A Study of Furmonertinib Combined With Chemotherapy in the Treatment of NSCLC With Leptomeningeal Metastasis

Inclusion Criteria:

• aged 18-75 years old (including 18 and 75 years old);
• ECOG PS 0-3 with no deterioration in the first 2 weeks；
• The lowest expected survival time was ≥12 weeks；
• NSCLC patients with EGFR sensitive mutations confirmed by tissue and/or cytology;
• Patients with EGFR sensitive mutations (EGFR exon 19 deletion or EGFR exon 21 L858Rmutation) without other driver genes with targeted therapy (such as C797X mutation,MET abnormality, etc.) were enrolled；
• Leptomeningeal metastasis after resistance to third-generation EGFR-TKIs;
• Histologically confirmed NSCLC LM patients by positive CSF cytology. The diagnosis ofLM can be based on MRI with malignant cells in the cerebrospinal fluid, focal ordiffuse enhancement of the leptomeninges, and enhancement of nerve roots or ependymalsurfaces;
• no severe liver and kidney dysfunction;
• no other serious chronic diseases;
• Women should use adequate contraceptive methods throughout the study; Termination ofpregnancy was recommended if pregnancy occurred during the study. Failure to heed theadvice was at your own risk.
• Informed consent was signed.

Exclusion Criteria:

• Other patients except lung cancer were considered as malignant tumors;
• any unresolved pretreatment toxicity (except alopecia and grade 2 platinum-basedneuropathy) greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the initiation of study treatment;
• Refractory nausea, vomiting, or chronic gastrointestinal disease, inability to swallowthe study drug, or previous significant intestinal resection surgery, resulting ininadequate absorption of vormetinib;
• Patients with clinical manifestations of nervous system failure included severeencephalopathy, grade Ⅲ-Ⅳ white matter lesions confirmed by imaging examination,moderate or severe coma, and Glasgow coma scale less than 9;
• known history of hypersensitivity reactions to active or inactive excipients ofvormetinib or drugs with a similar chemical structure or class to vormetinib;
• any of the following: pregnant women; Women who are lactating; Reluctance among men orwomen of childbearing potential to use appropriate contraception;
• previous history of myocardial infarction or other arterial thrombotic diseases (angina pectoris), symptomatic congestive heart failure (New York Heart Associationgrade ≥2), unstable angina pectoris or arrhythmia; Note: only allowed if the patienthad no evidence of active disease for at least 6 months before randomization;
• History of cerebrovascular accident (CVA) or transient ischemic attack (TIA) ≤6 monthsbefore enrollment;
• history of hemorrhagic diathesis or coagulopathy;
• lack of adequate bone marrow reserve or organ function (enrollment at investigator'sdiscretion) : absolute neutrophil count <1.0×109/L; Platelet count <75×109/L;Hemoglobin <90 g/L; Alanine aminotransferase > 2.5 times ULN; Aspartateaminotransferase >2.5 times ULN; Total bilirubin > 1.5 times ULN; Or liver metastasispatients AST and/or ALT > 5× ULN, total bilirubin >3×ULN; Serum creatinine >1.5 timesULN and creatinine clearance <50 mL/ minute (measured or calculated by the commonformula of Cockcroft and Gault) International normalized ratio (INR)> 1.5 and partialactivated prothrombin time (APTT)>1.5×ULN;
• major surgery within 28 days before the administration of the first dose of study drug (in China, major surgery was defined according to the "Administrative Measures for theClinical Application of Medical Technology" which was implemented on May 1, 2009 andreferred to grade 3 and 4 surgery);
• evidence of any severe or uncontrolled systemic illness, including uncontrolledhypertension, diabetes mellitus, and active bleeding, any nonadherence to the study orany active infection, including uncontrolled hepatitis B, hepatitis C, and humanimmunodeficiency virus (HIV), as considered by the investigator to be detrimental topatient participation or adherence to the protocol;
• For women of childbearing age, a negative urine or serum pregnancy test should beperformed 3 days prior to receiving the first dose of study drug; Participants andtheir sexual partners were required to use a medically approved contraceptive methodduring the study treatment period and for 6 months after the end of the studytreatment period. If a subject or a subject's partner becomes pregnant during thestudy, inform your study doctor immediately and the study doctor advises you or yourpartner to terminate the pregnancy; If you persist with the pregnancy, your doctor,with your consent, will continue to monitor the mother and baby until birth.