Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study.

Abstract

2020 Background: LM due to NSCLC progression are associated with poor prognosis. Osimertinib is an oral, CNS-active, irreversible EGFR-TKI selective for sensitizing (EGFRm) and T790M resistance mutations. Methods: In the BLOOM study (NCT02228369), pts with EGFRm advanced NSCLC who had progressed on prior EGFR-TKI therapy and had LM confirmed by positive cerebrospinal fluid (CSF) cytology received osimertinib 160 mg once daily (qd). Response was assessed (by investigator) in 2 cohorts: T790M unselected and T790M positive (by central test); results are presented as a combined analysis set. Analyses were based on CSF cytology, brain MRI imaging, and neurological examination every 6 weeks (wk; relative to first dose) until progression. Adverse events (AEs) were graded according to CTCAE. EGFR-mutant DNA in CSF was determined by ddPCR. Plasma and CSF samples were collected for PK analyses. Results: As of 24 Sep 2016,32 pts had received treatment: 21 T790M unselected; 11 T790M positive. Max treatment duration was 17.5 months (m; median 6.0 m); 21 pts ongoing. 23/32 pts had a 12-wk brain image assessment: 10 had radiological improvement, 13 had stable disease (SD). The same 23 pts had a 12-wk neurological assessment: of 8 symptomatic pts, 7 improved, 1 had SD; of 15 asymptomatic pts, 2 worsened, 13 remained asymptomatic. The geometric mean decrease in EGFR-mutant DNA copy was 57% (95% CI 30, 74) in 22 pts with pre-dose and Cycle 2 Day 1 CSF samples. Most common AEs were skin effects (n = 20), diarrhea (n = 13), nausea (n = 11) and paronychia (n = 9). All were grade (G) 1/2 except 1 case each of diarrhea and nausea (both G3). 9 pts had dose interruptions and 4 had dose reductions to 80 mg qd. Osimertinib mean concentration in CSF was 7.51 nM (range 2.19–21.1 nM) at steady state (N = 16); CSF:free plasma ratio: 16%. Accrual is now complete (n = 41; 21 T790M unselected, 20 T790M positive) and updated data (including overall survival) will be presented. Conclusions: Osimertinib penetrates the blood-brain barrier. Encouraging activity and manageable tolerability in pts with LM from EGFRm NSCLC was observed at 160 mg qd, with a median treatment duration of 6.0 m; continued evaluation is ongoing. Clinical trial information: NCT02228369.