Management Strategy of 1L Lorlatinib With Hyperlipidemia in Stage IIIB-IV ALK Positive NSCLC

ALK Gene Mutation, ALK-positive, Hyperlipidemia, Non-Small Cell Lung Cancer (NSCLC)

Lorlatinib, ALK-positive NSCLC, Hyperlipidemia, Lipid management, Statin, Ezetimibe, Evolocumab, PCSK9 inhibitor, Real-world study, Randomized controlled trial, Prospective study, Endothelial function, FMD, Multi-center

For Patients and Families Brief Title: Management of 1L Lorlatinib with Hyperlipidemia in ALK+ Advanced NSCLC What is this study about? This study is for people with ALK-positive non-small cell lung cancer (NSCLC) who are taking lorlatinib (Lorbrena®) as their first treatment and have developed high cholesterol (hyperlipidemia) as a side effect. Why is this study needed? Lorlatinib is a highly effective targeted therapy, but it frequently causes elevated cholesterol and triglycerides. There is currently no standard guideline on how to best manage this side effect. This study aims to find the best approach to control lipid levels while on lorlatinib treatment. What will happen in this study? The study has two parts: * Part A (Observational) : About 100 participants. Doctors manage hyperlipidemia according to routine clinical practice. Researchers simply observe and record which lipid-lowering treatments are used and how well they work. * Part B (Randomized Controlled Trial) : 60 participants with high-risk factors are randomly assigned to either: * Intensive treatment: rosuvastatin + ezetimibe + evolocumab * Standard treatment: rosuvastatin + ezetimibe What tests are involved? * Blood tests for lipid levels at baseline, Weeks 4, 8, 20, and 24 * Routine CT or MRI scans for tumor assessment * Some participants in Part B may have a non-invasive vascular ultrasound (FMD) test * Total participation per patient: up to 7 months Is this study safe? * ✅ Approved by the Ethics Committee of Sun Yat-sen University Cancer Center * ✅ All drugs used (lorlatinib, statins, ezetimibe, evolocumab) are already approved and widely used * ✅ An independent Data Monitoring Committee (DMC) monitors safety throughout the study * ✅ Participants may withdraw at any time without affecting their regular care For Healthcare Providers Study Title: Management strategy of 1L Lorlatinib with Hyperlipidemia in Stage IIIB-IV ALK positive NSCLC: A multi-center prospective study in China Sponsor / Investigators: Sun Yat-sen University Cancer Center (PI: Prof. Zhang Li) Study Type: * Part A: Observational, prospective, real-world cohort study * Part B: Prospective, randomized controlled trial (RCT) Estimated Enrollment: 160 participants (Part A: \ 100, Part B: 60) Study Duration: Approximately 4 years (anticipated completion: December 2029) Key Inclusion Criteria: * Stage IIIB-IV ALK+ NSCLC (confirmed by IHC, FISH, PCR, NGS, or ctDNA) * No prior systemic therapy for advanced/metastatic disease * ECOG PS 0-2 * Age ≥ 18 years * Hyperlipidemia (ULN ≤ TC \< 12.93 mmol/L, Grade 1-3) while on first-line lorlatinib * At least one measurable lesion per RECIST v1.1 * Life expectancy ≥ 6 months Primary Endpoints: * Part A: Describe real-world treatment patterns for hyperlipidemia management * Part B: Percentage change in LDL-C from baseline to Week 12 Oversight: * Independent Data Monitoring Committee (DMC) * Trial Management Committee * Ethics Committee of Sun Yat-sen University Cancer Center (Approval No. B2026-159-01) Participating Centers: 8 sites across China

Lorlatinib, a third-generation ALK-TKI, has demonstrated remarkable efficacy as first-line treatment for ALK-positive advanced NSCLC, with a 5-year PFS rate of 60% in the CROWN study. However, hyperlipidemia is the most common adverse event - hypercholesterolemia occurs in 72% and hypertriglyceridemia in 66% of patients. Despite this, no standardized lipid management guidelines exist specifically for the lorlatinib treatment context. This study addresses this gap through a dual-part design conducted across 8 sites in China. Part A documents real-world hyperlipidemia management patterns in routine clinical practice. Part B is a randomized controlled trial comparing intensive versus standard lipid-lowering strategies in patients with high-risk factors who develop hyperlipidemia on first-line lorlatinib. To address ethical review feedback, the protocol was revised from V1.1 (Dec 15, 2025) to V1.2 (Apr 7, 2026), with revisions including correcting the reversal of primary endpoints between Part A and Part B, expanding inclusion/exclusion criteria in the synopsis, removing "tissue donation" language from the ICF, and refining FMD testing requirements. Patient follow-up extends up to 60 months post-enrollment for survival data.

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