Low BMI patients with advanced EGFR mutation-positive NSCLC can get a better outcome from metformin plus EGFR-TKI as first-line therapy: A secondary analysis of a phase 2 randomized clinical trial

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The synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been confirmed in in vitro studies. It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment. Body mass index (BMI) was proved to be independently associated with prolonged progression-free survival (PFS) and overall survival (OS). This study aimed to investigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation (EGFRm)-positive non-small cell lung cancer (NSCLC) among nondiabetic Asian population. We performed a post hoc analysis of a prospective, double-blind phase II randomized clinical trial (COAST, NCT01864681), which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC. We stratified patients into those with a high BMI (≥24 kg/m2) and those with a low BMI (<24 kg/m2) to allow an analysis of the difference in PFS and OS between the two groups. The PFS and OS were analyzed using Kaplan–Meier curves, and the differences between groups were compared using log-rank test. In the univariate analysis, patients who had a high BMI (n = 56) in the gefitinib + metformin group (n = 28) did not have a better PFS (8.84 months vs. 11.67 months; P = 0.351) or OS (15.58 months vs. 24.36 months; P = 0.095) than those in the gefitinib + placebo group (n = 28). Similar results were also observed in the low-BMI groups. Strikingly, in the metformin plus gefitinib group, patients who had low BMI (n = 69) showed significantly better OS than those with high BMI (24.89 months [95% CI, 20.68 months–not reached] vs. 15.58 months [95% CI, 13.78–31.53 months]; P = 0.007), but this difference was not observed in PFS (10.78 months vs. 8.84 months; P = 0.285). Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.