High-dose osimertinib for CNS progression in EGFR+ non-small cell lung cancer (NSCLC): A multi-institutional experience.

Abstract

9586 Background: High-dose osimertinib 160 mg QD (osi160) has activity in osi-naïve, EGFR+ NSCLC pts with CNS or leptomeningeal disease (LMD) per the BLOOM trial, but the role of dose-escalation for CNS progression (PD) and/or LMD that develops while on 80 mg QD (osi80) is unclear. We describe here our multi-institutional experience with osi160. Methods: 105 pts from 8 institutions with advanced EGFR+ NSCLC treated with osi160 were retrospectively reviewed. To assess the CNS efficacy of dose escalation for CNS PD, we focused on pts who escalated from osi80 to osi160 for CNS PD without the addition of chemo and/or RT during dose escalation (cohort A, 24 pts). We also examined osi escalation for CNS PD while receiving chemo and/or RT (cohort B, 34 pts) and those who started on osi160 for CNS PD as the initial osi dose without overlapping therapies (cohort C, 11 pts). Radiographic responses were clinically assessed via chart review of scan reports. Kaplan-Meier analysis was used for time-to-event endpoints. We defined median duration of CNS disease control (MedDurCNSCon) on osi160 as time from the start of osi160 to CNS PD or discontinuation of osi160. Results: Among the 105 pts, 69 (26M, 43F; median age 57) EGFR+ NSCLC pts (29 del19, 31 L858R, 9 other) received osi160 for CNS PD between 10/2013 and 1/2020. Median lines of therapy pre-osi was 1 (range 0-8). While all 69 pts had CNS PD at the start of osi160, 61 (90%) had isolated CNS/LMD PD, without systemic PD. In cohort A, osi160 monotherapy had a MedDurCNSCon of 3.8 mos (95% CI, 1.7 – 5.8). Cohort A pts with isolated LMD (11) had MedDurCNSCon 5.8 mos (95% CI, 1.7 – 9) while those with parenchymal mets only (11) had MedDurCNSCon of 2 mos (95% CI, 1 - 4.9). In cohort B, osi160 in combination with RT (22) and/or chemo (14), had a MedDurCNSCon of 5.1 mos (95% CI, 3.1 – 6.5). In cohort C, osi160 monotherapy had a MedDurCNSCon of 4.2 mos (95% CI, 1.6 – NA). Pts on osi160 had no severe or life-threatening side effects. Conclusions: In this real-world cohort of EGFR+ NSCLC pts with CNS and/or LMD PD on osi80, dose escalation to 160 provided modest benefit with median 3.8 mos added CNS disease control. Dose escalation appeared more effective in pts with LMD versus parenchymal disease (MedDurCNSCon of 5.8 vs 2 mos). Treatment intensification with osi escalation plus RT and/or chemo appeared to confer about 1 month additional CNS disease control (power for comparison limited). Osi naïve pts started at 160 for CNS PD derived similar benefit. While limited by small numbers and retrospective design, this study suggests we need improved strategies to optimally manage CNS PD arising on osi80.