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<p>EGFR inhibitors (EGFRi), alone or combined with chemotherapy or bispecific antibodies, are standard first-line therapy for advanced EGFR-mutant NSCLC, but their efficacy is limited by heterogeneous resistance mechanisms. To define the impact of genetic co-alterations, we analyzed two complementary real-world cohorts. Patients with EGFR exon 19 deletion or L858R mutations were included from the University Hospital Zurich (USZ; <i>n</i> = 43) and the Flatiron Health–Foundation Medicine clinicogenomic database (FH-FMI CGDB; <i>n</i> = 1927). Duration of treatment (DOT) on first-line EGFRi was assessed in relation to co-alterations at diagnosis. In the FH-FMI CGDB, shorter DOT on osimertinib was associated with co-alterations in ERBB2 (<i>p</i> &lt; 0.01), PIK3CA (<i>p</i> = 0.04), and TP53 (<i>p</i> &lt; 0.01), with similar trends for MET, KRAS, BRAF, and CCNE1. For erlotinib/afatinib, shorter DOT was observed for ERBB2 (<i>p</i> = 0.027) and TP53 (<i>p</i> &lt; 0.01), alongside additional genes. The USZ cohort showed concordant trends. TP53 was the most frequent co-alteration; variants affecting zinc-binding and dimerization domains were associated with shorter DOT. These findings identify co-alterations linked to reduced EGFRi benefit, particularly ERBB2, PIK3CA, and TP53, and highlight residue-specific TP53 effects. This supports comprehensive genomic profiling and function-based stratification to refine treatment strategies in EGFR-mutant NSCLC.</p>

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Co-alterations associated with resistance to EGFR inhibitors in advanced EGFR-positive NSCLC: insights from the precision oncology program in two large international real-world cohorts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • LA Boos,
  • C. Doerig,
  • E. Camarillo-Retamosa,
  • M. Sarwary,
  • S. Rizzo,
  • G. Gut,
  • N. Miglino,
  • L. Fábregas-Ibáñez,
  • C. Früchtenicht,
  • M. Zoche,
  • B. Bodenmiller,
  • S. Chevrier,
  • AS Eklund,
  • M. Nowak,
  • S. Rahmani-Khajouei,
  • GC Berardo,
  • L. Kaczmarek,
  • K. Bosshard,
  • W. Archey,
  • M. Bodmer,
  • D. Glinz,
  • I. Opitz,
  • S. Ulrich,
  • M. Guckenberger,
  • L. Hempel,
  • I. Stiefel,
  • P. Rahimzadeh,
  • B. Gosztonyi,
  • U. Richter,
  • L. Bankel,
  • A. Wicki

摘要

EGFR inhibitors (EGFRi), alone or combined with chemotherapy or bispecific antibodies, are standard first-line therapy for advanced EGFR-mutant NSCLC, but their efficacy is limited by heterogeneous resistance mechanisms. To define the impact of genetic co-alterations, we analyzed two complementary real-world cohorts. Patients with EGFR exon 19 deletion or L858R mutations were included from the University Hospital Zurich (USZ; n = 43) and the Flatiron Health–Foundation Medicine clinicogenomic database (FH-FMI CGDB; n = 1927). Duration of treatment (DOT) on first-line EGFRi was assessed in relation to co-alterations at diagnosis. In the FH-FMI CGDB, shorter DOT on osimertinib was associated with co-alterations in ERBB2 (p < 0.01), PIK3CA (p = 0.04), and TP53 (p < 0.01), with similar trends for MET, KRAS, BRAF, and CCNE1. For erlotinib/afatinib, shorter DOT was observed for ERBB2 (p = 0.027) and TP53 (p < 0.01), alongside additional genes. The USZ cohort showed concordant trends. TP53 was the most frequent co-alteration; variants affecting zinc-binding and dimerization domains were associated with shorter DOT. These findings identify co-alterations linked to reduced EGFRi benefit, particularly ERBB2, PIK3CA, and TP53, and highlight residue-specific TP53 effects. This supports comprehensive genomic profiling and function-based stratification to refine treatment strategies in EGFR-mutant NSCLC.