Elucidating contributions to burden of disease in CNS progression for EGFR+ NSCLC.

e20692 Background: Central nervous system (CNS) metastases occur in 25-30% of patients with epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC). Osimertinib and CNS radiation have reduced CNS disease burden and improved survival after CNS progression. Limited data exists regarding predisposing factors to CNS lesion burden at time of progression. This study evaluates prior treatment strategy and disease characteristics in EGFR+ NSCLC patients to identify factors that contribute to burden of disease at time of CNS progression. Methods: Retrospective analysis of EGFR+ NSCLC patients treated at a tertiary referral center (1/1/2016–1/1/2025) identified first CNS progression after diagnosis. Primary outcome was total CNS lesions at progression, <5 (low lesion burden) or ≥5 (high lesion burden). Osimertinib vs erlotinib administration at time of progression, EGFR mutation type (exon 19 deletion, L858R), TP53 mutation, previous CNS metastases, time to CNS progression, and previous CNS radiation therapy were evaluated as potentially associated with low versus high lesion burden. Fisher's exact test determined significance (p <0.05). Secondary analysis identified patients with isolated CNS progression. Results: 67 EGFR+ NSCLC patients with CNS progression were included, with a median age of 65 years at diagnosis. Time to CNS progression was 28.5 months, 95% CI [24.0–32.9]. In the low lesion burden group (n=50), time to CNS progression was 29.2 months, 95% CI [20.5–37.2] with majority having CNS metastases at diagnosis (52%, p=0.2). In the high lesion burden group (n=17), time to CNS progression was 26.5 months, 95% CI [15.2–37.7] and majority with de novo CNS metastases (71%). Table 1 summarizes factors evaluated at time of progression in low versus high lesion burden groups. Conclusions: While no statistically significant trends in evaluated factors were seen, likely due to small sample size, a trend towards longer progression time was seen in those with lower lesion burden at time of CNS progression in EGFR+ NSCLC. High lesion burden was also more common in de novo CNS metastases. Low CNS lesion burden, possibly due to early osimertinib use, may benefit from local radiation before aggressive systemic therapy at progression. Larger studies are needed to validate these findings and develop strategies to help predict burden of CNS disease in EGFR+ NSCLC, incorporating quality of life metrics and outcomes in CNS metastatic disease to optimize treatment selection. Disease characteristics and treatment strategy at time of CNS progression stratified by low vs. high lesion burden. Low CNS burden (<5 lesions) High CNS burden (>5 lesions) p-value Exon19del 22 (69%) 10 (31%) L858R 21 (84%) 4 (16%) 0.23 Erlotinib 6 (100%) 0 (0%) Osimertinib 31 (74%) 11 (26%) 0.31 + WBRT 1 (100%) 0 (0%) *GK SRS 1 (50%) 1 (50%) No WBRT/GK SRS 47 (73%) 17 (27%) 0.62 CNS metastases at diagnosis 26 (52%) 5 (29%) No CNS metastases at diagnosis 24 (48%) 12 (71%) 0.2 *gamma knife stereotactic radiosurgery. + whole brain radiation therapy.