Could the addition of metformin to chemoradiotherapy, as a concurrent treatment as well as consolidation therapy, improve outcomes in patients without diabetes who have locally advanced non–small cell lung cancer?
In this randomized clinical trial including 54 of 96 planned patients, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with chemoradiotherapy alone. The proportion of patients who experienced a failure event within 1 year (ie, locoregional disease progression, distant metastases, death, or withdrawal) was 69.2% in the metformin arm vs 42.9% in the control arm.
Based on the results of this trial, metformin is not recommended as an adjunct to chemoradiotherapy for the treatment of unresected locally advanced non–small cell lung cancer in patients who do not have diabetes.
Unresected locally advanced non–small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied.
To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC.
Design, Setting, and Participants
The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019.
Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months.
Main Outcomes and Measures
The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis.
The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival 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 (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 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 (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event.
Conclusions and Relevance
In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy.
ClinicalTrials.gov Identifier: NCT02115464
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Tsakiridis T, Pond GR, Wright J, et al. Metformin in Combination With Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial. JAMA Oncol. 2021;7(9):1333–1341. doi:10.1001/jamaoncol.2021.2328
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