Arterial and venous thromboembolic events in ALK - and ROS1 -positive non–small cell lung cancer (NSCLC): A multicenter real-world analysis.

e23419 Background: Current risk assessment for cancer-associated thrombosis remain suboptimal in NSCLC, likely due to unaccounted tumor-specific biology. Although ALK and ROS1-positive NSCLC share closely related structure and elevated thrombotic risk, real-world data on thromboembolic outcomes remain limited. Methods: This multicenter retrospective study was conducted using TriNetX, a global federated health research network;14 of 113 healthcare organizations contributed to analysis. Adults (≥18 years) with NSCLC ROS1 or ALK from 2012-2025 were included. Index event was defined as the first documented NSCLC diagnosis. Outcomes included cumulative incidence, Kaplan–Meier survival analysis (KMS), and event recurrence for arterial thromboembolism (ATE), deep vein thrombosis (DVT), and pulmonary embolism (PE). Analyses were conducted pre and post-propensity score matching (PSM) adjusted for age and sex. Subgroup analyses evaluated outcomes at 1, 3, 6, and ≥12 months. Results: 3,310 NSCLC patients were identified (ALK n=3,155; ROS1 n=155). Mean age was 73 years, with 52.8% female and 46.2% male; 72.5% White, 12.7% Black, 9.5% Asian; South (49%), Northeast (29%). ALK NSCLC were older than those with ROS1 (mean 68.9 vs 64.6 years, p<0.0001), with similar sex distribution. ROS1 had higher proportion of White (85% vs 72%), while ALK included more Asian and Black. Median follow-up prior to matching was 482 days for ROS1 (post-PSM:482) and 546 days for ALK (post-PSM:601) Incidence proportions in ROS1 NSCLC were 12.3% for ATE, 9.7% for DVT, and 12.9% for PE (vs. ALK: 22.6% for ATE, 12.5% for DVT, 11.8% for PE) For ATE, prior to PSM, ROS1 NSCLC demonstrated a significantly lower risk compared with ALK (16.6% vs 25.0%), with an absolute risk difference of −8.4% (95% CI −14.7 to −2.2; p=0.02) and relative risk of 0.66 (95% CI 0.46–0.96). KMS showed longer ATE-free survival in ROS1 compared to ALK (48.2% vs 44.5%, p=0.01; HR 0.60, 95% CI 0.40–0.91, p=0.04). After PSM, overall ATE risk difference did not reach statistical significance, although ROS1 continued to demonstrate lower risk (16.6% vs 25.8%; risk difference −9.2%, p=0.06). Notably, in the subgroup analyses, this significant risk difference emerged ≥12 months, with improved late ATE-free survival in ROS1(91.1% vs 80.3%, p=0.01). For VTE and PE, no significant differences in risk, survival analyses or recurrence, were observed between ROS1 and ALK before or after PSM (DVT risk: 9.2% vs 9.7% pre-PSM; 9.2% vs 10.1% post-PSM; PE: 11.2% vs 9.9% pre-PSM; 11.2% vs 8.6% post-PSM; all p>0.05). Conclusions: Arterial thromboembolism differed by oncogenic subtype, with higher ATE risk in ALK compared with ROS1-positive NSCLC, particularly ≥12-months. In contrast, no significant difference in venous thromboembolism and pulmonary embolism were observed; further validation in prospective studies is warranted.