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 epidermalgrowthfactor receptor (EGFR)-tyrosinekinaseinhibitors (TKIs).

OBJECTIVE:

To assess the progression-free survival (PFS) in patients with advanced lungadenocarcinoma who received treatment with EGFR-TKIs plusmetformincompared with those who received EGFR-TKIs alone.

DESIGN, SETTING, AND PARTICIPANTS:

Open-label, randomized, phase2trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lungadenocarcinoma with an activating EGFR mutation.

INTERVENTIONS:

Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plusmetformin 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 plusmetformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plusmetformin 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 lungadenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT03071705.

JAMA Oncol. 2019 Sep 5:e192553. doi: 10.1001/jamaoncol.2019.2553.

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