A Study to Evaluate the Efficacy of Osimertinib With Early Intervention SRS Treatment Compared to the Continuation of Osimertinib Alone, in Patients With EGFR Mutated NSCLC and Asymptomatic Brain Metastases

A Multi-center, Open-label, Randomized, Two-arm Study, to Evaluate the Efficacy of Osimertinib With Early Intervention SRS Treatment Compared to the Continuation of Osimertinib Alone, in Patients With EGFR Mutated NSCLC and Asymptomatic Brain Metastases.

This study involves patients with EGFR-mutated NSCLC and asymptomatic brain metastases. This is an open-label, randomized study, comparing the continuation of Osimertinib treatment alone to Osimertinib treatment combined with early intervention stereotactic radiosurgery (SRS). The current first line of care for EGFR-mutated NSCLC is administration of Osimertinib, a small molecule that penetrates the blood brain barrier (BBB) well and controls majority, but not all, of the brain metastases. We hypothesize that relatively early intervention with SRS to brain metastases that are still visualized by MRI 2 months-post initiation of Osimertinib treatment, LUNG- will improve long term brain control, cognitive abilities and potentially overall survival. Patients with EGFR-mutated NSCLC and asymptomatic brain metastases will be treated with Osimertinib for 2 months. Brain MRI scans will be collected pre-Osimertinib and 2 months after treatment start. Patients with asymptomatic brain metastases present after 2 months of Osimertinib will be randomized into one of two study arms. Arm A patients will be treated with SRS while continuing Osimertinib, while arm B patients will continue with Osimertinib alone. Patients will be assessed based on brain and whole body progression by RECIST. Patients will also be assessed for CNS-PFS and body-PFS, cognitive function, Quality of life and overall survival status via routine follow-up tests.

Inclusion Criteria:

1. Newly diagnosed metastatic NSCLC, not amenable to curative surgery or curative radiotherapy.

2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice.

3. An MRI showing brain metastases. At randomization, number of brain lesions is under 20. Patients with over 20 brain lesions at randomization MRI will be suitable for whole brain radiation, and will not be randomized.

4. Brain metastases are asymptomatic or with minor symptoms (ECOG≤2) at study randomization.

5. ECOG performance status ≤2 and a minimum life expectancy of at least 6 months

6. Must be eligible and receive Osimertinib as their anti EGFR TKI at time of randomization.

7. Must be eligible for SRS treatment at time of randomization.

8. Provided written informed consent.

9. Be male or female and at least 18 years of age on the day of signing informed consent.

10. Female patients:

    1. Willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment
    2. Not breast feeding
    3. Have a negative pregnancy test prior to the start of dosing if of childbearing potential or have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
    4. Post-menopausal, defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range for the institution iii. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

11. Male patients who are willing to use barrier contraception (i.e. condoms) until 4 months after the final dose of study treatment.

Exclusion Criteria:

• a. Prior treatment with:

  1. Anti EGFR TKI treatment.

  2. Checkpoint inhibitors immunotherapy for metastatic NSCLC.

  3. Whole brain radiation (WBRT) and/or Stereotactic Radiosurgery (SRS).

  4. 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.

  5. An investigational drug within five half-lives of the compound.

  6. Any other cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of entry to the study.

     b. Systemic progression under Osimertinib treatment between screen and randomization systemic scan, per RECIST1.1.

     c. Spinal cord compression unless asymptomatic and stable. d. Leptomeningeal disease. e. 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 hospitalization 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.

     f. 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.

     g. 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.

     h. Involvement in the planning and conduct of the study i. 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.