Metformin No Silver Bullet in Locally Advanced NSCLC

Using metformin in combination with chemoradiotherapy in inoperable locally advanced non–small cell lung cancer (NSCLC) was no more effective than chemoradiotherapy alone, according to two phase II randomized studies.

Both studies, conducted in patients without diabetes, were published in JAMA Oncology.

In the NRG-LU001 trial, Heath Skinner, MD, PhD, of the University of Pittsburgh Medical Center, and other co-authors found that adding metformin to concurrent chemoradiotherapy improved neither overall survival (OS) nor progression-free survival (PFS).

Metformin, a diabetes drug, is known to inhibit the mitochondria oxidative phosphorylation chain, researchers explained.

They compared the use of chemoradiotherapy with and without metformin in patients without diabetes who were diagnosed with stage III NSCLC. Patients were randomized to receive either 60 Gy of radiation to involved sites combined with concurrent weekly carboplatin and paclitaxel chemotherapy, followed by two cycles of consolidative chemotherapy every 3 weeks, or the same regimen combined with metformin during both the concurrent and consolidation phases.

The primary outcome was 1-year PFS, designed to detect an improvement from 50% in the control arm to 65% in the metformin arm, the researchers explained.

A total of 167 patients were available for analysis (81 in the control group and 86 in the metformin group). At a median follow-up of 27.7 months, 1-year PFS was 60.4% (95% CI 48.5%-70.4%) in the control group and 51.3% (95% CI 39.8%-61.7%) in the metformin group (HR 1.15, 95% CI 0.77-1.73).

One-year OS was 80.2% (95% CI 69.3%-87.6%) in the control arm and 80.8% (95% CI 70.2%-87.9%) in the metformin arm.

There were no significant differences in local-regional recurrence or distant metastasis between the two arms, nor in grade 3 or higher adverse events, the researchers reported.

“The addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC,” Skinner and co-authors wrote, concluding that adding metformin to chemoradiotherapy in patients with locally advanced NSCLC “is not warranted.”

The OCOG-ALMERA (Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy) trial by Theodoros Tsakiridis, MD, PhD, of the Juravinski Cancer Center at McMaster University in Hamilton, and colleagues, found that adding metformin was associated with worse efficacy and increased toxicity compared with chemoradiotherapy alone.

The trial was stopped early, however, because of slow accrual, with just 54 patients randomized to either the experimental metformin arm (26 patients) or the control arm (28 patients) between 2014 and 2019.

The study was designed to enroll 96 patients to platinum-based chemotherapy concurrent with chest radiotherapy with or without consolidation chemotherapy, or the same treatment plus metformin at 2,000 mg/day during chemoradiotherapy and for up to 12 months afterwards. The authors set out to investigate the potential benefit of metformin given concurrently with chemoradiotherapy and continuing as consolidation therapy in patients with unresected locally advanced NSCLC.

The primary outcome was the proportion of patients who experienced a failure event, such as locoregional disease progression, distant metastases, death, or discontinuation of treatment, within 12 months.

Researchers found that of the 26 patients in the metformin arm, 18 experienced an event (69.2%) compared to 12 of 28 patients in the control arm (42.9%). The 1-year PFS rate was 34.8% (95% CI 16.6%-53.7%) in the metformin arm and 63.0% (95% CI 42.1%-78.1%) in the control arm (HR 2.42, 95% CI 1.14-5.10).

OS was 47.4% (95% CI 26.3%-65.9%) in the metformin arm and 85.2% (95% CI 65.2%-94.2%) in the control arm (HR 3.80, 95% CI 1.49-9.73).

In addition, 53% of patients in the metformin arm reported at least one grade 3 or higher adverse event (most commonly esophagitis and lung infections) compared with 25% of patients in the control arm.

“Based on these findings, metformin is not recommended in patients with [locally advanced]-NSCLC who do not have diabetes and are candidates for chemoradiotherapy,” Tsakiridis and colleagues concluded.

They noted that it was unclear why there was an increase in failure events with metformin, but suggested that the increased toxicity could have limited patients’ ability to receive the prescribed doses of chemoradiotherapy, that gross tumor volume and radiotherapy tumor volume were, on average, larger in the metformin group; and that metformin could have had properties that actually stimulated tumor growth.

In an accompanying commentary about both studies, Chukwuka Eze, MD, of University Hospital Ludwig-Maximilians-University in Munich, Germany, and colleagues, suggested that despite the negative results of the two studies there may still be a role for metformin in selected patients with NSCLC, such as those with KRAS/LKB1-mutated tumors or with elevated fluorodeoxyglucose metabolism.

Related to that, Skinner and co-authors in their study mentioned a recent phase II randomized trial that combined metformin with tyrosine kinase inhibitors in NSCLC showing that the combination “significantly prolonged PFS and OS, without significantly increasing adverse events.”

In addition, several ongoing trials are investigating combining metformin with immune checkpoint inhibitors, Skinner and colleagues noted.