Lorlatinib Plus Sacituzumab Tirumotecan With Peripheral ctDNA Guidance as First-Line Therapy for ALK Fusion-Positive NSCLC

Inclusion Criteria: 1. Patients aged ≥ 18 years at the time of signing the informed consent, regardless of gender; 2. Histologically/cytologically confirmed NSCLC, Stage III (locally advanced) or IV (metastatic), unsuitable for curative surgery and/or curative radiotherapy, with or without prior concurrent/sequential chemotherapy; 3. No prior systemic therapy for locally advanced or metastatic NSCLC, patients previously treated with curative-intent adjuvant/neoadjuvant chemo or concurrent/sequential chemoradiotherapy for non-metastatic disease are eligible if progression occurred ≥ 12 months after the last treatment; 4. Confirmation of ALK fusion by tumor histology, cytology, or blood-based testing; 5. Patients must have at least one measurable lesion according to RECIST v1.1. Lesions that have been previously irradiated should not be selected as target lesions. Subjects with only skin lesions or bone lesions are not eligible for inclusion; 6. ECOG performance status score of 0 or 1 within 7 days prior to the first dose of study drug; 7. Estimated survival of ≥ 12 weeks; 8. Adequate organ and bone marrow function, without having received blood transfusion, recombinant human thrombopoietin, or colony-stimulating factors within 2 weeks prior to the first dose of study drug. Exclusion Criteria: 1. Histological or cytological confirmation of mixed small cell lung cancer, neuroendocrine carcinoma, carcinosarcoma, or squamous cell carcinoma components; 2. Prior receipt of any of the following therapies (including in the adjuvant or neoadjuvant setting): a) TROP2-targeted therapy; b) Any therapy containing topoisomerase I, including antibody-drug conjugate (ADC) therapy; c) Lorlatinib targeted therapy; 3. Presence of factors affecting oral drug administration; 4. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or history of corneal disease that precludes or delays corneal healing; 5. Presence of spinal cord compression. Subjects who have received adequate local treatment (surgery or radiotherapy) and have clinical evidence of symptom relief for ≥ 1 week prior to the first dose may be enrolled; 6. Presence of active central nervous system (CNS) metastases. Subjects with stable asymptomatic CNS metastases may be enrolled; 7. Presence of other malignancy within 3 years prior to the first dose (except for tumors cured by local therapy or in situ carcinomas that do not require immediate treatment); 8. Presence of severe cardiovascular or cerebrovascular disease or cardiovascular risk factors; 9. History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid therapy, current ILD or non-infectious pneumonitis, or suspected ILD or non-infectious pneumonitis that cannot be ruled out by imaging at screening; 10. Prior antitumor therapy-related toxicities have not recovered to ≤ grade 1 (based on NCI CTCAE v5.0) or to the levels specified in the eligibility criteria (excluding toxicities deemed by the investigator to be of low safety risk, such as alopecia, fatigue, or peripheral neuropathy); 11. Active hepatitis B (hepatitis B surface antigen \[HBsAg\] positive, requiring HBV-DNA testing; HBV-DNA ≥ 2000 IU/mL or above the lower limit of detection, whichever is higher) or hepatitis C (positive for hepatitis C antibody with HCV-RNA above the lower limit of detection).