Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases

Despite the intracranial efficacy of osimertinib, central nervous system (CNS) metastases remain a major cause of morbidity and mortality in EGFR-mutant non-small-cell lung cancer (NSCLC). The genomic drivers of CNS dissemination are poorly understood.

We analyzed the clinicogenomic features of patients with EGFR-mutant NSCLC receiving first-line osimertinib with extracranial next generation sequencing (NGS) (n = 262) and individuals with intracranial NGS (n = 81). Paired extra- and intracranial NGS was available for 14 patients. Time-to-event analyses were conducted from time of metastatic diagnosis, except for time-to-treatment discontinuation (TTD), which began at treatment initiation.

Among 262 patients receiving first-line osimertinib, 53% developed CNS metastases (36% de novo, 16% acquired on treatment). The cumulative incidence of brain (BrM) and leptomeningeal metastases (LM) was 39% and 2% at 1 year, 49% and 6% at 3 years, and 54% and 12% at 5 years, respectively. CNS metastases correlated with a higher frequency of CARD11 amplifications (14% versus 3%, P = 0.031) and a lower frequency of MDM2 amplifications (1% versus 13%, P = 0.008) in extracranial NGS specimens, with otherwise similar genomic profiles. Patients who developed CNS metastases on treatment had worse overall survival (OS) [hazard ratio (HR) = 3.67, 95% confidence interval (CI) 2.41 to 5.59], followed by those with de novo (HR = 1.61, 95% CI 1.15 to 2.26), compared with those who never developed CNS metastases (P < 0.001). In multivariable Cox regression, atypical EGFR mutations were associated with shorter OS. Cell cycle pathway alterations were more frequent in BrM than LM samples (93% versus 47%, P = 0.003, q = 0.03). No other significant genomic differences were found between BrM and LM, or between paired CNS and systemic samples.

Patients with atypical EGFR mutations or acquired CNS metastases on osimertinib have worse outcomes. Comparative NGS profiling of intra- and extracranial tumors suggest that CNS dissemination is driven by mechanisms beyond single-gene alterations.