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

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