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Original Investigation
July 29, 2021

Metformin in Combination With Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial

Author Affiliations
  • 1Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada
  • 2Department of Oncology, McMaster University, Hamilton, Ontario, Canada
  • 3Walker Family Cancer Center, St Catharines, Ontario, Canada
  • 4Ontario Clinical Oncology Group, Hamilton, Ontario, Canada
  • 5Cancer Care Manitoba, Winnipeg, Manitoba, Canada
  • 6McGill University, Montreal, Québec, Canada
  • 7Cross Cancer Institute, Edmonton, Alberta, Canada
  • 8Queen’s University, Kingston, Ontario, Canada
  • 9Grand River Cancer Center, Kitchener, Ontario, Canada
JAMA Oncol. 2021;7(9):1333-1341. doi:10.1001/jamaoncol.2021.2328
Visual Abstract. Effect of Metformin in Combination With Chemoradiotherapy in Patients With Locally Advanced Non–Small Cell Lung Cancer
Effect of Metformin in Combination With Chemoradiotherapy in Patients With Locally Advanced Non–Small Cell Lung Cancer
Key Points

Question  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?

Findings  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.

Meaning  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.

Abstract

Importance  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.

Objective  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.

Interventions  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.

Results  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02115464

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    1 Comment for this article
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    Metformin in Combination with Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer
    Yong He, MD. | Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
    Tsakiridis and colleagues1 recently published an open label randomized clinical trial that investigated the potential benefit of metformin, administered concurrently with chemoradiotherapy and continuing after as consolidation therapy in patients with unresected LA-NSCLC (OCOG-ALMERA). The authors reported the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with chemoradiotherapy alone. However, there are some major issues about this work that need to be addressed.
    According to their article1, PFS and OS in the metformin combination group were indeed worse than those in the standard treatment group. However, it is obviously
    inappropriate to blame metformin for the failure of the metformin combination therapy group. Because the standard treatment of the two groups was significantly unbalanced. Concretely, the completion of chemotherapy(53.8% vs 75.0%) and radiotherapy(80.8% vs 96.4%%) in the combined treatment group was significantly lower than that in the standard treatment group. Even fewer patients in the combination group received duvalumab immunotherapy. This will inevitably lead to worse treatment outcomes in the combined treatment group. The authors attributed the differences in chemoradiotherapy completion to metformin side effects, but previous studies on metformin combination therapy did not support these conclusions2,3. In particular another similar study with a larger sample size, it was not observed that metformin combined with concurrent chemoradiotherapy would increase the toxicity (NRG-LU001)4. In addition, the higher esophagitis and pneumonia in the metformin combined treatment group in this study are not common adverse events of metformin treatment, but usually radiation-related toxic reactions, which will be affected by the radiation regimen. Actually, the total tumor volume (GTV) or planned target volume (PTV) in metformin combined treatment group were greater than those in standard treatment group.
    Although the statistical differences between the treatment of two groups were not significant, these differences in treatment are likely to lead to a gap in toxic effects between the two groups. And the sample size of this study is indeed too small, and the imbalance between the two treatment groups will be amplified. In brief, the imbalance of standard treatment between the two groups and too small sample size make the conclusion of OCOG-ALMERA study unreliable.
    CONFLICT OF INTEREST: None Reported
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