Clinical outcomes and genomic landscape of patients (pts) with EGFR-mutant lung cancer (EGFR plus LC) with central nervous system (CNS) metastases (mets)

e21146 Background: CNS mets are a major cause of morbidity and mortality in pts with LC. Up to 50% of pts with EGFR+ LC develop CNS mets over their disease course despite improvements in anti-EGFR therapies. The genomics alterations present in CNS mets in pts with EGFR+ LC and how these may compare to paired systemic samples has not been reported. Furthermore, it is unknown whether there are baseline clinicogenomic features that differ between EGFR+ LC pts with or without (w/wo) CNS mets. Methods: From an institutional database of LC pts with available next-generation sequencing (NGS) completed by MSK-IMPACT, we identified all EGFR+ LCs with molecularly characterized CNS tumor samples (CTS). We subsequently identified all pts with EGFR+ LCs with available paired CTS and systemic tumor samples (STS) profiled with MSK-IMPACT. All pts treated with 1L osimertinib with MSK-IMPACT available on their STS were also identified. We assessed clinicogenomic features of all selected EGFR+ LCs. Comparisons of frequencies of genes altered by somatic alterations were performed using Fisher’s exact test and logistic regression. Results: From 2014 to 2022, 90 EGFR+ LC pts with NGS performed on CTS were identified [brain metastasis (BrM), n = 38; leptomeningeal w/wo BrM (LM), n = 52]. 69 pts (77%) were female, median age 59 (IQR range:53-66 years), and 51 pts (57%) were never smokers. Patterns of EGFR+ were exon 19del (n = 43), L858R (n = 27) and atypical (n = 20). No genomic mutations were differentially altered in pts with LM vs BrM. Paired CTS and STS were available for 28 pts, where numerically higher rates of CDKN2A, CDKN2B loss and RAC1 amplification were seen in the CTS (respectively 43% vs 18%, 43% vs 18%, and 21% vs 0%, q > 0.05 for all). A total of 263 pts on 1L osi had NGS on their STS performed:136 pts (52%) had CNS mets during their disease course to date [94 pts (69%) de novo CNS mets; 42 pts with on-treatment CNS mets with median time to CNS mets of 25 mo (IQR: 13.5-35.3 mo)]. Between pts w/wo a lifetime history of CNS mets, there were no differences in sex, smoking history, EGFR alterations and co-alterations. CARD11 alterations were numerically higher in STS in pts with CNS mets (12% vs 2%, q > 0.05). Conclusions: In patients with EGFR+ LC, there were no genomic alterations that were significantly enriched in CNS mets compared to systemic disease, and no systemic genomic alterations that differentiate pts w/wo CNS mets.