Osimertinib With or Without Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

Study Overview
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Brief Summary
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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

Detailed Description
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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

Official Title
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A Randomized Phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

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

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: osimertinb group<br>Osimertinib 80 mg oral daily | Drug: Osimertinib<br>* Treatment of LM With osimertinb<br>* Other names: AZD9291;|
| Experimental: osimertinb combined with bevacizumab group<br>Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks | Drug: Osimertinib<br>* Treatment of LM With osimertinb<br>* Other names: AZD9291;Drug: Bevacizumab<br>* Treatment of LM With osimertinb combined with bevacizumab<br>* Other names: Anti-VEGF rhuMAb;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial progression-free | iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,) | Every 6 weeks, up to 2 years, | 
| Objective Response Rate | ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR) | Every 6 weeks, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LM Overall survival | LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up | Every 3 weeks, up to 5 years, | 
| progression-free survival | Proportion of patients progression-free by investigator assessment per RECIST v1.1 | Every 6 weeks, up to 2 years, | 
| adverse events | Number of patients with adverse events (AEs) as a measure of safety and tolerability | Every 3 weeks, up to 2 years, | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leptomeningeal metastasis, non small cell lung cancer, EGFR Activating Mutation, Osimertinib, Bevacizumab