1326P Osimertinib in patients with EGFR-mutated NSCLC and leptomeningeal or brain metastases: Results of the IFCT-1804 ORBITAL trial

Advanced Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are at an increased risk of developing central nervous system (CNS) metastases, which can lead to significant morbidity and mortality. Although osimertinib is the recommended first-line treatment in this population, its efficacy in treating CNS metastases has been poorly studied. ORBITAL is a multicenter phase II trial investigating the efficacy and safety of osimertinib 80 mg/d in EGFR-mutated NSCLC patients with leptomeningeal metastases (cohort 1) or patients with brain metastases who have not received prior EGFR-Tyrosine kinase inhibitor or radiation therapy (cohort 2). The primary endpoint was objective response rate (ORR) at 6 months, secondary endpoints included progressionfree survival (PFS), overall survival (OS), CNS ORR and CNS PFS. Brain magnetic resonance imaging (MRI) was performed every 6 weeks during first year and then every 8 weeks. 53 patients were included (8 patients in cohort 1 and 45 patients in cohort 2, 70% were female and 62% never smokers). Median age was 68 years. EGFR mutations were mostly del19 (60.4%) and L858R (30.2%). The number of previous lines of therapy was ≥1 in 75% of patients in cohort 1 and 11.1% in cohort 2. The median follow-up time was 11.2 months in cohort 1 and 19.8 months in cohort 2. ORR at 6 months was 37.5% (n=3/8, CI95%: 4.0%-71.0%) in cohort 1 and 60% (n=27/45, CI95%: 45.7%-74.3%) in cohort 2. Median PFS was 7.4 months [CI95%: 2.7-NR] (12-month PFS: 21.4%) and 12.6 months [CI95%: 6.9-26.2] (12-month PFS: 52.2%), in cohort 1 and 2 respectively. Median OS was 7.4 months [CI95%: 2.7-NR] (12-month OS: 46.9%) and 30.3 months [CI95%: 15.6-NR] (12-month OS: 74.7%), in cohort 1 and 2 respectively. In cohort 2, CNS ORR at 6 months was 57.8% (n=26/45, CI95%: 43.3%-72.2%) and CNS PFS was NR [CI95%: 9.7-NR]. Safety /tolerability were as expected with no new safety signal. Osimertinib demonstrated clinically meaningful responses in patients with EGFR-mutated NSCLC against both leptomeningeal and brain metastases. Safety profile was acceptable and manageable. Tumour and blood samples will be analysed for exploratory biomarkers.