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

Management Strategy of 1L Lorlatinib With Hyperlipidemia in Stage IIIB-IV ALK Positive NSCLC: A Multi-center Prospective Study in China

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

Study Overview

• Status: Not yet recruiting
• Conditions: Hyperlipidemia; Non-Small Cell Lung Cancer (NSCLC); ALK Gene Mutation; ALK-positive
• Intervention / Treatment: Drug: For Part A - Observational Cohort:; Drug: For Part B - Intensive Group; Drug: Part B: Intensive Lipid-Lowering Group

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 160

Contacts and Locations

• Study Contact: Name: Li Zhang; Phone Number: 020-87343458; Email: Zhangli6@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center
      • Contact: Li Zhang; Phone Number: 020-87343458; Email: Zhangli6@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients (≥ 18 years) with histologically or cytologically confirmed Stage IIIB-IV ALK-positive non-small cell lung cancer (NSCLC) who are receiving first-line lorlatinib and have developed hyperlipidemia (ULN ≤ TC < 12.93 mmol/L, Grade 1-3). Participants are recruited from 8 study centers across China.

For Part B specifically, patients must additionally have at least one prior major ASCVD event or baseline LDL-C ≥ 4.9 mmol/L with high-risk factors (premature CAD, familial hypercholesterolemia, CABG/PCI history, diabetes, hypertension, CKD stage 3-4, or current smoking).

Description

Inclusion Criteria:• Inclusion Criteria (Part A and Part B)

Subjects must meet all of the following inclusion criteria to be eligible for enrollment (Part A and Part B):

1. Diagnosis:

   1. Histologically or cytologically confirmed locally advanced [defined as Stage IIIB/C per AJCC v7.0 and not amenable to multimodality treatment] or metastatic (Stage IV) ALK-positive NSCLC; ALK status must be confirmed by Ventana ALK (D5F3) Companion Diagnostic (CDx) IHC (Ventana ULTRA or XT platform), FISH, PCR, next-generation sequencing (NGS), or circulating tumor DNA (ctDNA) testing;
   2. At least one measurable target lesion per RECIST v1.1, not previously irradiated; brain metastases are allowed;
2. No prior systemic therapy for advanced (Stage IIIB/C not amenable to multimodality treatment) or metastatic (Stage IV) disease;
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2;
4. Age ≥ 18 years;
5. Hyperlipidemia during first-line lorlatinib treatment, with ULN ≤ TC < 12.93 mmol/L (Grade 1-3);
6. Life expectancy ≥ 6 months;

7. Negative serum pregnancy test at screening for women of childbearing potential. Non-childbearing potential must meet at least one of the following:

   1. Postmenopausal status: regular menstrual cessation ≥ 12 months with no other pathological or physiological cause (serum FSH level may be used to confirm postmenopausal status, if applicable);
   2. Hysterectomy and/or bilateral oophorectomy;
   3. Medically confirmed ovarian failure; All other women (including those with tubal ligation) are considered of childbearing potential;
8. Provide signed and dated informed consent from the patient (or legal representative), indicating full understanding of the study-related information.

Part B Additional Inclusion Criteria

Patients with at least one prior major ASCVD event, or baseline LDL-C ≥ 4.9 mmol/L ± high-risk factors.

Major ASCVD events:

1. Acute coronary syndrome (ACS) within the past 1 year;
2. History of myocardial infarction (excluding recent ACS);
3. History of ischemic stroke;
4. Symptomatic peripheral artery disease (PAD), including prior revascularization or amputation.

High-risk factors (prioritized):

1. Premature coronary artery disease (male < 55 years; female < 65 years);
2. Familial hypercholesterolemia;
3. History of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI);
4. Diabetes mellitus;
5. Hypertension;
6. Chronic kidney disease (CKD) stage 3-4;
7. Current smoker. -

Exclusion Criteria:

Exclusion Criteria (Part A and Part B)

1. Mixed squamous cell carcinoma, large cell carcinoma, or small cell lung cancer
2. Prior systemic anticancer therapy for NSCLC, including chemotherapy, biologic therapy, immunotherapy, or any investigational drug
3. Diagnosed genetic hypercholesterolemia (e.g., familial hypercholesterolemia, Part A only) or secondary dyslipidemia with a clear etiology (e.g., hypothyroidism, uncontrolled diabetes, nephrotic syndrome)
4. Known allergy or history of severe adverse reaction to any study drug (including lorlatinib, statins, ezetimibe, or evolocumab)
5. Presence of other severe diseases that may affect study compliance or outcome assessment, including advanced renal failure (eGFR < 30 mL/min/1.73 m²) or severe hepatic impairment (Child-Pugh Class C)
6. Pregnant or lactating women, or fertile individuals (male or female) unwilling to use effective contraception during the study
7. Currently participating in another interventional clinical study that may interfere with this study; patients expected to be unable to complete follow-up or the first tumor efficacy assessment; patients with mental or psychological disorders who cannot provide informed consent or comply with study requirements (including treatment and follow-up)

Part B Additional Exclusion Criteria

Subjects meeting any of the following criteria will not be included in this clinical study:

1. Major surgery within 4 weeks prior to randomization; minor surgery (e.g., port placement) is permitted provided the incision is adequately healed
2. Radiotherapy within 2 weeks prior to enrollment, including stereotactic or partial brain radiotherapy. Patients who complete whole brain radiotherapy within 4 weeks prior to randomization, or palliative radiotherapy outside the CNS within 48 hours prior to randomization, are also excluded
3. Gastrointestinal abnormalities including: inability to take oral medication; need for parenteral nutrition; prior surgery affecting absorption (e.g., total gastrectomy, gastric banding); active inflammatory bowel disease, chronic diarrhea, symptomatic diverticular disease; treatment for active peptic ulcer within the past 6 months; malabsorption syndrome
4. Known or suspected severe hypersensitivity to the study drug or any of its excipients
5. History of extensive, disseminated, or bilateral disease, or current Grade 3-4 interstitial fibrosis/interstitial lung disease, including but not limited to: pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, bronchiolitis obliterans, and pulmonary fibrosis
6. Active malignancy within 3 years prior to randomization (excluding NSCLC, non-melanoma skin cancer, localized prostate cancer not requiring immediate treatment, or any carcinoma in situ)

7. Concurrent use within 12 days prior to first lorlatinib dose of:

   1. Strong CYP3A inhibitors (e.g., grapefruit juice or grapefruit/related citrus fruits [Seville oranges, pomelos]; boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole; ritonavir alone or with danoprevir, elvitegravir, indinavir, lopinavir, paritaprevir, ombitasvir, dasabuvir, saquinavir, tipranavir; telaprevir, troleandomycin, voriconazole. Topical use such as 2% ketoconazole cream is permitted where applicable)
   2. Known narrow therapeutic index CYP3A substrates (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl [including transdermal patch], or ergot alkaloids [ergotamine, dihydroergotamine]) (withdrawn from U.S. market)
   3. Known strong CYP3A inducers (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort)
   4. Known narrow therapeutic index P-gp substrates (e.g., digoxin)
8. Other severe acute or chronic medical or psychiatric conditions, including suicidal ideation or behavior within the past 1 year, that may increase the risk of study participation or study drug use, or laboratory abnormalities that may interfere with interpretation of study results, and patients deemed by the investigator to be unsuitable for enrollment
9. Participation in another investigational drug study within 2 weeks prior to enrollment and/or during the study period

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group/Cohort 1: Part A - Observational Cohort; Description: No intervention assigned. Real-world lipid-lowering treatment patterns recorded per routine clinical practice. May include statins, ezetimibe, PCSK9 inhibitors, or combinations.; Participants: ~100; Intervention: None (observational)	Drug: For Part A - Observational Cohort: No intervention assigned (observational)
Group/Cohort 2: Part B - Intensive Lipid-Lowering Group; Description: Intensive lipid-lowering therapy with rosuvastatin + ezetimibe + evolocumab (PCSK9 inhibitor); Participants: 30; Intervention: Rosuvastatin, Ezetimibe, Evolocumab	Drug: For Part B - Intensive Group; Rosuvastatin + Ezetimibe
Group/Cohort 3: Part B - Standard Lipid-Lowering Group; Active Comparator ,Patients with high CVD risk randomized to receive standard combination therapy. Rosuvastatin + Ezetimibe .	Drug: Part B: Intensive Lipid-Lowering Group; Rosuvastatin + Ezetimibe + Evolocumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in LDL-C from Baseline to Week 12	Description: The primary endpoint for Part B. The mean percentage change in low-density lipoprotein cholesterol (LDL-C) concentration from baseline to Week 12, compared between the intensive lipid-lowering group (rosuvastatin + ezetimibe + evolocumab) and the standard lipid-lowering group (rosuvastatin + ezetimibe).	Baseline, Week 12
Real-World Treatment Patterns for Hyperlipidemia Management	Description: The primary endpoint for Part A. A descriptive analysis of the lipid-lowering management strategies used in routine clinical practice for ALK+ NSCLC patients developing hyperlipidemia on first-line lorlatinib, including treatment class selection (statins, ezetimibe, PCSK9 inhibitors), monotherapy versus combination therapy, timing of initiation, dose adjustments, and adherence to standard guideline recommendations.	Baseline through Week 24 (measured at Baseline, Weeks 4, 8, 20, and 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dynamic Changes in Lipid Profile Parameters over 24 Weeks	Description: Changes in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations over the 24-week study period.	Baseline, Weeks 4, 8, 12, 16, 20, 24 (Part B); Baseline, Weeks 4, 8, 20, 24 (Part A)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Endothelial Function Measured by Brachial Artery Flow-Mediated Dilation (FMD)	Description: Change in brachial artery flow-mediated dilation (FMD) from baseline to within 24 weeks of treatment, as an exploratory assessment of endothelial function changes associated with lorlatinib-related dyslipidemia and lipid-lowering interventions. Only performed in Part B, on a voluntary basis and where the study center has the required equipment and qualified personnel.	Baseline, Week 24

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Pfizer

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): June 29, 2026

Study Record Updates

• Last Update Posted (Actual): June 29, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Endothelial function; Hyperlipidemia; Statin; Multi-center; Prospective study; Ezetimibe; ALK-positive NSCLC; PCSK9 inhibitor; Evolocumab; FMD; Lorlatinib; Real-world study; Lipid management
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Dyslipidemias; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Carcinoma, Non-Small-Cell Lung; Hyperlipidemias
• Other Study ID Numbers: B2026-159-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is an investigator-initiated trial (IIT) sponsored by an academic institution. The study protocol does not include provisions for IPD sharing. Data sharing is limited to publication of aggregate study results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No