Combination of metformin plus TKI vs. TKI alone in EGFR(+) LUNG adenocarcinoma: A randomized phase II study.

9013 Background: Metformin has been shown to have antitumor activity by increasing AMPK through different mechanisms involving tumor suppressor gene, LKB1. LKB1 inactivation is common in Non-small cell lung cancer (NSCLC) and is associated with a more aggressive clinical phenotype. Retrospective studies have shown that metformin could effectively increase the sensitivity to TKIs in NSCLC, thus improving Progression Free Survival (PFS) and potentially impacting Overall Survival (OS) in these patients. We compared the effect of metformin in combination with EGFR-TKI versus TKIs alone on the clinical prognosis of adenocarcinoma patients with EGFR mutations. Methods: In this phase 2 clinical trial (NCT03071705) we randomly assigned 116 patients with stage IV EGFR-mutated lung adenocarcinoma to receive therapy with metformin + EGFR-TKI (M+TKI) (n = 49) or EGFR-TKI (TKI) alone (n = 67). TKI was chosen upon clinician´s discretion. Patients were excluded if they had a history of diabetes or had received therapy with metformin or TKIs ( > 2 cycles) previous to enrollment. The primary endpoint was PFS, secondary endpoints included objective response rate (ORR), disease control rate (DCR) and OS. Results: Baseline characteristics were well balanced between treatment arms. Mean patient follow up was 12.9 (±10.9) months. Median PFS was significantly longer for patients receiving M+TKI compared to those who received TKI (14.0 months vs. 10.0 months; p = 0.017) . ORR was higher in the experimental arm of the trial, compared to the control group (67.4% vs. 47.5%; p = 0.044), although, the DCR was similar in the two groups (97% vs. 88.5%; p = 0.085). Median OS was 24.8 months. Patients receiving M+TKI had a longer OS compared to those receiving TKI (27.2 months vs. 19.0 months, p = 0.015). Multivariate analysis showed that, among others, the therapeutic arm (M+TKI vs. TKI) is an independently associated factor for both PFS and OS. Conclusions: Our study strongly suggests that the addition of Metformin to standard EGFR-TKI therapy has a significant effect in PFS, ORR and OS of patients with EGFR-mutated NSCLC. Metformin use is a safe and efficacious addition to the therapeutic scheme of EGFR+ NSCLC. Clinical trial information: NCT03071705.