Negative Metformin Trial Results for Advanced Pancreatic Cancer

Addition of an anti-diabetes agent to chemotherapy does not extend advanced pancreatic survival

medwireNews: Metformin does not improve outcomes in patients with advanced pancreatic cancer undergoing treatment with erlotinib and gemcitabine, indicate phase II trial findings.

Overall survival (OS) at 6 months was comparable for the 60 patients given twice daily oral metformin, increasing from 500 mg to 1000 mg, alongside their chemotherapy and the 61 patients given placebo, at 56.7% versus 63.9%.

Nor was there a difference in median OS between the metformin and placebo groups, at 6.8 and 7.6 months, respectively, report Johanna Wilmink, from Academic Medical Centre in Amsterdam, the Netherlands, and co-workers.

However, there was a trend towards improved OS in metformin-treated patients who achieved a reduction in insulin concentration compared with patients whose insulin levels did not change, as well as in patients who had a high plasma concentration of metformin, defined as above 1 mg/mL.

“Many in-vitro studies show direct antiproliferative actions of metformin at millimolar concentrations, but we determined blood metformin concentrations to be in the micromolar range in our study”, the team writes in The Lancet Oncology.

“Thus, future and ongoing studies of metformin and other more bioavailable oxidative Phosphorylation inhibitors should include pharmacokinetic and pharmacodynamic endpoints”, the authors suggest.

In an accompanying comment, researchers from the University of Toronto in Ontario, Canada, describe the study as “ambitious” and say that the failure to meet the primary endpoint of a 50% increase in OS was “not surprising” given that targeted drugs have failed to improve survival in non-selected patients on a gemcitabine regimen.

But Kyaw Aung and Malcolm Moore observe that metformin was “reasonably well tolerated” and that patients were more likely to discontinue treatment due to progressive disease than toxicity.

“Despite this disappointing outcome, attempts to repurpose metformin for treating cancer should not be abandoned”, they say, noting that over 100 studies assessing the agent in different tumour types and stages are underway.

“Careful patient selection and translational studies will be crucial to determine the success of these attempts to bring metformin into cancer therapy”, the commentators conclude.

References

Kordes S, Pollak MN, Zwinderman AH, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2015; Advance online publication 8 June. doi:10.1016/S1470-2045(15)00027-3

Aung KL, Moore MJ. Metformin for pancreatic cancer. Lancet Oncol 2015; Advance online publication 8 June. doi:10.1016/S1470-2045(15)00029-7

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