(A-085) Association Between Metformin Use and Mortality Among Individuals With Non-Small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors: A Retrospective Cohort Study

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. While immune checkpoint inhibitors (ICIs) have improved outcomes, response rates remain low, and identifying factors influencing effectiveness is critical. Metformin, a widely used type 2 diabetes mellitus (T2DM) medication, has shown potential immunomodulatory effects in preclinical studies, but its impact on ICI outcomes in NSCLC is unclear.

Objectives: To evaluate the association between prevalent metformin use prior to ICI initiation and cancer-specific and all-cause mortality among individuals with NSCLC.

Methods: This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 2013 to 2019, and included patients who had NSCLC diagnosis, initiated ICI therapy, and had a T2DM diagnosis with prior metformin or other diabetes medication use. Patients were required to have continuous coverage in fee-for-service Medicare for at least one year before ICI initiation, with a washout period excluding prior ICI use. The exposure group was prevalent metformin monotherapy users, while the comparator group was patients using sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, or both, without metformin use. The primary outcome was cancer-specific mortality and secondary outcome was all-cause mortality. We used inverse probability of treatment weighting (IPTW) to adjust for confounders, and Fine-Gray competing risk model to estimate cancer-specific mortality, and Cox proportional hazards model to assess all-cause mortality.

Results: The study included 1,485 NSCLC patients (1,123 metformin users; 362 sulfonylurea/DPP-4 users). Metformin users were younger (75.8 vs. 77.6 years, standardized mean difference (SMD)= -0.32) with fewer comorbidities (National Cancer Institute comorbidity index, 1.0 vs. 1.2, SMD = -0.35). However, all characteristics were well balanced after IPTW. The unadjusted cancer-specific incidence rate was 61 vs. 62 per 100 person-years among metformin users and sulfonylurea/DPP-4 users, respectively. Likewise, the all-cause mortality incidence rate was 70 vs. 68 per 100 person-years among metformin and comparator group. In the IPTW adjusted regression models, metformin was not associated with the risk of cancer-specific mortality (adjusted hazard ratio (aHR), 1.07; 95% CI, 0.87–1.32), and all-cause mortality (aHR, 1.07; 95% CI, 0.90–1.26).

Conclusions: In this study of a large, diverse population of individuals with NSCLC, there was no association between prevalent metformin use and either cancer-specific or all-cause mortality among ICI users.