High-dose Furmonertinib Combined With Bevacizumab and Intrathecal Pemetrexed Chemotherapy in Patients With EGFR-mutated Non-small Cell Lung Cancer and Meningeal Metastasis

• Histological or cytological confirmed NSCLC;
• confirmed EGFR sensitive mutations;
• Diagnosis of leptomeningeal metastases according to the European Association of Neuro-Oncology European Society for Medical Oncology (EANO-ESMO) guidelines: clinical symptoms of intracranial hypertension (headache, dizziness, vomiting, etc.) ; imaging confirmation (cerebral MRI diagnosis of meningeal aggravation) or cerebrospinal fluid cytology confirmation (meets two or more criteria);
• Patients with mild to minimal CNS symptoms who are tolerable for the treatment were allowed, and given the unique clinical nature of leptomeningeal metastasis, the use of corticosteroid is allowed;
• Newly diagnosed leptomeningeal metastasis, including meningeal metastasis after previous brain surgery and/or local radiotherapy for solid metastatic disease;
• Patients did not received systemic treatment after diagnosed meningeal metastases.
• Obtain informed consent signed by the patient's legal representative;
• Aged ≥18 years and ≤75 years;
• Eastern Tourism Cooperation Group (ECOG) Physical condition evaluation 0-2;
• Life expectancy ≥12 week;
• Able to follow the requirements of the study protocol and confirmation procedures, and able to accept cranial wall medications;
• contraception.

Exclusion Criteria:

• Mixed non-small cell and small cell carcinoma, or squamous cell carcinoma as the main pathological type;
• history of hypersensitivity reaction to active or inactive excipients of furmonertinib, bevacizumab or pemetrexed or to drugs of similar structure or class to the investigational drug;
• Currently participating in an interventional clinical trial, or having received other study drugs or study devices within 4 weeks before the first study drug;
• Patients who have received solid organ or blood system transplantation;
• Patients with severe intracranial hypertension symptoms that cannot be relieved by discontinuation of dexamethasone and/or glycol treatment, or patients in intensive care;
• Ensure control of the patient's symptomatic pericardial, peritoneal, and pleural effusions;
• History of cancer in the last five years Other malignancies or a history of other malignancies;
• Recent active digestive events, such as duodenitis, ileitis, intestinal perforation, intestinal catheters, or other conditions that may cause gastrointestinal tract or perforation; or refractory vomiting, chronic gastrointestinal disease, inability to swallow study drugs, or previous colorectal cancer resection that prevents adequate drug absorption;
• The patient has a physique that is prone to Japanese language learning or has active Japanese language learning; Central squamous cell carcinoma or Patients at greater risk for hemoptysis; Any diamond event ≥ CTCAE grade 3, presence of open wounds, injuries or fractures in the 28th century before the first creation; if in the first Asthma was accepted 28 days before the organization meeting, the wound treatment should be evaluated by the interval period;
• History of arterial thromboembolism within the last 6 months, including vascular cerebral accident, myocardial infarction, transient cerebral contemplation;
• History of grade 4 venous thrombosis within the last 6 months, including fire embolism;
• The presence of any severe or uncontrolled systemic evidence, including difficult-to-control hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg), uncontrolled diabetes, etc.;
• Active infections include, for example, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infections (including those requiring intravenous therapy, active hepatitis B infection includes patients with positive hepatitis B surface test based on serological assessment and hepatitis B virus DNA >1000 copies/ml);
• previous history of interstitial lung disease, drug-induced interstitial lung disease, pneumonitis requiring steroid therapy, or any evidence of active interstitial lung disease;

• The first 28-day inspection of the drug preparation showed Lack of adequate bone marrow reserve or organ function （Within 2 weeks before blood test, No blood transfusion or blood products, granulocyte colony-stimulating factor or other hematopoietic stimulating factors were used for repair）:

  • Absolute neutrophil count \<1.5 × 109/L; continuous count \<100×109/L; hemoglobin \<90 g/L;
  • Alanine aminotransferase > 2.5 times Upper limit of normal value (Upper limit of normal）; Aspartate aminotransferase>2.5 times ULN; Total bilirubin>1.5 times ULN; or liver transplant patients with AST and/or ALT > 5× ULN;
  • Albumin \<30 g/L;
  • Serum creatinine >1.5 times ULN, and Creatinine clearance \<50 mL/min （Measured or calculated by Cockcroft and Gault formula);
  • International normalized ratio (INR) > 1.5,Partially activated zymogen time （APTT>1.5 times Upper limit of normal;
  • Urine protein ≥++, and 24-hour protein >2.0g;

• Any of the following Bishop criteria:

  • Clinically significant resting electrocardiogram rhythm, respiratory, or morphological abnormalities, such as left bundle branch block, third-degree myocardial insufficiency, and second-degree myocardial insufficiency, within 28 days before the first study drug perfume;
  • Possibility Interphase Factors that increase the risk of prolonged or arrhythmic events, such as heart failure, congenital long Quantum Dots Syndrome, long Quantum Dots Family history or first-degree relatives 40 Sudden death due to coma or known prolonged Quantum Dots Any sudden or difficult to fully compensate low potassium tariffs, low tariff tariffs, and low tariff-to-tariff tariffs during the period;
  • Left ventricular ejection fraction (LVEF)Left ventricular ejection fraction）\<50%, recent History of myocardial infarction, severe or unstable angina, or coronary artery bypass grafting within the past month or heart failure≥ New York Heart Association (New York Heart Association (NYHA) 2 class;
• Pregnancy or breastfeeding.