From the Journals

Metformin disappoints in two phase 2 lung cancer trials



Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”


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