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.

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