Metformin Plus Paclitaxel for Metastatic or Recurrent Head and Neck Cancer: Final Results of the Randomised Prospective Mettax Trial (Nct01333852)

Abstract

ABSTRACT Background: Metformin, the most common anti-diabetic drug worldwide, has shown anticancer properties as single agent and synergistic effect with taxanes in preclinical models. This study evaluated the combination of paclitaxel and metformin for platinum-refractory recurrent or metastatic head and neck cancer. Methods: Patients (ECOG 0-2) were randomised in a 1:1 ratio to paclitaxel 175mg/m2 every 21 days plus placebo or metformin (1500-2500mg daily) until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS) at week 12. Secondary end-points were PFS, overall response rate (ORR), overall survival (OS) and safety. Results: Between February 2011 and January 2013, 45 patients were randomised, and three were further excluded due to protocol violations (paclitaxel plus placebo N = 22; paclitaxel plus metformin N = 20). The study was closed prematurely due to low accrual. PFS at week 12 were 31.8% and 50% for placebo and metformin, respectively (p = 0.23). Median PFS was 64 days for placebo and 80 days for metformin - stratified-p = 0.124. The addition of metformin reduced the risk of progression or death by 30% (HR 0.70 - 95%CI 0.38-1.31, p = 0.266). The study arm, performance status and age were strong prognostic factors for PFS in multivariate analysis. In multivariate analysis, metformin reduced the risk of progression or death by 52% (HR 0.48 95% CI 0.24-0.97, p = 0.040). OS was not different between placebo and metformin groups. Only performance status and age were prognostic for OS in the multivariate analysis. ORR were 4.5 and 10% for placebo and metformin arm, respectively (p = 0.49). Overall, both treatments were well tolerated. Patients in metformin arm experienced more diarrhoea and weight loss, all grades 1-2. Grade 3-5 adverse events were not different between placebo and metformin (45.5 and 50%, p = 0.76). In general, adverse events were manageable, notably diarrhoea. Conclusions: This is the first report of a randomised trial evaluating metformin as anticancer agent. Metformin improved PFS in this population. Further investigation as single agent or combination in head and neck and other cancers is needed. Disclosure: All authors have declared no conflicts of interest.