Phase-Ib trial of metformin combined with nivolumab for refractory/recurrent solid tumors

Our previous findings showed that the addition of metformin to nivolumab achieved remarkable tumor regression and increased the number of tumor-infiltrating T cells in mouse models. Therefore, we conducted a phase Ib study with a combination therapy of nivolumab and metformin for patients with refractory/recurrent solid tumors. The study consisted of part 1, evaluating the maximum-tolerated dose (MTD), safety, pharmacokinetics, and efficacy in solid tumors, and part 2, investigating principally safety at the recommended dose limited in thoracic and pancreatic cancers. Metformin and nivolumab were given orally at a dose of 750 mg to 2250 mg/day and biweekly at an intravenous fixed dose of 3mg/kg, respectively. The dose-limiting toxicity (DLT) was evaluated for each patient within the first 4 weeks. Both metformin and nivolumab were continued until confirmed progression or discontinued due to toxicity. Seventeen and twenty-four patients were enrolled in parts 1 and 2, respectively. The primary lesions were pancreatic cancer in 24 patients, thymic epithelial tumor in three patients, non-small cell lung cancer in two patients, and others in ten patients. The DLT was observed in one of six patients at a dose of 750 mg/day for metformin, one of six patients at a dose of 1500mg/day for metformin, and none of three patients at the maximum dose level of 2250 mg/day for metformin, which did not reach the MTD. Therefore, the dose of 2250 mg/day for metformin was selected in part 2. An objective response was observed in 4 of 41 patients (9.8% [95% confidence interval (CI): 2.7-23.1]. The one-year progression-free and overall survival rates were 9.8% [95% CI: 3.1-21.0] and 56.8% [95% CI: 34.2-74.3], respectively. Two patients have remained alive without progression for more than three years. There was no correlation between blood levels of metformin and treatment efficacy. Grade 1 hypoglycemia was observed in two patients, and Grade 3 lactic acidosis was observed in one patient. This combination therapy was well tolerated and demonstrated clinically meaningful efficacy in selected patients. In the future, further verification of the mechanism in cases in which treatment was effective is required.