1. Provided written informed consent
2. ≥ 18 years of age
3. Histological or cytological documented NSCLC
4. Metastatic NSCLC, not amenable to curative surgery or radiotherapy
5. Brain metastases that meet the following criteria;
1. Four or less lesions amenable to SRS
2. Lesion/s visible and measurable on MRI
3. Sum of lesion diameters ≤40mm
4. Diagnosed de novo (i.e. at the same time with a new diagnosis of NSCLC) or
developed as a new site of progression while on first line EGFR TKI
NOTE: Surgery as part of local practice for management of brain metastasis is allowed.
Patients must still fulfil all other criteria, particularly criteria 5a, 5b, 5c and 5d
pre-surgery, to be eligible for the study. Lesions that are partially or completely
resected should not be used as a target lesion for MRI assessment.
6. Documented EGFR mutation
7. Karnofsky performance status 80-100 with no deterioration over the previous 2 weeks
and a minimum life expectancy of 12 weeks
8. Female patients who;
1. are willing to use adequate contraceptive measures until 6 weeks after the final
dose of study treatment
2. are not breast feeding
3. have a negative pregnancy test prior to start of dosing if of child bearing
potential or have evidence of non-child bearing potential
9. Male patients who are willing to use barrier contraception (i.e. condoms) until 4
months after the final dose of study treatment
1. Treatment with any of the following:
1. Prior systemic therapy for patients with newly diagnosed metastatic NSCLC and
brain metastases de novo.
2. More than one prior line of treatment for patients who developed brain metastases
while on first line EGFR TKI.
3. An EGFR TKI (e.g. Erlotinib, Gefitinib or Afatinib) within 8 days or
approximately 5x half life, whichever is the longer, of the first dose of study
4. Previous treatment with Osimertinib or a 3rd generation EGFR TKI.
5. Previous treatment with checkpoint inhibitors immunotherapy.
6. Major surgery (excluding placement of vascular access) within 4 weeks of
7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation within 4 weeks of randomization.
8. Medications or herbal supplements known to be potent inhibitors or inducers of
CYP3A4 and are unable to stop use within the recommended wash out period prior to
receiving the first dose of Osimertinib
9. An investigational drug within five half-lives of the compound.
10. Any other cytotoxic chemotherapy, investigational agents or other anticancer
drugs from a previous treatment regimen or clinical study within 14 days of
2. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the
exception of alopecia grade 2) at the time of starting study treatment.
3. Spinal cord compression unless asymptomatic and stable.
4. Leptomeningeal disease.
5. Prior history of brain metastases with previous treatment that would preclude SRS.
These patients will include those where tumour assessments as per RANO-criteria are
6. Moderate or severe symptomatic brain metastases defined as per Radiation Therapy
Oncology Group acute morbidity grade 3 to 4.
7. Brain metastases in the brainstem.
8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the patient to participate in the trial or which would jeopardize
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of Osimertinib.
10. Any of the following cardiac criteria:
1. Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3
2. Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block or
second degree heart block.
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
11. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.
12. Inadequate bone marrow reserve or organ function
13. History of hypersensitivity of drugs with a similar chemical structure or class to
Osimertinib or any excipients of these agents.
14. Involvement in the planning and conduct of the study
15. Judgement by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and