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

Conditions: Leptomeningeal Metastasis

Summary: we aim to compare the efficacy and safety of double dose of third-generation egfr-tki plus intrathecal pemetrexed versus double dose of third-generation egfr-tki in patients with leptomeningeal progression following the treatment of routine dose of egfr-tki,


Eligibility criteria:
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.