P1.13-27 A Randomized Study of Concurrent vs Sequential Alternating EGFR-TKIs and Chemotherapy for Advanced NSCLC with EGFR Mutations

Abstract

Background: Osimertinib has demonstrated promising efficacy in T790M-positive NSCLC patients with central nervous system (CNS) metastases, but there is limited data on Chinese patients. We aim to investigate the efficacy and safety of osimertinib in T790M-positive advanced NSCLC patients with brain metastases and to explore the dynamic genetic changes as well as drug penetration in CNS with paired cerebrospinal fluid (CSF) and plasma samples. Method: In this single arm, multi-center, prospective trial (NCT2972333), patients with confirmed EGFR T790M positive by Cobas, advanced NSCLC with brain metastases, who had progressed following first-generation EGFR-TKI treatment, received osimertinib 80 mg qd. The primary endpoint was overall progression free survival (PFSo). Paired CSF-plasma samples were collected at baseline, 6 weeks after treatment and disease progression and analyzed by NGS. Result: Thirty-eight eligible patients were enrolled and 12 paired CSF-plasma samples were collected. Baseline characteristics and efficacy results are summarized in Table 1. Median PFSo (60% maturity, 23/38) was 8.4 months (95% CI 5.8-11.0). Adverse events of grade 3 or higher were reported in 39.5% patients. Analyzed in 12 paired samples, the median CSF penetration rate of osimertinib was 31.7% (range 19.8-57.7%), with a median CSF concentration of 10.83nM (range 5.2-30.3nM). T790M mutation was detected in 83% (10/12) of plasma and 17% (2/12) of CSF samples at baseline, with a concordance rate of 8.3% (1/12). Median PFSo was prolonged in patients with EGFR sensitizing mutation clearance at week 6 compared with those with persisting EGFR mutations (not reached vs 2.83 months; HR 0.09, 95% CI 0.02-0.54; p<0.01).