Structure-based classification for differential tyrosine kinase inhibitors efficacy of EGFR exon 19 deletions in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) exon 19 deletions (19del) in non-small cell lung cancer (NSCLC) confer sensitivity to tyrosine kinase inhibitors (TKIs). However, the efficacy of the individual EGFR 19del variant remains unclear. This study aims to dissect the structural disparities of various EGFR 19del mutations and associate these variations with clinical outcomes. Here, a total of 399 patients from two cancer centers covering 35 distinct EGFR 19del variants were included in this study. Through molecular docking analysis, we identified a structure-based subgroup of EGFR 19del mutations, termed CLASS 3G (E746_A750>X, E746_S752>V, L747_A750>P, and L747_T751>P). In silico and in vitro analysis demonstrated that CLASS 3G mutations had reduced binding affinity to third-generation EGFR-TKIs. Clinically, patients with CLASS 3G showed inferior PFS to non-CLASS 3G after receiving third-generation EGFR-TKIs (first-line progression-free survival: 12.8 vs. 25.6 months, P=0.045; second-line progression-free survival: 7.7 vs. 15.2 months, P=0.039). This finding was further validated in an independent cohort, confirming consistent results with the primary analysis. Additionally, we found that CLASS 3G mutations derived significant benefits from third-generation EGFR-TKIs plus chemotherapy compared with third-generation EGFR-TKIs monotherapy (32.5 vs. 12.8 months, P=0.0038). Our study identified a subgroup of EGFR 19del that responded poorly to third-generation EGFR-TKIs based on structural features of the EGFR tyrosine kinase domain. These patients benefit substantially from the combination treatment of third-generation EGFR-TKIs plus chemotherapy.