Double Dose of Third-generation EGFR-TKI Plus Intrathecal Pemetrexed Versus Double Dose of Third-generation EGFR-TKI in Patients With LM Progression Following the Treatment of Routine Dose of Third-generation EGFR-TKI

Inclusion Criteria:

* Age 18 years at the time of signing informed consent, both sexes;
* advanced or metastatic NSCLC, TNM stage IV according to the eighth edition of IASLC 2015;
* with EGFR sensitive mutation (exon 19 deletion or L858R mutation), LM progression after conventional doses of three generation EGFR targeted agents (after 1 + 3,2 + 3 or direct 3-generation targeted therapy). There is no limit on the number of chemotherapy lines. The enrolled patients required brain parenchyma and extracranial lesion stable
* ECOG PS score: 0-3
* Normal main organ function, That is, the following criteria are met:

  1. routine blood examination (no blood transfusion within 14 days, no hematopoietic stimulating factor drugs are corrected state): hemoglobin (Hb) 90g / L; Absolute neutrophil count (ANC) 1.5109 / L; Platelet (PLT) 100109 / L; White blood cell count (WBC) 3.0109 / L;
  2. Biochemical examination: alanine transaminotransferase (ALT) and alanine transaminotransferase (AST) 2.5 upper limit of normal (ULN); Serum total bilirubin (TBIL) 1.5 ULN; Serum creatinine (Cr) of 1.5 ULN or creatinine clearance of 50 ml/min; If any liver metastasis, Then, the total bilirubin 3 ULN, ALT and AST 5 ULN; C) Coagulation function: activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time 12 (PT) 1.5 ULN;

  d) Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) 50%;
* If previously treated with chemotherapy, A washout period of at least 21 days between the last chemotherapy dose and enrollment (if the patient does not receive radiotherapy) is required; Patients who treated brain parenchymal metastases with local radiotherapy or surgery before enrollment, Must be completed and fully recovered from the acute toxicity of radiotherapy / surgery. A minimum 14-day washout period is required between the end of radiotherapy and enrollment. A minimum 30-day washout period is required between the end of surgery and enrollment.
* Expected survival of not less than 3 months
* patients can swallow oral medication (if not oral, can be ground by gastric tube)
* Women of childbearing age must have negative pregnancy test (serum or urine) within 14 days before observation period and 3 months after the last administration; for men, they should undergo surgical sterilization or agree to use appropriate contraception during the observation period and 3 months after the last administration of study drug
* patients voluntarily participate and sign an informed consent (or legal agent), expected to have good compliance and able to cooperate with the study according to the protocol requirements.

Exclusion Criteria:

* Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the study program;
* Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS)
* patient with active bacterial infection, fungal infection (intravenous antibiotics required at initiation of study treatment);
* past history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonia requiring steroid therapy, Or any signs of clinically active interstitial lung disease;
* arterial / venous thrombosis events within 6 months prior to enrollment, Such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;
* congestive heart failure (NYHA grade\> 2); unstable angina pectoris; a myocardial infarction within 3 months prior to signing an ICF; any 12 supraventricular or ventricular arrhythmia requiring treatment or intervention; Mean QTcF\> 470ms from 3 ECG recordings
* other systemic malignancies in the last 5 years, (Except for cured skin basal cell carcinoma and cervical situ carcinoma and ovarian carcinoma);
* Use drugs or supplements known to be the main cause of CYP3A4.
* Persons known to be allergic to any test drug or its excipients;
* pregnant, lactating, reproductive patients unwilling to use effective contraception; ●a clear prior history of neurological or psychiatric disorders, including epilepsy and dementia;
* other conditions considered inappropriate by the investigator.