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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lung Cancer Non-small Cell Stage IV, Brain Metastases

Intervention / Treatment
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* Drug: Osimertinib
* Radiation: Stereotactic radiotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SRS + Osimertinib<br>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<br>* Daily oral osimertinib<br>Radiation: Stereotactic radiotherapy<br>* 1-5 fractions of stereotactic radiotherapy<br>|
| Experimental: Osimertinib alone<br>Osimertinib 80mg PO daily | Drug: Osimertinib<br>* Daily oral osimertinib<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR positive, Osimertinib, SRS