Osimertinib with/without chemotherapy in patients with persistent ctDNA EGFR mutant (EGFRm) NSCLC at 3 weeks after 1L osimertinib: A randomized phase II study (FLAME study).

Abstract

LBA101 Background: Persistent plasma ctDNA EGFR mutations (EGFRm) at 3 weeks after first-line osimertinib predict poor outcomes in advanced EGFR-mutated NSCLC. Though osimertinib plus chemotherapy outperformed osimertinib alone in the FLAURA2 trial, it remains unclear whether patients(pts) with persistent ctDNA EGFR mutations can benefit from this combination therapy. This study aims to evaluate the efficacy and safety of osimertinib plus chemotherapy versus osimertinib monotherapy in locally advanced or metastatic EGFRm NSCLC pts with persistence plasma ctDNA EGFRm at 3weeks of 1L osimertinib monotherapy. Methods: FLAME study is a multicenter, randomized controlled, phase II study in advanced NSCLC with EGFR Ex19del/L858R mutation who retain detectable plasma ctDNA EGFRm after 3 weeks of osimertinib. Plasma ctDNA EGFRm were analyzed by Super ARMS-PCR. Pts were randomized 1:1 to osimertinib plus carboplatin-pemetrexed or osimertinib monotherapy until progression or discontinuation criterion. The clinical data of screen failures patients were collected as part of real-world study. Randomization was stratified by CNS metastases (yes/no) and EGFRm subtype. The primary endpoint is investigator-assessed PFS per RECIST 1.1. Secondary endpoints include OS rate at 18 months, ORR, DCR, DoR, depth of response, safety and resistance profile. Exploratory endpoints: dynamic multi-omics biomarkers and quality of life. Data cutoff: 26 Jan 2026. Results: Of 448 screened pts with EGFRm, 134 had persistent plasma ctDNA EGFRm after 3 weeks of osimertinib. 80 pts were randomized to osimertinib plus chemotherapy (n=40) or continued osimertinib monotherapy (n=40). Baseline characteristics were generally balanced across arms (osimertinib plus chemotherapy/osimertinib): median age, 58/61 years; 60/55% female; 53/50% Ex19del; 48/50% L858R; 35/35% CNS metastases. Osimertinib plus chemotherapy significantly improved PFS versus osimertinib monotherapy (HR 0.53; 95% CI 0.31, 0.92; p=0.024; 67.5% maturity). Median PFS was 23.1 vs.12.7 months. ORR per investigator assessment was 50% vs. 35%, and median DoR was 15.6 months and 10.5 months, respectively. Grade≥3 treatment related adverse events (TRAEs) were higher in the combination group (65% vs. 10%) but manageable; no new safety signals were identified. Conclusions: This is the first perspective randomized controlled trial showing osimertinib plus chemotherapy significantly prolongs PFS versus osimertinib in pts who exhibit persistent ctDNA EGFR mutation at 3 weeks after 1L osimertinib monotherapy. This study provides prospective evidence for individualized escalation combination therapy based on dynamic molecular detection. Funded by AstraZeneca; ClinicalTrials.gov number, NCT04769388. Clinical trial information: NCT04769388 .