Role of iron supplementation in the efficacy of immune checkpoint inhibitors (ICIs): A real-world propensity-matched analysis.

11131 Background: Iron plays a crucial role in the induction of ferroptosis mediated by immune checkpoint inhibitors (ICIs) in cancer. However, it plays a complex role in T-cell and macrophage function in the tumor immune microenvironment, which could influence anti-cancer immunity. Currently, the role of iron supplementation in affecting the therapeutic outcomes in patients receiving ICIs is unknown. Methods: A retrospective analysis utilizing TriNetX, a global federated health research network database, of patients receiving ICIs from January 2006 to January 2026, was conducted. Patients were divided into 3 cohorts based on whether they received intravenous (IV) iron (cohort A), oral (PO) iron (cohort B), or no iron supplementation (cohort C), 1 month prior to or up to 3 months after receiving ICIs. Propensity score matching (PSM) was used to balance the cohorts based on age, race, ethnicity, hemoglobin (Hb), ferritin, CRP, albumin, metastatic disease, line of treatment and underlying comorbidities. Kaplan-Meier analyses were used to analyze overall survival (OS). Results: A total of 4464, 5299, and 201,014 patients were identified across cohorts A, B and C, respectively. The most common primary sites of malignancies were the lung and/or bronchus, the gastrointestinal tract (and associated glands), and the urinary tract. Although IV iron recipients had better survival outcomes than PO iron recipients, both groups had worse outcomes than patients receiving no supplementation (Table 1). Similar trends were seen in subgroups receiving anti-PD1 and anti-PDL1. In the subgroup of patients with likely true iron deficiency (Hb≤11g/dl and ferritin<100ng/ml) ( n =508 after PSM), IV iron recipients had better outcomes than PO iron recipients (2Yr OS HR (95% CI): 0.822 (0.691,0.978) p=0.027). In the subgroup of patients having Hb≤11g/dl and ferritin≥300ng/ml, likely anemia of chronic disease ( n =2483 after PSM), iron supplement recipients, whether IV or PO, had worse survival outcomes than patients receiving no supplementation (2Yr OS HR (95% CI): 1.22 (1.137,1.308) p<0.0001). Conclusions: Our study highlights the adverse impact of concurrent iron supplementation in patients receiving ICIs, especially in those without true iron deficiency. When clinically indicated, the IV route is preferred. Clinical studies are planned or ongoing to determine the role of iron supplementation in patients receiving ICIs, given its potential to induce ferroptosis. We suggest careful reconsideration or appropriate stratification of the cohort based on iron deficiency and/or type of iron supplementation in such studies. 2-year overall survival (OS). Comparison groups Number of patients after PSM 2-Year OSHR (95% CI) p-value (log-rank test) IV Iron v/s PO Iron 2762 0.898 (0.83,0.97) p=0.006 IV Iron v/s No Iron 3808 1.199 (1.121,1.283) p<0.0001 PO Iron v/s No Iron 5210 1.405 (1.327,1.488) p<0.0001