Metformin plus lrinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial

Abstract

Background Patients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting. Methods A phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks. Results Between December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0–4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9–10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12–4.7, p = 0.02; and HR 0.21, CI 95%, 0.08–0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3). Conclusions In this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…From other placebo-controlled studies the placebo response rate in this setting was 13% after 12 weeks. In this study 41% reached disease control after 12 weeks, consistent with a beneficial effect of metformin [ 94 ].…”

Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions

“…Findings showing the possible contribution of metformin to reducing the risk of cancer in diabetes patients in 2005 was a prelude to the study of metformin in cancer prevention and treatment [23,27]. A group of clinical trials suggested that metformin showed well-tolerated safe profiles combined with or without traditional or targeted therapies in various cancers [28][29][30][31][32][33][34][35][36]. Clinical applications of metformin in cancer prevention and treatment recently indicated its promising therapeutic effects in colorectal cancer, breast cancer, non-small cell lung cancer, head and neck cancer, and other cancer types, whereas other studies found no beneficial effects in many cancers in non-diabetic patients [37][38][39].…”

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

“…Despite these constraints, electronic health records were used to identify a reduction in cancer-related mortality in patients with diabetes who received treatment with metformin compared with those who did not receive this drug 35 . Observational studies have suggested that patients with diabetes and using metformin have a decreased risk of incident cancer and cancer-related mortality compared with patients not using metformin (reviewed previously 36 , 37 ), and several clinical interventional studies have indicated the beneficial effect of metformin in the treatment of colorectal and ovarian cancers 38 , 39 . Importantly, however, these findings have not been confirmed in prospective, randomized trials.…”