Call to Action: Investigation of Metformin as Adjunctive Therapy to Immunotherapies in Non-Small Cell Lung Cancer

The field of oncology has come a long way since 1986, when the first immunotherapy, interferon-alpha 2 (IFN-a2), was introduced.¹ Today, immunotherapy appears in therapeutic plans for many tumor types.²

However, response as measured by progression-free survival (PFS) and/or overall survival (OS) for many tumor types shows there is still significant room for improvement.³ One area of study for improvement is the addition of supportive medications that may synergize with immunotherapy in a similar manner to that of leucovorin and 5-fluorouracil.⁴

One such opportunity is the addition of the anti-diabetic medication, metformin, to immunotherapy, specifically to anti-PD-1 or anti-PD-L1 agents. Recently, phase 2 trials carried out on the back of preclinical studies in animals have demonstrated improvement in response to immunotherapy treatment.

However, currently there is inadequate evidence to support a category 1 recommendation for metformin’s addition to cancer treatment, but as we describe below, there are significant reasons for enthusiasm for this combination of agents.

Metformin is an antihyperglycemic medication used in the management of type 2 diabetes. It has been shown to decrease hepatic gluconeogenesis while also increasing glucose reuptake via activation of adenosine monophosphate protein kinase (AMPK), a master regulator for many metabolic pathways.

By activating this pathway, metformin has shown anti-neoplastic activity by depriving tumor cells of oxygen.⁵ Importantly, this medication has also been shown to decrease pro-inflammatory cytokines that appear to improve the immune response to tumor cells and improve the efficacy of immunotherapy.⁶

Lung cancer is the second most common cancer diagnosis in the United States today, and our home state, Kentucky, has the highest lung cancer mortality rate in the nation, leading to 25% of cancer deaths among men and women.⁷

According to the National Foundation for Cancer Research, non-small cell lung cancer (NSCLC) accounts for nearly 90% of lung cancer diagnoses, but is often not detected until the later stages of disease progression.⁸ In 2019, researchers set out to determine whether metformin would be a beneficial addition to NSCLC therapy.

The trial design was a phase 2, single blind, open-label study with a single group. Nivolumab was immunotherapy of interest and with addition of metformin.

The primary outcome was objective response rate (ORR) in patients treated with nivolumab and metformin based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. However, after 17 patients were added to the study in September 2019, the trial was suspended without results being posted.

It is also unclear as to why the trial was suspended, but there were several adverse events reported in this study, including death, disease progression, and mortality from other causes.³ Therefore, a gap in evidence still exists as to whether the addition of metformin to immunotherapy can improve OS and PFS for patients assigned to immunotherapy.

To determine the utility of metformin as an addition to immunotherapy in NSCLC treatment, we suggest that a phase 3, parallel, randomized, controlled, single center, single-blind study be carried out that compares the standard of care alone (immunotherapy/pembrolizumab) to pembrolizumab with addition of metformin in stage III and stage IV NSCLC.

The primary objective of this study would be to determine whether the addition of metformin to pembrolizumab is superior to current standard of care with the goal of measuring OS. Diabetic patients and those with targetable mutations would be excluded from this to eliminate any confounding factors.

Patients previously treated with immunotherapies and/or metformin will also be excluded. Patients will be eligible for the study if they have a new diagnosis of NSCLC with metastases and PD-L1 expression ≥ 1% using local pathology results.

Although lung cancer cases among men have been consistently dropping, there are more than 130,000 deaths annually calling for action in treatment options past those of targeted therapies.⁹ We believe there is a need for further clinical research to evaluate metformin use in NSCLC patients treated with immunotherapy, and the proposed trial is worth consideration.

It is crucial to continue advancements in oncology research to improve survival outcomes in these patients and improve health outcomes in this area. In the absence of new medications to treat metastatic NSCLC, exploring the use of FDA-approved medications, in addition to the current treatment regimens for patients with NSCLC, may provide value.

Metformin has a desirable adverse effect profile, and the proposed activity against cancer makes it an ideal adjunct to current standard of care therapy. In addition, metformin can be obtained at a relatively low cost, which would make this addition more financially feasible for patients with NSCLC. We conclude by challenging clinical researchers to continue to develop well-constructed clinical trials to investigate the rational addition of agents to improve response to immunotherapies in NSCLC treatment.

References

1. Eno, J. (2017). Immunotherapy through the years. Journal of the advanced practitioner in oncology. Retrieved June 7, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188092/
2. Immunotherapy by cancer type. Cancer Research Institute. (n.d.). Retrieved June 7, 2022, from https://www.cancerresearch.org/en-us/immunotherapy/cancer-types
3. Northwestern University. (2017, February 9). Nivolumab and metformin hydrochloride in treating patients with stage III-IV non-small cell lung cancer that cannot be removed by surgery. Study Results - ClinicalTrials.gov. Retrieved June 7, 2022, from https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclinicaltrials.gov%2Fct2%2Fshow%2Fresults%2FNCT03048500%3Fterm%3Dmetformin%252C%2Bimmunotherapy%26cond%3Dlung%2Bcancer%26draw%3D2%26rank%3D1&data=05%7C01%7CStevee.Candrl%40uky.edu%7Cc9b1fe525cc5459bd60508da2d080de2%7C2b30530b69b64457b818481cb53d42ae%7C0%7C0%7C637871809866947642%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=PzHIFNTehZBDjWdgoYwQmrz%2BIpUVjIOfPcRuOTRWydk%3D&reserved=0
4. Tsujimoto, H., Tsukioka, S., Ono, S., Sakamoto, E., Sakamoto, K., Tsuta, K., Nakagawa, F., Saito, H., Uchida, J., Kiniwa, M., & Fukushima, M. (2010, September 17). Effect of leucovorin on the antitumor efficacy of the 5-fu prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncology letters. Retrieved June 7, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412464/
5. WU N, GU C, GU H, HU H, HAN Y, LI Q. Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153. Neoplasma. 2011;58(6):482-490. doi:10.4149/neo_2011_06_482
6. Aljofan, M., & Riethmacher, D. (2019, August 22). Anticancer activity of Metformin: A systematic review of the literature. Future science OA. Retrieved June 1, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC674 (Alifan, 2019)5597/
7. Lung cancer statistics: How common is lung cancer? American Cancer Society. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed June 1, 2022.
8. Ciupka, B. (2020, November 3). Small cell lung cancer vs. non-small cell lung cancer: What's the difference? NFCR. Retrieved June 7, 2022, from https://www.nfcr.org/blog/small-cell-lung-cancer-vs-non-small-cell-lung-cancer-whats-the-difference/
9. Lung cancer - non-small cell - statistics. cer.Net. https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics. Published April 14, 2022. Accessed June 6, 2022.