Addition of Metformin to TKI Therapy Delivers ‘Unusual’ Result in Lung Cancer


Researchers examined how metformin and TKI therapy did in combatting lung cancer.

The addition of metformin to an epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) extended survival among patients with EGFR-positive metastatic lung cancer, according to trial results published in JAMA Oncology.1

Metformin is a drug used to manage type 2 diabetes, and retrospective clinical evidence has indicated that it may have synergistic activity when combined with an EGFR TKI in metastatic lung cancer.2

The prospective, open-label randomized phase II trial (NCT03071705) enrolled 139 adult patients with stage IIIB to stage IV lung adenocarcinoma with an activating EGFR mutation from Instituto Nacional de Cancerología in Mexico City, Mexico, between March 31, 2016, and December 31, 2017. Seventy patients received a TKI [either gefitinib, afatinib (Gilotrif), or erlotinib (Tarceva)] and 69 received a TKI plus metformin.

Patients in the TKI plus metformin arm experienced superior progression-free survival (13.1 vs 9.9 months; HR, 0.60; 95% CI, 0.40-0.94; P = .03) and overall survival (31.7 vs 17.5 months; 95% CI, 11.4-23.7 months; P = .02), compared with those who received a TKI only.

Lastly, the objective response rate was also significantly higher among patients in the TKI plus metformin arm compared with the TKI arm (71.0% vs 54.3%; P = .04).

“The thing that is striking is that all the results are positive,” trial investigator Giuseppe Giaccone, MD, PhD, oncologist at Weill Cornell Medicine and NewYork-Presbyterian in New York, New York, told CancerNetwork. “This is extremely unusual in patients with metastatic lung cancer, If this is true, then it is fantastic, but one has to be aware that this is very unusual.”

He explained that the findings could just be the result of a single study, and before implementing the them, the data have to be reproduced in a larger confirmatory study.

In addition, the trial has considerable limitations. First, the use of TKIs in the trial do not align with practice patterns in the United States today.

“The number of afatinib-treated patients is very high,” said Giaccone. For the TKI arm, the majority of patients received afatinib (42.9%), followed by gefitinib (40.0%), and erlotinib (17.1%). Similarly, for the TKI plus metformin arm, the majority of patients received afatinib (47.8%), followed by gefitinib (31.9%), and erlotinib (20.3%).

In the United States, Giaccone said, erlotinib has been the preferred choice for this patient population, not afatinib, but despite that, osimertinib (Tagrisso) is currently the standard of care for the first-line treatment of metastatic lung cancer patients with EGFR mutations. Osimertinib was approved by the FDA in April 2018 as first-line treatment for metastatic non-small cell lung cancer harboring EGFR mutations.

Given this, Giaccone said the results of the trial may not be relevant and replicating this study would be “essentially impossible” because the standard or care has changed.

Another limitation of the study is that, while patients enrolled in the trial were randomized to treatment arms, the randomization was not stratified by smoking status, the EGFR mutation profile, or receipt of TKI.

Giaccone explained that, as a result, the two treatment arms may not be balanced, meaning the survival differences may be due to differences in prognostic factors between treatment arms. “This [imbalance] can happen quite easily in a small study,” he said.


1. Arrieta O, Barron, Salinas Padilla MA. Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone in Patients With Epidermal Growth Factor Receptor–Mutated Lung Adenocarcinoma. JAMA Oncol. doi:10.1001/jamaoncol.2019.2553.
2. Chen H, Yao W, Chu Q, et al. Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Letters. 2015;369(1):97-102. doi:10.1016/j.canlet.2015.08.024.

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