Association between T-cell LAG-3 expression and clinical benefit in patients with type 2 diabetes and metastatic melanoma treated with immune checkpoint inhibitors.

e14578 Background: Anti-PD-1/anti-LAG-3 combination checkpoint inhibitors, such as nivolumab/relatlimab (nivo/rela), show marked efficacy in treatment of metastatic melanoma. As with all immunotherapy, this success depends in part on the presence of the relevant target receptors on circulating immune cells. Type II diabetes mellitus (T2DM), a disease characterized by inflammation and immune dysregulation, has been observed in limited analyses to be associated with lower LAG-3 gene expression in peripheral blood. We hypothesized that patients with T2DM would also have lower baseline T-cell surface expression of LAG-3 and consequently worse clinical outcomes on nivo/rela. Methods: 90 patients with metastatic melanoma treated with ipilimumab/nivolumab (ipi/nivo) or nivo/rela were identified from the University of Pittsburgh Melanoma Center biospecimen repository. Baseline blood samples were available for 14 patients. Clinical outcomes were obtained via retrospective chart review. Statistical analysis utilized Kaplan-Meier and Cox Proportional Hazard models. Baseline T-cell surface expression of LAG-3 was quantified using flow cytometry. Results: 72% of the overall cohort (n = 65) received ipi/nivo and 28% (n = 25) received nivo/rela. 22% (n = 20) of patients had T2DM. Of those with baseline blood samples, 36% (n = 5) had T2DM. Kaplan-Meier analysis of patients treated with nivo/rela revealed no statistical difference in Overall Survival (p = 0.50) or Progression Free Survival (PFS) (p = 0.36) for patients with T2DM compared to those without. Flow cytometry results also demonstrated no statistically significant difference in baseline T-cell surface expression of LAG-3 in patients with T2DM. In sub-analysis of patients with T2DM, those treated with nivo/rela had significantly longer PFS compared to those treated with ipi/nivo (p = 0.02). Conclusions: Contrary to prior findings, this study demonstrates no difference in baseline T-cell surface expression of LAG-3 among patients with T2DM and indicates that nivo/rela remains an effective treatment option. Data regarding nivo/rela response in melanoma patients with T2DM remains limited. While sample size is limited, our findings support the use of this regimen for patients with T2DM and highlight the need for larger, multicenter studies to better inform treatment guidelines for diabetic patients with metastatic melanoma.