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Addition of Metformin to Tyrosine Kinase Inhibitor Therapy in EGFR-Mutant NSCLC


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In a single-center phase II trial reported in JAMA Oncology, Arrieta et al found that the addition of metformin to EGFR tyrosine kinase inhibitor therapy resulted in improved progression-free and overall survival in patients with non–small cell lung cancer (NSCLC) with an activating EGFR mutation.

Study Details

The open-label trial, conducted at the Instituto Nacional de Cancerologia in Mexico City, included 139 patients with recently diagnosed stage IIIB or IV lung adenocarcinoma with an activating EGFR mutation. Patients were randomly assigned between March 2016 and December 2017 to receive metformin at 500 mg twice daily plus standard doses of an EGFR tyrosine kinase inhibitor (erlotinib, afatinib, or gefitinib) selected according to physician preference (n = 69) or EGFR tyrosine kinase inhibitor treatment alone (n = 70).

Treatment was continued until intolerable toxicity or withdrawal of consent. Patients could not have a history of diabetes and could not be using any hypoglycemic agent. For the metformin plus tyrosine kinase inhibitor and the tyrosine kinase inhibitor monotherapy groups, the tyrosine kinase inhibitors used were gefitinib in 32% and 40%, afatinib in 48% and 43%, and erlotinib in 20% and 17%, respectively. 

The primary outcome measure was progression-free survival in the intention-to-treat population.  

Progression-Free Survival

Median follow-up was 16.9 months. Median progression-free survival was 13.1 months in the metformin plus tyrosine kinase inhibitor group vs 9.9 months in the tyrosine kinase inhibitor monotherapy group (hazard ratio [HR] = 0.60; P = .03). Median overall survival was 31.7 months vs 17.5 months (HR= 0.50; P = .02). Objective response was observed in 71.0% vs 54.3% of patients (P = .04).

KEY POINTS

  • The addition of metformin to tyrosine kinase inhibitor therapy increased progression-free survival.
  • Increases in response rate and overall survival were observed with metformin plus tyrosine kinase inhibitor therapy.

Adverse Events

The most common adverse events of any grade in the metformin plus tyrosine kinase inhibitor group were diarrhea (78% vs 84% in tyrosine kinase inhibitor group), rash (70% vs 67%), nausea (45% vs 44%), and mucositis (38% vs 40%). The most common grade ≥ 3 adverse events were diarrhea (11% vs 7%), nausea (3% vs 3%), and rash (2% vs 6%).

The investigators concluded, “To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR tyrosine kinase inhibitor therapy in patients with advanced lung adenocarcinoma significantly improves [progression-free survival]. These results justify the design of a phase III placebo-controlled study.”

Oscar Arrieta, MD, of the Thoracic Oncology Unit, Instituto Nacional de Cancerologia, Mexico City, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by a grant from the National Council for Science and Technology in Mexico. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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