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Addition of metformin to TKI therapy improves survival in EGFR-mutant lung cancer
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The addition of metformin hydrochloride to standard epidermal growth factor receptor tyrosine kinase inhibitors significantly improved PFS and OS among patients with advanced EGFR-mutated lung adenocarcinoma, according to randomized phase 2 study results published in JAMA Oncology.
“The use of EGFR TKIs has dramatically improved patient outcomes; however, patients ultimately progress due to acquired resistance,” Oscar Arrieta, MD, MSc, director of the thoracic oncology unit and laboratory of personalized medicine at National Institute of Cancer in Mexico City and professor of medical and thoracic oncology at National Autonomous University of Mexico, and colleagues wrote. “Previous reports have identified that metformin hydrochloride, an oral biguanide used for treating type 2 diabetes, might be beneficial when repurposing its use as an antineoplastic agent.”
Arrieta and colleagues studied the effect of adding metformin to EGFR TKIs among 139 patients (mean age, 59.4 years; 65.5% women) with stage IIIB or stage IV, EGFR-mutated lung adenocarcinoma.
The researchers randomly assigned participants in the open-label, phase 2 trial to receive EGFR TKI therapy at standard dosage (n = 70), or EGFR TKI therapy with 500 mg twice-daily metformin hydrochloride (n = 69).
EGFR TKIs included erlotinib (Tarceva; Astellas Oncology, Genentech), afatinib (Gilotrif, Boehringer Ingelheim) and gefitinib (Iressa, AstraZeneca).
PFS served as the primary endpoint. OS, objective response rate, disease control rate and safety served as secondary endpoints.
Median follow-up was 16.9 months (95% CI, 7-24.9).
Results showed patients who received metformin plus EGFR TKI therapy achieved significantly longer median PFS (13.1 months vs. 9.9 months; HR = 0.6; 95% CI, 0.4-0.94) and OS (31.7 months vs. 17.5 months; HR = 0.5; 95% CI, 0.28-0.9).
Researchers also reported a significantly higher ORR in the metformin group (71% vs. 54.3%; P = .04).
Rates of grade 3 or grade 4 adverse events — including diarrhea, rash, nausea and mucositis — appeared similar in both groups.
A lack of randomization stratification based on smoking status, EGFR mutation profile or type of EGFR TKI received served as the study’s primary limitation.
“The addition of metformin to a standard EGFR TKIs treatment in patients with EGFR-mutated lung adenocarcinoma significantly prolongs PFS and OS, without significantly increasing adverse events,” Arrieta and colleagues wrote. “The results from this phase 2 study warrant the design of a larger phase 3, placebo-controlled study to draw more robust conclusions.” – by John DeRosier
Disclosures: Arrieta reports research funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, National Council for Science and Technology in Mexico, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures.
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