Hyperlipidemia as adverse event of lorlatinib, a multicenter cohort study.

Abstract

e24040 Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK mutations, has shown superior efficacy in patients with advanced non-small cell lung cancer (aNSCLC) harboring ALK fusion mutations. Hyperlipidemia is the most common drug-related adverse event with lorlatinib. However, data concerning detailed hyperlipidemia management is scarce. Methods: Patients with ALK+ aNSCLC who received lorlatinib as first or later line treatment were enrolled. Blood lipid test results at baseline, before and after lipid-lowering drugs were retrospectively collected. Treatment outcomes were evaluated as per RECIST 1.1, including partial response (PR) , stable disease (SD), etc. Follow-up of cardiovascular events and death was also collected. Results: We enrolled 120 aNSCLC patients treated with lorlatinib from 15 medical centers in China. Hyperlipidemia occurred in 96 cases (including 19 at baseline) within 3 months of lorlatinib treatment. Among them, the incidence of hypercholesterolemia was 88.5% (85/96), hypertriglyceridemia was 86.5% (83/96) [of which 40/83 were grade 1, 27/83 were grade 2, 11/83 were grade 3, and 5/83 were grade 4 (one of them developed acute pancreatitis, the highest value in our cohort, 39.02 mmol/L), and there was no grade 5], elevated LDL-C incidence 70.8% (68/96), HDL-C decrease incidence 5.2% (5/96). Seventy-five patients had documented use of at least one lipid-lowering drug. Among them, statins were most frequently used in 64 cases (85.3%) when resuvastatin was most frequently used (40/64, 62.5%), followed by ezetimibe (13/75, 17.3%), fenofibrate (12/75, 16%), and PCSK9 inhibitors (3/75, 4%). 24 (32%) patients were on a combo of two or more lipid-lowering drugs, with the most common being ezetimibe + statins (13/27, 48.1%). After 3 months of using lipid-lowering drugs, most patients did not reach normal lipid levels (59/75, 78.7%). Different lipid-lowering drugs did not affect the lipid-lowering effect ( p = 0.364). There was no association between treatment outcomes and total cholesterol levels (7.91±2.28 mmol/L in PR, 8.37±3.66 mmol/L in SD, p = 0.477) or triglyceride levels (4.24±3.50 mmol/L in PR, 5.31±7.03 mmol/L in SD, p = 0.342). Five cases developed cardiovascular events, but none of them led to death. Of the 6 deaths in our cohort, 5 died of disease progression; 1 cause of death was not clearly documented. Conclusions: Hyperlipidemia had high incidence in real world use of lorlatinib, predominantly grade 1-2 hypercholesterolemia and hypertriglyceridemia, while no grade 5 cardiovascular events had been observed. Different lipid-lowering drugs did not significantly affect the lipid-lowering effect. No association was observed between treatment outcomes and blood lipid levels. A prospective clinical trial [Trial Registration Number: ChiCTR2400092915] is ongoing to evaluate lorlatinib-associated hyperlipidemia on cardiovascular events and long-term survival.