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

Abstract 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.