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<p>Osimertinib, the first approved third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), exhibits notable efficacy in <i>EGFR</i>-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 <i>EGFR</i> 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 <i>MET</i> amplification. At the first-line treatment failure of osimertinib (study entry), <i>EGFR</i> alterations in tissue samples included <i>EGFR</i> Ex19del (49.0%, 73/149), <i>EGFR</i> L858R mutation (43.0%, 64/149), <i>EGFR</i> amplification (32.9%, 49/149), <i>EGFR</i> L718Q/V mutation (4.7%, 7/149), and <i>EGFR</i> C797S mutation (3.4%, 5/149); bypass signaling activation and downstream pathway activation alterations included <i>TP53</i> mutation (69.8%, 104/149) and <i>MET</i> amplification (30.9%, 46/149). Among the 136 patients with <i>EGFR</i> Ex19del/L858R mutation in tissue samples, 72.1% (98/136), 35.3% (48/136), and 32.4% (44/136) had <i>TP53</i> mutations, <i>EGFR</i> amplification, and <i>MET</i> 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 <i>MET</i> 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 <i>MET</i> amplification.</p>

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A prospective, multicenter, comprehensive genomic profile signature study in patients with EGFR-mutant advanced non-small cell lung cancer at the first-line treatment failure of osimertinib

  • 期刊论文

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  • 发表日期：

    2025年12月2日

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  • Yuankai Shi,
  • Dongqing Lv,
  • Weineng Feng,
  • Shuoyan Liu,
  • Puyuan Xing,
  • Yan Yu,
  • Jun Yin,
  • Xiubao Ren,
  • Junqiang Zhang,
  • Gaohua Han,
  • Yongchang Zhang,
  • Shundong Cang,
  • Jun Chen,
  • Enguo Chen,
  • Lingxin Meng,
  • Yong Zhang

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.