osimertinib with or without bevacizumab for egfr- mutant non-small cell lung cancer with leptomeningeal metastasis

Conditions: Leptomeningeal Metastasis; Non-small Cell Lung Cancer; EGFR Activating Mutation

Summary: leptomeningeal metastasis (lm) is a devastating and terminal complication of advanced non-small-cell lung cancer (nsclc), especially in patients harboring epidermal growth factor receptor (egfr) mutations. osimertinib is an oral,third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr-tki) that selectively inhibits both egfr-tki-sensitizing and egfr t790m resistance mutations .aura i/ii study and other preclinical study suggested that osimertinib exhibited a better blood-brain barrier(bbb) penetration than the other egfr-tkis (gefitinib, erlotinib, or afatinib).the bloom 、aura and flura study demonstrated that osimertinib showed encouraging activity and manageable tolerability in pretreated egfr-mutant nsclc patients with lm. bevacizumab is a monoclonal antibody against vascular endothelial growth factor (vegf). animal study and autopsy specimens showed that vegf is an essential factor in lm. recently study showed egfr-tkis plus bevacizumab prolonged pfs and os in patients with egfr-mutant nsclc and multiple brain mteastasis when compared with egfr-tkis alone. howerver osimertinib combined with bevacizumab could benefit patients with lm from egfr- mutant nsclc remains undetermined. therefore, the purpose of the study is to evaluate the safety and efficacy of osimertinib combined with bevacizumab for egfr- mutant non-small cell lung cancer with leptomeningeal metastasis

this is a randomized phase ii clinical trial. the objective of the study is to assess the efficacy of osimertinib combined with bevacizumab for lm from egfr- mutant nsclc. patients were randomized with equal allocation to 80 mg of oral osimertinib daily alone or with 7.5 mg/kg of intravenous bevacizumab every 3 weeks. study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent

Eligibility criteria:
inclusion criteria: * age in 18-80 years * pathologically proven nsclc * egfr mutation , the egfr status was identified from primary lung tumors using the amplification refractory mutation system (arms) or next-generation sequencing (ngs) analysis. * lm diagnosis was based on the detection of malignant cells in the csf, the focal or diffuse enhancement of leptomeninges, and nerve roots or the ependymal surface on gadolinium-enhanced mri . * no severe abnormal liver and kidney function; * no other severe chronic diseases; * signed informed consent form exclusion criteria: * patients with the clinical manifestation of nervous system failure including severe encephalopathy, grade iii-iv white matter lesions confirmed by imaging examination, moderate or severe coma, and glasgow coma score less than 9 points; * allergic to osimertinib or bevacizumab * any of the following: pregnant women ;nursing women ;men or women of childbearing potential who are unwilling to employ adequate contraception * history of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (new york heart association ≥ grade 2), unstable angina pectoris, or cardiac arrhythmia; note: allowed only if patient has no evidence of active disease for at least 6 months prior to randomization; * history of cerebral vascular accident (cva) or transient ischemic attack (tia)≤ 6 months prior to randomization * history of bleeding diathesis or coagulopathy * history of hemoptysis da≥ grade 2 (defined as bright red blood of at least 2.5 ml) ≤3 months prior to randomization * leukocytes below 2\*10\^9/l, neutrophils below 1\*10\^9/l; platelets below 50\*10\^9/l; * had major surgery within 60 days; * history of arteriovenous thrombosis * gastrointestinal perforator in the past 6 months * inadequately controlled hypertension (systolic blood pressure of \> 150 mmhg or diastolic pressure \> 100 mmhg on anti-hypertensive medications); note: history of hypertensive crisis or hypertensive encephalopathy not allowed * grade 4 proteinuria

Keywords: leptomeningeal metastasis non small cell lung cancer egfr activating mutation osimertinib bevacizumab