Abstract Body (Do not enter title and authors here): Introduction:
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is crucial in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). It exerts its effect by selectively binding to mutant EGFR and inhibiting downstream signaling pathways involved in cell proliferation and survival. However, emerging evidence has raised concerns about its potential cardiovascular toxicity. This meta-analysis evaluates the incidence and relative risk of cardiac adverse events in NSCLC patients treated with Osimertinib.

Methods:
We conducted a comprehensive literature search using MEDLINE and EMBASE databases from inception through May 31st, 2025. Phase III randomized controlled trials (RCTs) utilizing Osimertinib in NSCLC reporting cardiac adverse events were included. The Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. The random effects model was applied.

Results:
A total of 2,863 patients from six phase III RCTs (MARIPOSA n=849, LAURA n=216, AURA3 n=415, FLAURA n=556, ADAURA n=680, NCT02959749 n=147) were included in the analysis. QT prolongation of any grade occurred in 4.83% of patients receiving Osimertinib versus 1.50 % in controls (RR 3.32; 95% CI: 2.06-5.34; P<0.00001). High-grade QT prolongation was reported in 1.24% of the Osimertinib group compared to 0.30% of the control group (RR 3.25; 95% CI: 1.16-9.12; P=0.02 ). Any grade of decreased ejection fraction was documented at 2.35 % in the Osimertinib arm versus 1.05 % in the control arm (RR 2.25; 95% CI: 1.23-4.11; P=0.008). The incidence of high-grade cardiac failure in the Osimertinib groups was 1.70% compared to 0.53% in the control groups (RR 3.02; 95% CI: 1.32-6.95; P=0.009). There was no statistically significant difference in the incidence of high-grade decreased ejection fraction (0.85% vs. 0.15%; RR 3.40; 95% CI: 0.95–12.15; P=0.06) and high-grade pericardial effusion (0.33% vs. 0.38%; RR 1.01; 95% CI: 0.31–3.28; P=0.98).

Conclusions:
This study demonstrated a higher risk of QT prolongation, reduced ejection fraction, and high-grade cardiac failure with Osimertinib versus placebo or other standard therapies, highlighting the need for careful cardiac monitoring for early recognition and intervention to improve quality of life and clinical outcomes.