CSF Analysis in EGFR Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease

CSF Liquid Biopsy Based Characterization of Leptomeningeal Disease in EGFR Mutant Non-Small Cell Lung Cancer

Leptomeningeal disease is malignant seeding of the leptomeninges and presents with a variety of symptoms frequently impacting quality of life. With improvement in treatment options, rates of leptomeningeal disease are increasing and currently found in up to 9% of EGFR mutant NSCLC.

Systemic therapy may be more effective if it can target the correct molecular aberration. The molecular characterization of central nervous system disease may differ from disease outside of the central nervous system. The aim of this pilot trial is to evaluate for molecular differences between cerebral spinal fluid (CSF) and blood circulating tumor DNA (ctDNA) through the use of ddPCR and BC Cancer NGS panel molecular testing.

Study Overview

• Status: Recruiting
• Conditions: Non Small Cell Lung Cancer; EGFR Activating Mutation; Leptomeningeal Metastasis
• Intervention / Treatment: Diagnostic test: Lumbar puncture and Phlebotomy

Detailed Description

The aim of this pilot trial is to evaluate the concordance/discordance of molecular profiling of CSF and plasma ctDNA after the development of leptomeningeal disease in EGFR mutant NSCLC. Patients with EGFR mutant NSCLC who develop leptomeningeal disease on a first, second or third generation tyrosine kinase inhibitor are potentially eligible for this clinical trial.

This is a prospective pilot study designed to accrue 10 patients. Baseline MRI brain and spine must be completed prior to enrolment to insure that a lumbar puncture can be completed safely. All eligible subjects will be consented for ddPCR and Canexia Follow It plasma and CSF based molecular testing. Patients will have baseline information collected and will complete baseline quality of life (QoL) questionnaires. QoL questionnaires will be obtained every 12 weeks +/- 2 weeks and survival will be measured through chart review. There will be no treatment intervention; however we will collect information on treatment received after enrolment in trial. Volume of leptomeningeal disease will be scored by number of gadolinium enhancing sites in 8 predetermined locations.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cheryl Ho, MD; Phone Number: 604.877.6000; Email: cho@bccancer.bc.ca
• Study Contact Backup: Name: Barbara Melosky, MD; Phone Number: 604.877.6000

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z4E6
      • Recruiting
      • BC Cancer
      • Contact: Cheryl Ho, MD; Phone Number: 604-877-6000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject age is greater than or equal to 18 years at the time of signature of informed consent.
• Histologically or cytologically confirmed metastatic EGFR mutant NSCLC.
• Leptomeningeal disease based on brain MRI or CSF cytology.
• ECOG 0-3.
• Life expectancy of at least 8 weeks.
• Adequate hematologic and end organ function for testing.
• Ability to give informed consent for the study procedures defined in this protocol.

Exclusion Criteria:

• Inability to undergo a lumbar puncture due to thrombocytopenia, bleeding disorders, as well as inability to cooperate or consent to procedure.
• Subjects who are otherwise felt by the treating clinician to be unfit to proceed with this protocol.
• MRI spine demonstrating spinal leptomeningeal disease preventing a safe lumbar puncture.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm; ddPCR and BC Cancer NGS panel completed on cerebral spinal fluid and blood circulating tumor DNA	Diagnostic test: Lumbar puncture and Phlebotomy; Sampling of cerebral spinal fluid and plasma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concordance of molecular profiling of CSF and plasma in EGFR mutation positive NSCLC patients with leptomeningeal disease	To determine the concordance rate of molecular alterations detected in the CSF and plasma of EGFR mutation positive NSCLC patients with leptomeningeal disease	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concordance of treatment recommendations based on ctDNA and CSF	To determine the concordance and discordance between physician treatment recommendations based on ctDNA versus CSF molecular profiling.	36 months
Molecular profiling comparison	To assess concordance/discordance rates between ddPCR and Canexia Follow It completed on CSF and plasma based testing.	36 months
Molecular profiling descriptive comparison of patients treated with first/second generation versus 3rd generation EGFR TKIs	To identify molecular aberrations in the ctDNA and CSF of patients who progress on first/second EGFR TKIs and third generation EGFR TKIs to perform a descriptive comparison of shared and unique mutations identified based on prior exposure to first/second versus third generation EGFR TKI	36 months
Correlation between MRI and CSF	To correlate burden of leptomeningeal disease found on MRI and CSF positivity for tumor DNA.	36 months
Overall survival	To determine overall survival from time of developing leptomeningeal disease.	36 months
Quality of life with leptomeningeal disease	To assess the quality of life using the validated instrument, EuroQol 5 Dimension (EQ5D) (Scale of 0-100 where 0 is worst health and 100 is best health)	36 months

Collaborators and Investigators

• Sponsor: British Columbia Cancer Agency
• Investigators: Principal Investigator: Cheryl Ho, MD, BC Cancer

Publications and helpful links

General Publications

• White MD, Klein RH, Shaw B, Kim A, Subramanian M, Mora JL, Giobbie-Hurder A, Nagabhushan D, Jain A, Singh M, Kuter BM, Nayyar N, Bertalan MS, Stocking JH, Markson SC, Lastrapes M, Alvarez-Breckenridge C, Cahill DP, Gydush G, Rhoades J, Rotem D, Adalsteinsson VA, Mahar M, Kaplan A, Oh K, Sullivan RJ, Gerstner E, Carter SL, Brastianos PK. Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid. JAMA Netw Open. 2021 Aug 2;4(8):e2120040. doi: 10.1001/jamanetworkopen.2021.20040.
• Nevel KS, DiStefano N, Lin X, Skakodub A, Ogilvie SQ, Reiner AS, Pentsova E, Boire A. A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer. Neuro Oncol. 2020 May 15;22(5):675-683. doi: 10.1093/neuonc/noz208.

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 5, 2022
• First Submitted That Met QC Criteria: February 24, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 8, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: non-small cell lung cancer; EGFR; leptomeningeal disease
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: LUEGFRLM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No