(11):e192553. doi:10.1001/jamaoncol.2019.2553
Key Points

Question  Does the addition of metformin hydrochloride to standard epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors for EGFR-mutated lung adenocarcinoma improve progression-free survival compared with EGFR–tyrosine kinase inhibitors therapy alone?

Findings  In this phase 2 randomized clinical trial that included 139 patients, the addition of metformin to standard EGFR–tyrosine kinase inhibitors significantly improved both progression-free survival and overall survival.

Meaning  In this phase 2 trial of patients with EGFR-mutated lung adenocarcinoma, the addition of metformin increased survival, warranting the design of a larger phase 3 study.


Importance  Metformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs).

Objective  To assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone.

Design, Setting, and Participants  Open-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation.

Interventions  Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent.

Main Outcomes and Measures  The primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety.

Results  Between March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n = 70) or EGFR-TKIs plus metformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P = .03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P = .02).

Conclusions and Relevance  To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study.

Trial Registration  ClinicalTrials.gov identifier: NCT03071705