OA16.03 Matched Targeted Therapy by cfDNA of CSF Beyond Leptomeningeal Metastases Progression Upon Osimertinib in EGFR-Mutated NSCLC Patients

Despite better efficacy of osimertinib for central nervous system (CNS) metastases, CNS progression is still frequently seen in EGFR-mutated NSCLC patients. Currently, clinical utility of cerebrospinal fluid (CSF) as well as subsequent treatments were unexplored after standard-dose osimertinib failure with leptomeningeal metastases (LM) progression. EGFR-mutated NSCLC patients who failed osimertinib 80 mg and had diagnosis of LM were included. Reasons for osimertinib failure were collected. CSF next-generation sequencing was performed where available. A total of 112 EGFR-mutant NSCLC patients with LM who experienced osimertinib 80 mg failure were identified. Only those with LM as progression site were finally included for analysis (n=70), median age of 54 years, nearly a half female (47.1%), and predominantly never smokers (87.4%). EGFR mutations were exon 19 deletion (52.9%), L858R (41.4%) and uncommon mutations (5.7%). Among the entire cohort, continuing osimertinib had longer OS than regimen switch (10.4 versus 4.2 months, P=0.04). This benefit of continuation maintained in the LM-only progression group (10.9 versus 3.3 months, P<0.001), not in the systemic progression group (7.5 versus 16.9 months, P=0.3). Based on CSF NGS at the time of LM-only progression upon osimertinib, resistant mechanisms were found: C797S mutations, MET copy number gain, EGFR copy number gain and NTRK fusion. These patients then received matched treatments and showed a median OS of 7.9 months. Matched targeted therapies indicated no difference in OS compared with unmatched group (7.9 versus 12.5 months; P=0.4). Serial monitoring by CSF also saw dynamic changes of genetic alterations (KRAS, CDKN2A) at baseline, first and second osimertinib progression. (Figure) For patients who failed osimertinib with LM as the progression site, continuation of osimertinib demonstrated an improved OS. Besides, biomarker-matched therapy based on CSF NGS might be considered beyond LM progression upon osimertinib.