Real-world Patterns of Hyperlipidemia and Cardiometabolic Toxicity in Patients with ALK-fusion- Positive NSCLC Treated with Lorlatinib.

e20724 Background: Lorlatinib is highly effective for ALK-rearranged NSCLC but is associated with hyperlipidemia (HLD) and metabolic complications. Real-world data on the severity, timing and management of cardiometabolic consequences remain limited. Methods: Patients (pts) with ALK-rearranged NSCLC treated with lorlatinib at Rush University Medical Center from 2017–2025 were identified via prescription records. Clinical and laboratory data, including lipid profiles and lipid-lowering therapy use or intensification, were collected to identify severe HLD and cardiovascular events. Protocol was approved by IRB. Results: Thirty-seven pts started lorlatinib with median age of 59.8 years. Most were White (n=22, 59.5%) and had never used tobacco (n=25, 67.6%); 18 (48.6%) were female. Eleven pts died during the assessment period. Among pts with baseline or first on-treatment lipid values ≤14 days, HLD occurred early (median 85 days, table); total cholesterol (CHL) and LDL increased within 2–12 weeks (median change +60.5 mg/dL and +58.0 mg/dL respectively). Triglycerides (TG) increased from 131 to 258 mg/dL (median +136 mg/dL; p=0.04) while HDL remained stable. LDL showed a significant time-dependent increase of 32.9 mg/dL per 4 weeks (95% CI 16.5–49.3; p<0.001) in the first 3 months. CHL, TG and HDL showed greater variability with non-significant slopes. Among pts not on baseline lipid-lowering therapy, 17.2% (n=5) initiated statins within 90 days; PCSK9 inhibitors were used in 4 (10.8%). Coronary events (CAD/MI) and stroke/TIA occurred in 9 and 11 pts respectively. HLD frequently co-occurred with stroke/TIA (p=0.02, OR 5.8). Conclusions: Lorlatinib was associated with early, clinically meaningful increases in atherogenic lipids, particularly LDL, with delayed vascular and cardiac complications. Lipid derangements may be associated with downstream cerebrovascular risk, supporting early and systematic lipid monitoring with proactive cardio-oncology–guided risk mitigation. Analyte Paired N Baseline Median (IQR), mg/dL 2–12 Week Median (IQR), mg/dL Median Change (IQR), mg/dL Wilcoxon p-value Mixed-Effects Change per 4 Weeks (95% CI), mg/dL Mixed-Effects p-value Total Cholesterol 8 185 (178.2–217.8) 241.5 (209.5–313.2) +60.5 (−3.8 to 130.5) 0.24 +30.1 (−18.3 to 78.7) 0.22 LDL 5 111 (88–116) 152 (151–210) +58 (35–99) 0.13 +32.9 (16.5 to 49.3) <0.001 Triglycerides 8 131 (95.8–212.3) 258.5 (190.8–351) +136 (28.5 to 253) 0.04 +121.1 (−50.5 to 292.8) 0.17 HDL 8 49.5 (41.8–57.5) 47 (40.8–52) −2.5 (−8.3 to 4) 0.8 −1.1 (−6.3 to 4) 0.67 Outcome Baseline diagnosis n/N (%) Incident after lorlatinib n/N (%) Median time to incident days (range) Hyperlipidemia 10/37 (27.0%) 13/27 (48.1%) 85 (25–350) Coronary event 5/37 (13.5%) 9/32 (28.1%) 356 (27-2092) Stroke/TIA 10/37 (27.0%) 11/23 (47.8%) 301 (18–1619) Peripheral arterial disease 5/37 (13.5%) 2/32 (6.2%) 748 (136–1360)