Research objective Main purpose Exploring the real-world effectiveness of Ivonescimab combined with chemotherapy for EGFR mutant NSCLC with leptomeningeal metastasis after EGFR-TKIs resistance. Outcome measure: Real world intracranial disease-free survival time (iPFS).

Secondary purpose Federation patterns: describing different treatment modes in the real world; Outcome measures: Combination chemotherapy regimen and duration of chemotherapy.

Efficacy: Further explore the effectiveness of Ivonescimab combined with chemotherapy for EGFR mutant NSCLC with leptomeningeal metastasis failed with EGFR-TKI treatment; Outcome measures: Objective response rate (LM-ORR), duration of intracranial response (iDoR), overall progression free survival (PFS), overall survival (OS), improvement in neurological function, CSF response rate based on CSF cytology.

Safety: Explore the safety of Ivonescimab combined with chemotherapy for NSCLC patients with leptomeningeal metastases who have failed EGFR-TKI treatment; Outcome measures: incidence of adverse events (TEAEs), laboratory test outliers, and serious adverse events (SAEs).

Research endpoint Primary endpoint

• iPFS (intracranial progression free survival). Secondary endpoint
• Efficacy: leptomeningeal ORR (LM-ORR), intracranial duration of response (iDoR), overall progression free survival (PFS), overall survival (OS), improvement in neurological function, and CSF response rate based on CSF cytology;
• Safety: Determine the incidence and severity of adverse events (AE) and serious adverse events (SAE) according to NCI-CTCAE5.0 standards; Changes in vital signs, laboratory abnormalities, and quality of life scores.

Exploratory endpoint: efficacy related biomarkers

Inclusion Criteria:

• Age range: 18-75y
• EGFR mutation NSCLC
• LM was diagnosed through head enhanced MRI or (and) CSF cytology
• EGFR activation mutations were positive
• Patients who have failed to first or second-generation EGFR-TKI treatment，without T790M mutation; or failed to third-generation EGFR-TKI treatment
• Hematological, coagulation, renal and liver function is sufficient
• Women of childbearing age must undergo a pregnancy test and the result must be negative

Exclusion Criteria:

• Patients with squamous cell carcinoma, large cell carcinoma, mixed cell lung cancer
• The patient has other driver genes that can be treated with targeted drugs
• Subjects who have previously received immunotherapy with a discontinuation time of less than 3 months
• Received EGFR-TKI treatment within one week prior to the first administration
• Received non-specific immunomodulatory therapy
• Clinical manifestations of neurological failure
• Non malignant neurological disorders
• Radiotherapy for the chest and whole brain should be completed within 4 weeks before enrollment
• Tumor surrounded important blood vessels or had obvious necrosis or cavities
• Tumor has invaded important surrounding organs and blood vessels
• History of severe bleeding tendency or coagulation dysfunction
• The risk of developing esophagotracheal fistula or esophageal pleural fistula