Pilot, Phase 2 Study Assessing Intracranial Activity of AZD9291 (TAGRISSO) in Advanced EGFRm(EGFR Mutation) NSCLC Patients With Asymptomatic Brain Metastases

Patients will receive AZD9291 at a dose of 80 mg once daily. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan. In case of isolated CNS progression which may or may not be accompanied by asymptomatic systemic progression, and having in mind the blood-brain-barrier as a possible pharmacokinetic resistance mechanism here, AZD9291 dose will be escalated to 160 mg once daily. For patients whose intracranial disease will progress further, brain radiotherapy (in the form of SRS or WBRT) will be administered; treatment with AZD9291 will be interrupted and re-initiated at a standard dose after the end of radiotherapy course in the absence of symptomatic systemic progression. The treatment will be continued until symptomatic systemic progression, unacceptable toxicity or further intracranial progression following brain radiotherapy administration (whichever occurs first). All patients will be followed until death or 5 years.

Intracranial outcomes will be assessed by modified RECIST criteria (mRECIST) and analyzed. The added value of the increased dose (160 mg) after failure of the standard dose will be assessed as well. Since only neurologically asymptomatic patients are planned to be enrolled, it is important to use mRECIST criteria which allows small brain lesions to be assessed (according to these criteria, ≥ 5mm tumors are considered measurable and up to 5 target lesions are allowed) 1. Systemic response assessment will be done using RECIST 1.1. Exploratory analysis of the outcomes will be performed according to the treatment setting ( treatment-naïve vs. acquired resistance setting) and EGFR mutation subtype. Additionally, serum protein biomarker analysis will be performed in correlation with intracranial and systemic response. Safety parameters will be monitored.