Patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with brain metastases remain a major clinical challenge. Although EGFR-TKIs have demonstrated intracranial activity, disease control is still suboptimal in some patients.

Limertinib (ASK120067) is a novel third-generation EGFR tyrosine kinase inhibitor with favorable central nervous system penetration and encouraging intracranial antitumor activity. The potential synergistic effect of limertinib combined with radiotherapy warrants further investigation.

This prospective, multicenter, single-arm phase II study aims to evaluate the efficacy and safety of first-line limertinib combined with radiotherapy in this patient population.

Inclusion Criteria:

Patients must voluntarily agree to participate in this study and sign a written informed consent form.

Patients aged 18-75 years. Patients must have histologically or cytologically confirmed advanced non-small cell lung cancer (NSCLC), staged as IV according to the 9th edition of the American Joint Committee on Cancer (AJCC) TNM staging system.

Histological or cytological reports issued by nationally accredited hospitals or third-party testing institutions confirming the presence of EGFR classical mutations (19Del & 21L858R).

ECOG PS score of 0-1, and an estimated survival of ≥3 months, as determined by the investigator.

Brain metastases (meningeal/parenchymal) confirmed by CT or MRI, with or without symptoms.

Patients must have at least one measurable lesion according to RECIST 1.1 criteria.

≥3 primary brain lesions, with at least one lesion ≥2 cm. Patients must not have received any prior systemic anti-cancer treatment for advanced/metastatic non-small cell lung cancer, including standard chemotherapy, biological therapy, targeted therapy, immunotherapy, or investigational drug therapy. Patients who have received adjuvant or neoadjuvant therapy (chemotherapy and/or radiotherapy) are eligible if no disease progression occurred within 6 months after completion of treatment. Patients who have received local treatment (radiotherapy or pleural perfusion therapy) are also eligible if the treated lesions are not target lesions.

Patients must meet the following organ function criteria:

Absolute neutrophil count (ANC) ≥1.5×10⁹/L. 2) Platelet count ≥100×10⁹/L. 3) Hemoglobin (HGB) ≥90 g/L. 4) Serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN). For patients with liver metastases, TBIL may be up to 3× ULN.

5) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× ULN. For patients with liver metastases, AST and ALT may be up to 5× ULN.

6) Serum creatinine (SCr) ≤1.5× ULN, or creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula).

Male patients with reproductive potential and female patients who may become pregnant must use highly effective contraceptive methods during the study and for 12 months after treatment discontinuation.

Exclusion Criteria:

Patients unable to confirm a diagnosis of non-small cell lung cancer (NSCLC) through histological or cytological examination.

Patients expected to require other systemic anti-cancer treatments outside of this study during the trial period.

Patients diagnosed with malignant tumors within the past 2 years, except for well-controlled cutaneous basal cell carcinoma, cervical carcinoma in situ, or ductal carcinoma in situ of the breast.

Patients with significant gastrointestinal diseases that may affect drug intake or absorption, including but not limited to peptic ulcer disease or inflammatory bowel disease.

Patients with known or suspected hypersensitivity to the study interventions (lielitinib and radiotherapy) or components of study-related preparations.

Patients who have previously received any epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.

Patients who have used strong CYP3A4 inhibitors or inducers within 7 days prior to the first dose of study drug, or who are expected to require long-term use of these medications during the trial. Additionally, patients who have used traditional Chinese medicine or preparations with anti-tumor indications within 2 weeks prior to the first dose of study drug, or who are expected to require such use during the trial, will also be excluded.

Patients with a history of interstitial lung disease, drug-induced interstitial lung disease, or radiation pneumonitis requiring corticosteroid treatment. Patients with acute exacerbation or progressive pulmonary symptoms at baseline, or those considered unsuitable for inclusion by the investigator due to high-risk factors for interstitial lung disease, will also be excluded.

Patients with significant arrhythmia (e.g., QT interval >470 ms) or heart failure (left ventricular ejection fraction <50%).

Pregnant or lactating women. Patients currently participating in or who have participated in other clinical trials within the past 4 weeks.

Patients with serious acute or chronic medical or psychiatric conditions, as determined by the investigator, that may increase the risks associated with study participation or interfere with the interpretation of study results.