A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer

Abstract

BackgroundEverolimus significantly improves progression-free survival (PFS) and has been approved to use in aromatase inhibitor pretreated patients with hormone receptor positive advanced breast cancer. Metformin has been shown to inhibit mTOR pathway, with more favorable safety profile, leading to this hypothesis-generating trial to assess whether metformin enhances the efficacy of aromatase inhibitors.Methods60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer were randomly assigned 1:1 to aromatase inhibitor (exemestane 25mg/d or letrozole 2.5mg/d depending on the most recent treatment) plus metformin (0.5g bid, orally) or placebo. The primary endpoint was PFS, and secondary endpoints were objective response rate, clinical benefit rate, overall survival and safety.ResultsMedian PFS was 4.7 months in the combination group and 6.0 months in the control group (hazard ratio, 1.2; 95% confidence interval [CI], 0.7 to 2.1; P =0.48). ORR was 6.7% in the combination group and 0% in the control group (odds ratio for ORR not available; P =0.99), and CBR was 33.3% and 50.0%, respectively (OR for CBR 0.5; 95% CI, 0.2 to 1.4; P=0.15). No significant difference in overall survival was observed between the combination and control groups (median OS, 30.9 vs. 32.4 months; P = 0.81). Subgroup analyses didn't find any specific population favoring the combination treatment. No substantial difference in incidence or severity of adverse events was seen between the two treatment groups.ConclusionThis randomized phase II clinical trial failed to show an improved efficacy with the addition of metformin to endocrine therapy, although with excellent tolerability.

Phase 1 lead‐in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma

“…In accordance with the results from our study, a phase 2 trial of metformin 1000 mg twice daily in combination with carboplatin and pemetrexed for nonsmall cell lung cancer reported 2 grade 3 adverse events: nausea and reflux . Like other studies, there were no clinical reports of hypoglycemia or lactic acidosis in association with metformin …”

“…Studies evaluating the toxicity of aromatase inhibitors in combination with metformin reported no significant difference in the rate of adverse events, but the metformin dose in those studies was relatively low at 500 mg twice daily. 39 In accordance with the results from our study, a phase 2 trial of metformin 1000 mg twice daily in combination with carboplatin and pemetrexed for nonsmall cell lung cancer reported 2 grade 3 adverse events: nausea and reflux. 40 Like other studies, there were no clinical reports of hypoglycemia or lactic acidosis in association with metformin.…”

“…40 Like other studies, there were no clinical reports of hypoglycemia or lactic acidosis in association with metformin. 39,40 No significant adverse events were attributed to mefloquine treatment. The final recommended dose of mefloquine in the doublet, triplet, and quadruplet treatment arms was the predefined target dose of 250 mg 3 times weekly.…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Gyawali et al have provided a critical review of this study, arguing lack of study power, imbalance between the two groups and other confounding factors. A study by Zhao et al also randomly assigned 60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer to aromatase inhibitor plus metformin or placebo. This clinical trial also failed to show an improved efficacy with the addition of metformin to endocrine therapy.…”

“…66 At present, there are only a few prospective randomised controlled trials aimed at validating the findings from observational studies, and the few that are available have failed to confirm the anticipated benefits in NSCLC, 67 pancreatic cancer 68,69 and breast cancer. 70 For example, Kordes et al 68 randomly assigned 121 patients with advanced pancreatic cancer to receive gemcitabine and erlotinib with either placebo (n = 61) or metformin (n = 60) and reported that overall survival at 6 months was 63.9% (95% CI: 51.9-75.9) in the placebo group and 56.7% (CI: 44.1-69.2) in the metformin group (P = 0.41). This may be due to the possibility that pancreatic cancer patients lack a hyperinsulinaemic state.…”