Metformin Appears to Fight Lung Cancer-But Only in Overweight or Obese Patients, reveals study

A widely accessible drug commonly used to control blood glucose levels in diabetic patients has the potential to strengthen the effects of immunotherapy and improve recurrence-free survival in people with lung cancer who are overweight or obese, new research published in the Journal of the National Cancer Institute shows. Sai Yendamuri, MD, MBA, FACS, Chief Strategy Officer and Chair of Thoracic Surgery at Roswell Park Comprehensive Cancer Center, led the retrospective study as co-senior author.

Over the past 20 years, researchers have seen evidence suggesting that metformin might slow cancer progression, but the results of clinical trials have largely failed to confirm the connection. Based on prior findings, Dr. Yendamuri and his colleagues from Roswell Park hypothesized that the anticancer benefits of the drug might be experienced in a specific group of lung cancer patients-Diabetes Drug Appears to Fight Lung Cancer-But Only in Overweight or Obese Patientsthose who are overweight or obese. They further suspected that strong evidence of these effects may have been obscured in past clinical trials that included normal-weight patients.

To test that theory, the team looked at data from two groups of patients who had non-small cell lung cancer (NSCLC). One group included 511 patients with a body mass index (BMI) of 25 or higher, considered overweight/obese, and 232 with a BMI of less than 25, not considered overweight-all of whom underwent surgery. Data from a second group were used to evaluate the drug’s effect on progression-free survival in 284 overweight vs. 184 non-overweight patients with NSCLC who received a type of immunotherapy called an immune checkpoint inhibitor. Additionally, the team documented metformin’s effects on tumor progression, antitumor immunity and response to immune checkpoint inhibitors in the lab in preclinical lung cancer models.

“Our work shows that the anticancer effect of metformin is active only in the context of obesity,” says Dr. Yendamuri. “We observed longer recurrence-free survival in overweight patients who took metformin and underwent surgery.”

The preclinical studies in animal models showed that metformin slowed tumor growth and reversed obesity-driven suppression of the immune system. Combined treatment with metformin plus an immune checkpoint inhibitor (anti-PD-1 antibody therapy) achieved even better tumor growth control — but this effect was essentially seen only in obese models, paralleling the improved progression-free survival seen only in overweight patients receiving immune checkpoint inhibitors.

Joseph Barbi, PhD, Assistant Professor of Oncology in Roswell Park’s Department of Immunology, and co-senior author on the new work, adds that the team’s findings show that in obese or overweight patients, metformin appears to shift the balance between immune-suppressing mechanisms and those that activate tumor-killing processes.

“By calling attention to the potential of metformin-containing treatment regimens to improve clinical outcomes for obese and overweight patients, we hope to inspire future studies,” says Dr. Barbi. “We believe our findings provide a rationale for testing drug combinations that might have the potential for preventing or treating lung cancer more effectively in this growing pool of patients.”

Based on their clinical and preclinical observations, Drs. Yendamuri and Barbi designed a phase 2 clinical trial (NCT04931017) to evaluate the drug’s potential for preventing lung cancer in overweight or obese people at high risk for the disease. Roswell Park is one of only three sites in the U.S and Canada to offer the trial, which is funded by the National Cancer Institute.

“Metformin has been used for 30 years and has a long record of safety-and it’s one of the most widely accessible and affordable drugs of any kind,” says Dr. Yendamuri. “If we can repurpose it to fight cancer, that’s very exciting.”

Reference:

Randall J Smith, Robert Zollo, Sukumar Kalvapudi, Yeshwanth Vedire, Akhil Goud Pachimatla, Cara Petrucci, Garrison Shaller, Deschana Washington, Vethanayagam Rr, Stephanie N Sass, Aravind Srinivasan, Eric Kannisto, Sawyer Bawek, Prantesh Jain, Spencer Rosario, Joseph Barbi, Sai Yendamuri, Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin, JNCI: Journal of the National Cancer Institute, 2024;, djae295, https://doi.org/10.1093/jnci/djae295