Abstract 5947: Efficacy and safety of lorlatinib in first-line and later-line treatment for Chinese patients: a real-world study with retrospective and prospective bidirectional cohorts

Abstract Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Lorlatinib, a third-generation ALK inhibitor, is an important treatment for ALK-positive NSCLC. Hyperlipidemia is a common side effect, but its mechanism is not well understood. This study evaluates the efficacy and safety of lorlatinib in the Chinese population and explores the mechanisms of hyperlipidemia. Method: This study included ALK-positive advanced NSCLC patients treated with lorlatinib between February 2020 and September 2024 at the Cancer Hospital of the Chinese Academy of Medical Sciences. Patients received lorlatinib either as first-line or later-line therapy. Data collected covered demographics, treatment efficacy (ORR, DCR), and survival outcomes using the Kaplan-Meier method. Safety analyses, focusing on hyperlipidemia, were performed with Fisher's exact test. Result: This study included 63 ALK-positive advanced NSCLC patients, with 26 on first-line and 37 on later-line lorlatinib treatment. Most patients were female (55.6%), nonsmokers (66.7%), and had an ECOG score of 0-1 (98.4%). The median age was 57, and adenocarcinoma was the predominant type (87.3%). The median follow-up was 9.86 months. For first-line patients, the ORR was 85.7%, DCR was 100%, and the 12-month PFS rate was 94.4%, with median PFS not yet reached. For later-line patients, the ORR was 26.7%, DCR was 86.7%, and the 12-month PFS rate was 60.3%, with median PFS also not reached. Among 28 patients with baseline brain metastases (6 on first-line and 22 on later-line therapy), the intracranial ORR was 41.7%, DCR was 100%, and the median intracranial PFS was 30.59 months. The study found that all patients experienced hypercholesterolemia, with most also developing hypertriglyceridemia. Common side effects included peripheral edema, CNS effects, hypertension, weight gain, neuropathy, and joint pain. One patient discontinued lorlatinib due to grade III proteinuria. Patients without brain metastases had milder hypercholesterolemia, while severe hypercholesterolemia was more common in those with brain metastases (37.04% vs. 12.50%, P=0.03). Lipid metabolism testing in 12 patients (5 with brain metastases) showed no significant differences in enzyme levels between patients with and without brain metastases. However, patients on lipid-lowering therapy (n=9) had significantly improved LPL activity compared to untreated patients (n=3) (t=2.69, P=0.038), confirming the effectiveness of lipid-lowering therapy. Conclusion: Lorlatinib shows strong efficacy for ALK-positive advanced NSCLC, with median PFS not yet reached in both first-line and later-line settings. Hyperlipidemia was common, especially in patients with brain metastases, and lipid-lowering therapy improved LPL activity. Further research into lipid metabolism mechanisms is underway. Citation Format: Jiayu Liu, Xin Zhang, Puyuan Xing, Junling Li. Efficacy and safety of lorlatinib in first-line and later-line treatment for Chinese patients: a real-world study with retrospective and prospective bidirectional cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5947.