摘要
Osimertinib,the first approved third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI),exhibits notable efficacy in EGFR-mutant non-small cell lung cancer(NSCLC).This is a prospective,multicenter,comprehensive genomic profile signature(GPS)study in paired tissue and plasma samples from 149 patients with advanced NSCLC harboring EGFR exon 19 deletion(Ex19del)or L858R mutation at the first-line treatment failure of osimertinib(NCT05219162).Next-generation sequencing(NGS)was used for comprehensive GPS analysis of paired tissue and plasma samples.Fluorescence in situ hybridization(FISH)and next-generation sequencing(NGS)were used for tissue samples,while droplet digital polymerase chain reaction(ddPCR)and NGS were used for plasma samples to perform a concordance analysis of MET amplification.At the first-line treatment failure of osimertinib(study entry),EGFR alterations in tissue samples included EGFR Ex19del(49.0%,73/149),EGFR L858R mutation(43.0%,64/149),EGFR amplification(32.9%,49/149),EGFR L718Q/V mutation(4.7%,7/149),and EGFR C797S mutation(3.4%,5/149);bypass signaling activation and downstream pathway activation alterations included TP53 mutation(69.8%,104/149)and MET amplification(30.9%,46/149).Among the 136 patients with EGFR Ex19del/L858R mutation in tissue samples,72.1%(98/136),35.3%(48/136),and 32.4%(44/136)had TP53 mutations,EGFR amplification,and MET amplification,respectively.Taking tissue samples as references,the GPS in plasma samples showed high specificity(90.7–100%)for almost all genomic alterations.Compared with FISH(gene copy number[GCN]≥10),the overall percent agreement of tissue NGS,optimized tissue NGS(GCN≥8.63),plasma NGS,and plasma ddPCR for MET amplification were 75.0%(27/36),100%(36/36),88.9%(32/36),and 94.4%(34/36),respectively.This study represents the largest-scale,prospective study with paired tissue and plasma samples to enable comprehensive analysis of GPS,providing a novel perspective into coalterations at the first-line treatment failure of osimertinib.A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable.Moreover,the integration of FISH,NGS,and ddPCR provided a comprehensive assessment of MET amplification.
