• Oscar Arrieta, Feliciano Barrón, Miguel-Ángel Salinas Padilla, Alejandro Avilés-Salas, Laura Alejandra Ramírez-Tirado, Manuel Jesús Arguelles Jiménez, Edgar Vergara, Zyanya Lucia Zatarain-Barrón, Norma Hernández-Pedro, Andrés F Cardona, Graciela Cruz-Rico, Pedro Barrios-Bernal, Masao Yamamoto Ramos, and Rafael Rosell.
• Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.
• JAMA Oncol. 2019 Nov 1; 5 (11): e192553.

ImportanceMetformin 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).ObjectiveTo 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 ParticipantsOpen-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.InterventionsPatients 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 MeasuresThe primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety.ResultsBetween 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 RelevanceTo 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 RegistrationClinicalTrials.gov identifier: NCT03071705.

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