Synergistic prognostic effect of the renin‐angiotensin‐aldosterone system and immune‐checkpoint inhibition in advanced lung cancer: The <scp>SPERICIL</scp> study

Preclinical studies revealed that renin-angiotensin-aldosterone system inhibitors (RAASi) may exhibit synergistic effects with immune-checkpoint inhibitors (ICIs). Although limited clinical data support this synergy, the findings in lung cancer remain inconsistent. This study investigated the synergistic prognostic effect of concomitant RAASi use in patients with advanced lung cancer treated with ICIs. In this retrospective observational study, patients with advanced lung cancer who received ICIs between July 2018 and August 2024 were analyzed. Patients were dichotomised according to RAASi use. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS) and tumor response parameters. Cox regression analyses were performed to identify variables associated with OS and PFS. A total of 286 patients were included, among whom 94 (33%) received concomitant RAASi. The baseline characteristics of the two groups were relatively comparable. The RAASi user group demonstrated a significantly longer median OS (17.47 months vs. 10.02 months, p = 0.001) and PFS (8.31 vs. 3.84 months, p = 0.008) compared to the RAASi non-user group. Multivariate analysis demonstrated that concomitant RAASi use was an independent predictor for OS (HR: 0.58; 95% CI, 0.43-0.80, p = 0.001). Although concomitant RAASi use was not an independent predictor for PFS, a trend toward statistical significance was observed (HR: 0.76; 95% CI, 0.57-1.00, p = 0.055). Our retrospective study demonstrated that the concomitant use of RAASi is associated with improved survival outcomes in patients with advanced lung cancer receiving ICIs. These findings suggest a potential therapeutic synergy that warrants further validation in prospective clinical trials.