Metformin in Locally Advanced Non–Small Cell Lung Cancer

Metformin is proposed to suppress tumor growth through metabolic stress caused by inhibition of the mitochondria oxidative phosphorylation chain. In preclinical non–small cell lung cancer (NSCLC) models, metformin enhances tumor response to radiotherapy and chemotherapy. In addition, epidemiologic studies suggest improved survival in patients with locally advanced (LA) NSCLC who take metformin for diabetes. Two recent phase 2 trials examined use of metformin in patients with LA-NSCLC and without diabetes.

In the NRG-LU001 trial, 167 patients with inoperable LA-NSCLC were randomized to receive either radiation (60 Gy) plus concurrent weekly carboplatin and paclitaxel chemotherapy, followed by two cycles of consolidative chemotherapy every 3 weeks, or the same regimen combined with metformin, with a goal dose of 2000 mg/day, during both the concurrent and consolidation phases.

Progression-free survival (PFS) at 1 year, the primary outcome, did not differ significantly between the control and metformin groups (60.4% and 51.3%; hazard ratio, 1.15; 95% CI, 0.77–1.73). There was also no significant difference in grade 3 or higher adverse events.

In the OCOG-ALMERA (Ontario Clinical Oncology Group Advanced Lung Cancer Treatment with Metformin and Chemoradiotherapy) trial, 54 patients were randomized to platinum-based chemotherapy plus radiotherapy with or without consolidation, or the same treatment plus metformin at a dose of 2000 mg/day during chemoradiotherapy and afterward for 12 months. The trial was stopped early due to slow accrual.

At 1 year, the rate of treatment failure (disease progression, distant metastases, death, discontinuation of treatment) — the primary outcome — was higher in the metformin arm than in the control arm (69.2% vs. 42.9%; P=0.05) and PFS was significantly lower in the metformin arm (34.8% vs. 63.0%; HR, 2.42; 95% CI, 1.14–5.10). Grade 3 or higher adverse events were more common in the metformin arm (53.8% vs. 25.0%).