Improved survival with sodium-glucose cotransporter-2 inhibitors and immune checkpoint inhibitors in metastatic solid tumors.

Abstract

2650 Background: Immune checkpoint inhibitors (ICI) are used in the first-line setting for the treatment of many advanced solid tumor malignancies. Patients with type 2 diabetes mellitus (T2DM) have decreased response rates to ICI, and poor glycemic control is associated with worse outcomes in patients with cancer. Further adjunctive therapies increasing the efficacy of ICI in these patients are needed. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as effective antihyperglycemic medications with concomitant cardiovascular benefits. SGLT2i have been approved by the Food and Drug Administration for use in patients with DM and congestive heart failure (CHF). Pre-clinical studies have demonstrated the potential benefit of SGLT2i in slowing tumor growth in-vitro and in-vivo; however, there is a lack of clinical data regarding SGLT2i use in patients with advanced malignancy receiving ICI. Methods: We performed a retrospective, matched cohort study of patients with stage IV malignancy and T2DM or CHF, who were treated with ICI using the Epic Cosmos dataset (2013–2024). Ten different solid tumor types, five ICI, and three SGLT2i were analyzed. Among 4,808 patients treated with ICI, 282 had at least one overlapping cycle of ICI and SGLT2i. 1:1 propensity score matching was conducted to balance baseline covariates including cancer type, comorbidities, age at diagnosis, and sex. Kaplan-Meier curves were generated to examine survival differences and Cox proportional hazards models were used to estimate hazard ratios (HR). The primary outcome was overall survival (OS) for the entire matched cohort and sub-groups by cancer, ICI, and SGLT2i types. Results: Patients who received ICI and SGLT2i had significantly improved OS compared to those who received ICI alone (HR = 0.62, 95% CI: 0.49-0.79). Among cancer types, significant improvements in survival were observed in patients with renal cell carcinoma (RCC, HR = 0.48, 95% CI: 0.27–0.84) and non-small cell lung cancer (NSCLC, HR = 0.60, 95% CI: 0.37–0.96). Among ICI types, ipilimumab + nivolumab (HR = 0.35, 95% CI: 0.15–0.79) and pembrolizumab (HR = 0.49, 95% CI: 0.32-0.74) showed a significant improvement in survival when used with SGLT2i. There was no statistically significant difference in OS amongst the three SGLT2i types. Conclusions: In this retrospective, matched cohort study we observed encouraging improvements in OS in patients with T2DM or CHF receiving SGLT2i in addition to ICI across multiple solid tumor types. Patients with RCC and NSCLC derived the greatest benefit. Patients treated with either ipilimumab + nivolumab or pembrolizumab had the best responses to therapy. SGLT2i may be beneficial as adjunctive therapies in patients with advanced malignancy receiving ICI. However, further prospective studies to validate our observations and determine potential underlying mechanisms are needed.