Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial

Abstract

Purpose: Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm).Patients and Methods: A total of 224 patients without diabetes with treatment-na€ ve stage IIIB-IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis.Results: The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2%[95% confidence interval (CI), 30.0-52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6-52.7) with gefitinib plus placebo (P ¼ 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%).Conclusions: Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC.

The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials

“…Consistent with experimental findings [7][8][9][10][11], epidemiologic and observational studies have reported that metformin was associated with reduction in the incidence of and mortality from various cancers [2][3][4][5][6]43]. Based on these results, several randomized controlled trials have been conducted to investigate the effect of metformin added to anticancer therapy in patients with advanced or metastatic cancer [20][21][22][23][24][25][26][27][28][29]. However, no studies indicated the addition of metformin to anticancer agents to be more effective, compared with anticancer therapy alone.…”

“…Of remaining 20 potentially eligible studies, 11 were further excluded by the inclusion or exclusion criteria. Eventually, nine randomized, clinical trials fulfilling the eligibility criteria were included in the meta-analysis [20][21][22][23][24][25][26][27][28]. Table 1 summarizes the major characteristics and clinical outcomes of the nine included studies.…”

“…All the studies were randomized phase II trials. The studies enrolled patients with advanced or metastatic PC [20,22], BC [23,25,26], and NSCLC [21,24,27,28]. The dose of metformin used was from 500 mg/d to 2 g/d.…”

“…Based on these results, several randomized controlled trials have been conducted to investigate the effect of adding metformin to anticancer agents in patients with various types of cancer [20][21][22][23][24][25][26][27][28][29][30]. Contrary to the observational studies, the most randomized trials failed to demonstrate a significant improvement of clinical outcomes in patients treated with metformin in combination with systemic anticancer treatment [20][21][22][23][24][25][26][27]. However, the results were inconclusive because most studies were phase II trials with a small sample size.…”

High Body Mass Index Was Related to Favorable Therapeutic Efficacy of Epidermal Growth Factor Receptor Targeted Therapy in Advanced Non-Small Cell Lung Cancer

“…Thirdly, the patients with high BMI in our study probably suffered from Diabetes Mellitus and took metformin. These drugs might impact EGFR TKI e ciency positively or negatively [39][40][41][42]. To exclude this probability, the patients with Diabetes Mellitus were screened in the whole cohort.…”