Association of PCSK9 inhibitors with clinical outcomes in patients with cancer receiving immune checkpoint inhibitors: A real-world analysis.

Abstract

2657 Background: Although developed as lipid-lowering agents, PCSK9 inhibitors (PCSK9i) have shown preclinical potential to synergize with immune checkpoint inhibitors (ICIs) by increasing tumor antigen presentation and overcoming ICI resistance. However, there is limited evidence describing their use and associated outcomes in real-world oncology practice. We aimed to explore the clinical outcomes in relation to PCSK9i use in patients with cancer receiving ICIs. Methods: This propensity score-matched (PSM) cohort study utilized the TriNetX research network, encompassing real-time electronic health records from > 70 U.S. healthcare organizations. The study population included adults (aged ≥18 years) diagnosed with non-small cell lung cancer, melanoma, renal cell carcinoma, or breast cancer, who underwent concurrent ICI therapy (e.g., pembrolizumab, nivolumab, atezolizumab, durvalumab) plus PCSK9i (e.g., evolocumab, alirocumab; with or without statins) or high-intensity statins alone (atorvastatin ≥ 40 mg, or rosuvastatin ≥ 20 mg) between 01/01/2011 (the earliest year of ICI approval) and 01/01/2025 for hyperlipidemia. The primary outcome was overall survival (OS). Secondary outcomes included emergency room (ER) visits, all-cause hospitalization, ICU admission, and 4-point (acute myocardial infarction, heart failure, stroke, and unstable angina) major adverse cardiovascular event (MACE). A 1:1 PSM was applied to balance potential confounders, including demographics, socioeconomic status, cancer site, Charlson-Comorbidity-Index comorbidities, and laboratory parameters [Albumin, LDL, AST/ALT, and BMI]. Time-to-event analyses were performed using Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with log-rank test for significant survival differences. Follow-up began at the initiation of concurrent ICI plus PCSK9i or statin and continued until 01/05/2025, or until the occurrence of the study outcomes. Results: A total of 254 patients in PCSK9i cohort were matched to 254 patients from the statin-only cohort (n = 13734). Patients receiving PCSK9i demonstrated significantly improved OS compared with those receiving statins alone (HR 0.67, 95% CI 0.52-0.88) and associated with lower risk of ER visits (HR 0.64, 95% CI 0.49-0.83), hospitalization (HR 0.68, 95% CI 0.54-0.85), and ICU admission (HR 0.69, 95% CI 0.50-0.95; all p<0.01). No significant difference was observed for MACE outcomes (HR 0.79, 95% CI 0.59-1.07, p=0.13). Conclusions: In this large, real-world analysis, the use of PCSK9i in patients with cancer and hyperlipidemia treated with ICIs was associated with improved overall survival and reduced healthcare utilization. These findings support ongoing prospective clinical trials evaluating the potential synergistic effects of PCSK9 inhibition with ICI therapy.