In the phase II NRG-LU001 trial reported in JAMA Oncology, Skinner et al found that the addition of metformin to concurrent chemoradiation did not improve progression-free survival or overall survival at 1 year in patients with unresectable stage III non–small cell lung cancer (NSCLC).
Study Details
In the open-label trial, 167 eligible patients from sites in the United States, Canada, and Israel were randomly assigned between August 2014 and December 2016 to receive chemoradiation with (n = 86) or without (n = 81) metformin at a target dose of 2,000 mg/d during both concurrent chemoradiation and consolidative chemotherapy. Chemoradiation consisted of radiotherapy at 60 Gy in 30 2-Gy fractions and concurrent weekly paclitaxel (50 mg/m2 per week) and carboplatin (AUC 2 twice per week during radiotherapy). Between 28 and 42 days after the completion of radiotherapy, paclitaxel (200 mg/m2) and carboplatin (AUC 6) were given every 3 weeks for two cycles.
The primary outcome was 1-year progression-free survival, designed to detect a 15% improvement from 50% to 65%. The analysis includes all data received at NRG Oncology up to February 2019.
Progression-Free Survival
Median follow-up was 27.7 months (range = 0.03–47.21 months) among surviving patients. Progression-free survival at 1 year was 51.3% (95% confidence interval [CI] = 39.8%–61.7%) in the metformin group vs 60.4% (95% CI = 48.5%–70.4%) in the control group (hazard ratio [HR] = 1.15, 95% CI = 0.77–1.73, P = .24). Rates at 2 years were 34.5% vs 40.1%. On multivariate analysis, clinical stage was the sole factor significantly associated with progression-free survival (HR for higher vs lower stage = 1.79, P = .005).
Overall survival at 1 year was 80.8% vs 80.2% (HR = 1.03, 95% CI = 0.64–1.68, P = .89), with 2-year rates of 64.9% vs 65.4%. Local regional recurrence rates were 19.2% vs 14.5% at 1 year (HR = 0.91, P = .75) and 27.0% vs 27.9% at 2 years. Rates of distant metastasis were 20.5% vs 17.2% at 1 year (HR = 1.29, P = .41) and 29.5% vs 24.0% at 2 years.
KEY POINTS
- The addition of metformin to chemoradiotherapy did not improve 1-year progression-free survival.
- No significant differences were observed in 1-year rates of overall survival, local-regional recurrence, or distant metastases.
Adverse Events
Grade ≥ 3 adverse events considered at least possibly related to treatment occurred in 65.8% of the metformin group vs 68.0% of the control group. Grade ≥ 3 adverse events included nausea in 2.5% vs 1.3%, vomiting in 1.3% vs 1.3%, diarrhea in 1.3% vs 2.7%, and pneumonitis in 1.3% vs 2.7%.
The investigators concluded: “In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC.”
Heath D. Skinner, MD, PhD, of UPMC Hillman Cancer Center, and Theodoros Tsakiridis, MD, PhD, of Juravinski Cancer Centre at Hamilton Health Sciences, Ontario, are the corresponding authors for the JAMA Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.
