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

Overview

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

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: March 1, 2021

Detailed Description

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

Interventions

  • Drug: Osimertinib
    • Treatment of LM With osimertinb
  • Drug: Bevacizumab
    • Treatment of LM With osimertinb combined with bevacizumab

Arms, Groups and Cohorts

  • Experimental: osimertinb group
    • Osimertinib 80 mg oral daily
  • Experimental: osimertinb combined with bevacizumab group
    • Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Second Affiliated Hospital of Nanchang University
  • Collaborator
    • Nanchang University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Liu Anwen, Phd, Study Director, Second Affiliated Hospital of Nanchang University
  • Overall Contact(s)
    • Liu Anwen, Phd, +8613767120022, awliu666@163.com

References

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