When it comes to the use of metformin as a treatment for lung cancer, the jury is still out on its potential.
“Metformin’s utility as an anticancer drug is still being investigated,” said Benjamin Levy, MD, clinical director of medical oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital. “There are some investigators who think it may hold promise while others are more skeptical of its potential benefit.”
Metformin is an oral antidiabetic drug in a class of drugs called biguanides that improves insulin action by increasing insulin-mediated glucose utilization in peripheral tissues.1
“We know that there is a link between glucose metabolism and potential oncogenesis,” Dr. Levy said. “On a broader level, it is a drug that has garnered interest based on the ability to interfere with glucose metabolism, but beyond that there are other more detailed pathways that are starting to be ironed out in preclinical models.”
In fact, there were a lot of data from preclinical models that suggested that radiation, chemotherapy, and targeted therapies might be enhanced by a drug like metformin, according to Karen L. Reckamp, MD, MS, director of the division of medical oncology at Cedars-Sinai Cancer Center.
For example, a 2013 mouse study found that metformin inhibited NSCLC cell and tumor growth and radiosensitized the cells to ionizing radiation through the ataxia-telangiectasia mutated (ATM) and adenosine monophosphate-activated kinase (AMPK) pathways.2
Experiments have also suggested that metformin may have an effect on cancer cell signaling, tumor proliferation, and tumor genetics.2
“[Metformin] was taken from laboratory work and brought into the clinic and the hope was that because metformin is a ubiquitous drug it would be straightforward to start using in the setting of cancer,” Dr. Reckamp said. “It has not been very straightforward though.”
Prospective Data
When examining the role of metformin in lung cancer, Dr. Levy emphasized the importance of focusing on the results of prospective—versus retrospective or observational—studies.
One of the most well-known prospective trials of metformin in lung cancer is the NRG-LU001 randomized phase II trial testing concurrent chemoradiotherapy with or without metformin in locally advanced NSCLC.3 This trial of 170 unresected, non-diabetic patients showed no difference for overall survival or progression-free survival with no alteration of local-regional failure or distant metastasis.
“There were also patients who had to discontinue metformin due to toxicity, which indicates that although metformin is thought to be a well-tolerated drug, it may not be best with concurrent chemoradiotherapy,” Dr. Levy said.
“These data were definitely disappointing.”
More recently, another phase II trial out of Mexico was published in JAMA Oncology looking at the use of metformin with or without a TKI inhibitor in 139 patients with EGFR-mutated lung cancer.4 Patients were randomly assigned to erlotinib, afatinib, or gefitinib plus metformin or the EGFR inhibitor alone. Median progression-free survival was more than 3 months longer with metformin (13.1 vs. 9.9 months; hazard ratio [HR] 0.60, 95% CI [0.40, 0.94]; p = 0.03). Median overall survival was also significantly improved (31.7 vs. 17.5 months; p = 0.02).
“It is very good to see a randomized trial show positive results,” Dr. Reckamp said. “One caveat though is that this is a single-center study, and it has relatively small numbers.”
Dr. Reckamp also pointed out that there were a handful of patients in the metformin arm who had non-exon 19 or non-exon 21 EGFR mutations, which are less sensitizing than exon 18 mutations. Additionally, approximately 50% of patients were treated with afatinib or gefitinib, whereas, in the United States—prior to osimertinib—it would have been erlotinib in the front line.
“These caveats make the study less generalizable,” she said.
Finally, Dr. Reckamp pointed out that the published paper did not include full information on toxicity assessments but instead included that information in a supplement.
Another phase I trial from researchers in China looked at gefitinib with or without metformin in 224 patients without diabetes with treatment-naive stage IIIB-IV EGFR-mutant NSCLC.5 There was a nonsignificant worsening of outcomes with the addition of metformin and increased toxicity.
Dr. Levy was involved in another small, single-arm phase II study looking at metformin plus chemotherapy in advanced NSCLC.6 Fourteen patients received carboplatin plus pemetrexed plus metformin at 1,000 mg per day for week 1, 1,500 mg per day for week 2, and 2,000 mg per day thereafter. The addition of metformin did not significantly improve clinical outcomes in these patients compared with historical phase III controls.
Another small study of 25 patients with chemotherapy-naive advanced or metastatic nonsquamous NSCLC randomly assigned patients 3:1 to carboplatin, paclitaxel, and bevacizumab with or without metformin.7 The study was stopped early due to low accrual and changes in standard of care for first-line therapy; however, the 1-year progression-free survival was 47% for patients given metformin compared with a historical control of 15%.
“Unfortunately, the data are really very conflicting as to whether this drug can be leveraged in the right settings for patients with lung cancer,” Dr. Levy said.
Questions Remain
According to Dr. Reckamp, the negative results of the NRG-LU001 trial dampened enthusiasm for looking at metformin in combination with chemoradiotherapy. However, the results from Mexico published in JAMA Oncology provide intrigue for looking at metformin in specific populations, like EGFR-mutant disease.
With the use of osimertinib as a front-line therapy, trials of metformin going forward would have to test the drug in combination with this new standard.
Dr. Levy agreed. “The story of metformin is not over yet,” he said.
Moving forward, Dr. Levy said he would love to see further exploration of metformin in combination with osimertinib and in EGFR-mutant cancer, but he noted that front-line treatment is a very competitive landscape right now and these trials may not come to fruition. It is also worth exploring the use of metformin in tumors with other genetic alterations, like the KRAS mutation.
“The most important piece is that patients should know this is not ready for recommended use,” Dr. Reckamp said. “Since it is a widely available medication, some patients request to take it, but it should not be routinely prescribed.”
References:
- Levy A, Doyen J. Metformin for Non–Small Cell Lung Cancer Patients: Opportunities and Pitfalls. Crit Rev Oncol Hematol. 2018;125:41-47.
- Storozhuk Y, Hopmans SN, Sanli T, et al. Metformin Inhibitors Growth and Enhances Radiation Response on Non–Small Cell Lung Cancer (NSCLC) Through ATM and AMPK. Br J Cancer. 2013;108(10):2021-2032.
- Tsakiridis T, Hu C, Skinner H, et al. Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy (CRT) +/- metformin HCL in Locally Advanced Non-Small Cell Lung Cancer (NSCLC). J Clin Oncol. 2019;7(15_suppl):8502-8502.
- Arrieta O, Barron F, Padilla M-AS, et al. Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared with Tyrosine Kinase Inhibitors Alone in Patients with Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: a Phase 2 Randomized Clinical Trial. JAMA Oncol.2019;5(11):e192553.
- Li L, Jiang L, Wang Y, et al. Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: a Randomized, Double-Blind Phase II Trial. Clin Cancer Res.2019;25(23):6967-6975.
- Parikh AB, Kozuch P, Rohs N, et al. Metformin as a Repurposed Therapy in Advanced Non-Small Cell Lung Cancer (NSCLC): Results of a Phase II Trial. Invest New Drugs.2017;35(6):813-819.
- Marrone KA, Zhou X, Forde PM, et al. A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-naïve Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer. Oncologist. 2018;23(7):859-865.
