Study of Osimertinib + SRS vs Osimertinib Alone for Brain Metastases in EGFR Positive Patients With NSCLC

Open Label, Multicenter, Phase II Study of Patients With Treatment Naïve Metastatic Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases Randomized to Stereotactic Radiosurgery (SRS) and Osimertinib or Osimertinib Alone

This open-label, multicenter, randomized phase II study will evaluate the usage of osimertinib alone for brain metastases compared to SRS and osimertinib in patients with newly diagnosed, treatment naiive EGFR positive lung cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Brain Metastases; Lung Cancer Non-small Cell Stage IV
• Intervention / Treatment: Drug: Osimertinib; Radiation: Stereotactic radiotherapy

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer, Vancouver Centre
  • Ontario
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • Princess Margaret Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able to provide written informed consent by patient or legally acceptable representative
• Meets the criteria in the approved regulatory indication for first line treatment with osimertinib and agree to the restrictions, monitoring, and dose-adjustment criteria stipulated in the associated product label
• Epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations)
• No prior systemic therapy except neoadjuvant, adjuvant or concurrent chemotherapy given greater than 3 months prior to enrollment on study
• Asymptomatic or minimally symptomatic brain metastases (ie. Headache, nausea, or seizure responsive to dexamethasone/analgesic/antiepileptic on stable doses of medications for a minimum of 3 days)
• Brain metastases must meet the following criteria on a diagnostic MRI: at least one lesion can be classified as measurable disease per RANO-BM, ≤ 10 brain or brainstem metastases, ≤ 30 mm and brainstem metastases must be ≤ 5 mm, metastases > 5 mm from the optic nerve or chiasm
• ECOG performance status 0-2
• Life expectancy > 6 months
• Willing to abstain from sexual activity or willing to use double-barrier method during sexual intercourse

Exclusion Criteria:

• Previous treatment with osimertinib, or any other EGFR TKI
• Patient with symptomatic brain metastases causing any neurologic deficit (not including headache, nausea, or medically controlled seizure)
• Multiple sclerosis
• Pacemaker or MRI-incompatible metal in the body
• Allergy to gadolinium MRI contrast
• Brain metastasis requiring surgery for decompression
• Leptomeningeal disease
• Previous cranial RT, or surgery for brain metastases
• Uncontrolled systemic lupus erythematosis, scleroderma or other connective tissue disorders considered a contraindication for radiotherapy
• Active cancer from another anatomical site within 5 years (non-melanomatous skin and cervical cancers permitted)
• Any medical or non-medical issue that would render patient unable to reliably complete regular QOL and neurocognitive assessments
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater
• Patients with symptomatic CNS metastases who are neurologically unstable
• Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4
• Patients taking any drugs that are known to prolong QT interval that can't be withdrawn prior to Osimertinib
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SRS + Osimertinib; Stereotactic radiotherapy will be delivered in 1-5 fractions to each brain metastases according to the volume and location of the metastases and clinician discretion. Osimertinib will start 1-7 days post radiotherapy.	Drug: Osimertinib; Daily oral osimertinib; Radiation: Stereotactic radiotherapy; 1-5 fractions of stereotactic radiotherapy
Experimental: Osimertinib alone; Osimertinib 80mg PO daily	Drug: Osimertinib; Daily oral osimertinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial progression free survival	Absence of progressive brain metastases according to the Response Assessment in Neuro-Oncology Brain Metastasis (RANO-BM criteria)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial overall response rate	partial or complete response to therapy based on RANO-BM criteria	2 years
Time to whole brain radiotherapy (WBRT)	time from randomization to WBRT	2 years
Time to stereotactic radiosurgery (SRS)	time from randomization to SRS (not including initial SRS in the SRS + osimertinib treatment arm)	2 years
Rate of radionecrosis	according to institutional standards based on radiologic findings with or without pathologic confirmation and multidisciplinary review when required	2 years
Overall survival	defined as time from randomization to death by any cause	2 years
Time to distant progression	time from randomization to progression of extracranial metastases or development of new sites of disease per RECIST 1.1	2 years
Quality of life	Assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30. Subscales for: general presence of symptoms in patients with cancer question 1-28 (1=Not at all; 4=very much); overall health/quality of life question 29-30 (1=very poor; 7=excellent) & EORTC-QLQ Brain Neoplasm (BN)20: Subscales for presence of symptoms in patients with brain tumours question 31-50 (1=Not at all; 4=very much)	2 years
Neurocognitive function	Assessed by Montreal Cognitive Assessment. Total score:30. 1=poor function; 30=good function	2 years
Exposure to osimertinib	Osimertinib dose (40mg or 80mg) for x number of days (max=730 days)	2 years

Collaborators and Investigators

• Sponsor: British Columbia Cancer Agency
• Collaborators: Sunnybrook Health Sciences Centre; AstraZeneca; Princess Margaret Hospital, Canada
• Investigators: Principal Investigator: Shilo V Lefresne, MD, FRCPC, BC Cancer, Vancouver Centre; Principal Investigator: Cheryl Ho, MD, FRCPC, BC Cancer, Vancouver Centre

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2019
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 6, 2018
• First Posted (Actual): December 7, 2018

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Osimertinib; SRS; EGFR positive
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Osimertinib
• Other Study ID Numbers: LUOSICNS

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