A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-Naïve Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer

Background: In the absence of a targeted oncogenic driver mutation or high programmed death-ligand 1 expression, systemic therapy with platinum-based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non-small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin-dependent and insulin-independent mechanisms and to be potentially synergistic with chemotherapy.

Materials and methods: This open-label single-center phase II study (NCT01578551) enrolled patients with chemotherapy-naïve advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab ± metformin continued until disease progression, intolerable toxicity, or study withdrawal. The primary outcome was 1-year progression free survival (PFS). Secondary outcomes included overall survival, response to therapy, and toxicity.

Results: A total of 25 patients were enrolled from August 2012 to April 2015, of whom 24 received at least one cycle of therapy administration. The study was stopped early due to slow accrual and changes in standard first-line therapy of advanced NSCLC. The 1-year PFS on Arm A (n = 18) was 47% (95% confidence interval [CI]: 25%-88%), which exceeded the historical control 1-year PFS of 15%. Median overall survival of patients treated on Arm A was 15.9 months (95% CI: 8.4-not available [NA]) and 13.9 months (95% CI: 12.7-NA) on Arm B. There were no significant differences in toxicity between the study arms.

Conclusion: To the authors' knowledge, this is the first study to show a significant benefit in PFS with the use of metformin in this patient population and is a signal of efficacy for metformin in advanced NSCLC.

Implications for practice: The anticancer effects of metformin continue to be elucidated. To the authors' knowledge, this is the first trial in nondiabetic advanced non-small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first-line chemotherapy. Well tolerated and widely available, metformin is a drug that should be considered for further study in the lung cancer treatment landscape.