An Open-Label, Single-Arm, Dose-Escalation Phase I Study Evaluating the Safety, Tolerability, and Preliminary Efficacy of EDB-102 in Patients With EGFR L858R-Mutant, Third-Generation TKI-Resistant Advanced Non-Small Cell Lung Cancer With Liver Metastases

Prior treatment

• Prior exposure to any gene-editing therapies (e.g., CRISPR, TALEN, ZFN)
• 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
• Receipt of any investigational, unapproved therapy within 4 weeks prior to the first dose of study drug.
• 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.

Other illness

• Known allergy or adverse reaction to any lipid nanoparticle (LNP) components.
• Uncontrolled hypertension (systolic BP \>150 mmHg and/or diastolic BP \>100 mmHg despite regular antihypertensive therapy) or history of hypertensive crisis or hypertensive encephalopathy.
• Liver disease, including cirrhosis, hepatitis, or history of hepatitis B or C infection.
• Unstable angina or acute myocardial infarction, or history of these events within the past 6 months.
• History of malignancy within the past 5 years, except for treated basal cell carcinoma, cutaneous squamous cell carcinoma, cervical cancer, or gastrointestinal cancers.
• Any condition deemed by the investigator to make the subject unsuitable for participation in the study.

Lab values

• 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.

Age

• 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.

• Age ≥18 and ≤75 years, any sex.
• Histologically or cytologically confirmed, unresectable locally advanced or metastatic (stage IV) non-small cell lung cancer (NSCLC)
• 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.
• 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).
• 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).
• ECOG performance status of 0 or 1.
• 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.
• Ability and willingness to provide written informed consent, comply with study procedures, and cooperate with study personnel.