CRISPR therapy takes on Drug-Resistant lung cancer in liver

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: 1. Age ≥18 and ≤75 years, any sex. 2. Histologically or cytologically confirmed, unresectable locally advanced or metastatic (stage IV) non-small cell lung cancer (NSCLC) 3. Prior treatment with at least one third-generation EGFR-TKI (e.g., osimertinib) with radiologically confirmed disease progression according to RECIST 1.1 or intolerance, and no concomitant anticancer therapy during this period. 4. Availability of tumor tissue obtained after progression on third-generation EGFR-TKI, with EGFR L858R mutation confirmed in the post-progression tumor tissue or blood sample by central laboratory- or study site-validated methods (e.g., WES or RNAseq). 5. At least one measurable hepatic lesion per RECIST 1.1, confirmed by biopsy, with the EGFR L858R mutation verified in the lesion by central laboratory- or study site-validated methods (e.g., WES or RNAseq). 6. ECOG performance status of 0 or 1. 7. Adequate organ and bone marrow function: a) Hematologic: within 14 days prior to enrollment and without recent transfusion or growth factor therapy: ANC ≥1.5×10⁹/L, Hb ≥90 g/L, PLT ≥75×10⁹/L, WBC \>3.0×10⁹/L. b) Hepatic: TBIL ≤1.5×ULN, ALT ≤5×ULN, AST ≤5×ULN. c) Renal: serum creatinine ≤1.5×ULN or creatinine clearance (CrCl) ≥50 mL/min. d) Coagulation: PT ≤1.5×ULN, APTT ≤1.5×ULN, INR ≤1.5×ULN. 8. Ability and willingness to provide written informed consent, comply with study procedures, and cooperate with study personnel. Exclusion Criteria: 1. Prior exposure to any gene-editing therapies (e.g., CRISPR, TALEN, ZFN) 2. Receipt of chemotherapy, radiotherapy, biologic therapy, endocrine therapy, targeted therapy, immunotherapy, or other anticancer agents within 4 weeks prior to the first dose of study drug. For oral fluoropyrimidines or small-molecule targeted agents, the washout period is 2 weeks or 5 half-lives of the drug, whichever is longer 3. Receipt of any investigational, unapproved therapy within 4 weeks prior to the first dose of study drug. 4. Presence of other known driver gene alterations conferring TKI resistance, excluding EGFR mutations, unless these occur as co-mutations, including: Bypass pathway activation: High-level MET amplification: detected by WES (gene copy number \>5) or FISH (MET/CEP7 ratio ≥2.0). High-level HER2 amplification: detected by ISH (gene copy number ≥6 per nucleus, HER2/CEP17 ratio ≥2.0). Other acquired resistance driver mutations: Newly emerged confirmed resistance mutations, e.g., KRAS or BRAF-V600E. Activating mutations in PI3K/AKT/mTOR pathway genes (e.g., PIK3CA). Loss of primary EGFR mutation: absence of the original EGFR L858R mutation in post-resistance tumor tissue. 5. Known allergy or adverse reaction to any lipid nanoparticle (LNP) components. 6. Uncontrolled hypertension (systolic BP \>150 mmHg and/or diastolic BP \>100 mmHg despite regular antihypertensive therapy) or history of hypertensive crisis or hypertensive encephalopathy. 7. Liver disease, including cirrhosis, hepatitis, or history of hepatitis B or C infection. 8. Unstable angina or acute myocardial infarction, or history of these events within the past 6 months. 9. History of malignancy within the past 5 years, except for treated basal cell carcinoma, cutaneous squamous cell carcinoma, cervical cancer, or gastrointestinal cancers. 10. Pregnant, breastfeeding, positive pregnancy test, or unwillingness to use contraception in premenopausal women. Women are considered postmenopausal if amenorrheic for ≥2 years. Male patients unwilling to use contraception during the study are also excluded. 11. Leptomeningeal, brainstem, or spinal metastases, or active CNS metastases with compression. Subjects with previously treated brain metastases may participate if clinically stable ≥4 weeks prior to first study drug administration and off corticosteroids for ≥14 days. 12. Any condition deemed by the investigator to make the subject unsuitable for participation in the study.