OUTRUN: This Phase III trial is comparing the effects of giving an oral drug (Osimertinib) alone and in combination with stereotactic radiosurgery (SRS) in patients with non-small cell lung cancer (NSCLC) that has spread to the brainA Randomised Phase II Trial of Osimertinib With or Without Stereotactic Radiosurgery for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

Exclusion

1. Treatment with any of the following:

   1. Prior systemic therapy for patients with newly diagnosed metastatic NSCLC and brain metastases de novo.

      NOTE: Prior adjuvant chemotherapy or chemotherapy used as radio sensitisation followed by maintenance immunotherapy for non-resectable early stage NSCLC are allowed if such treatments were more than 6 months ago.

   2. Prior whole brain radiotherapy (WBRT)
   3. Radiologically progressive brain metastasis that underwent prior SRS (second line patients)
   4. Previous treatment with Osimertinib or a 3rd generation EGFR TKI.
   5. Previous treatment with checkpoint inhibitors immunotherapy for metastatic NSCLC.
   6. Major surgery within 4 weeks of randomisation (excluding placement of vascular access and surgery as part of local practice for the management of brain metastases, as outlined in inclusion criterion 5).
   7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomisation.
   8. Medications or herbal supplements known to be potent inducers of CYP3A4 and are unable to stop use within the recommended wash out period prior to receiving the first dose of Osimertinib, see Table 7: Medications to avoid and withdrawal periods and Table 8 NOTE: All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
   9. An investigational drug within five half-lives of the compound or 3 months, whichever is greater.
   10. Any other cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of randomisation.
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. Moderate or severe symptomatic brain metastases defined as per Radiation Therapy Oncology Group acute morbidity grade 3 to 4.

   NOTE:

   • Grade 3 refers to neurological findings requiring hospitalisation for initial management.
   • Grade 4 refers to serious neurological impairment including paralysis, coma or seizures more than three times per week despite medication and requires hospitalization.
6. Brain metastases in the brainstem.
7. 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 required.
8. 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.

9. Any of the following cardiac criteria:

   1. Resting corrected QT interval (QTc) > 470 msec, obtained from an electrocardiogram (ECG).
   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, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN), 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 interval.
10. Patients with congenital long QT syndrome (CLQTS)
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 as demonstrated by any of the following laboratory values:

    1. Absolute neutrophil count < 1.5 X 109/L
    2. Platelet count < 100 X 109/L
    3. Haemoglobin < 90 g/L
    4. Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
    5. Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases.
    6. Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
    7. Creatinine > 1.5 times ULN concurrent with creatinine clearance < 50ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.
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 requirements.