Prognostic implications of uncommon EGFR exon 19 deletion-insertion mutations in non-small cell lung cancer treated with third-generation EGFR-TKIs

Purpose

The sensitivity of various epidermal growth factor receptor (EGFR) mutations to different EGFR tyrosine kinase inhibitors (EGFR-TKI) varies significantly. This study evaluated the survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletion-insertion (19delins) to third-generation EGFR-TKIs administered as first- or second-line therapy.

Methods

We retrospectively analyzed clinical, molecular, and survival data from 215 patients detected with EGFR 19delins between March 2020 and July 2024. To evaluate progression-free survival, 57 patients with EGFR 19del who received first-line third-generation EGFR-TKIs (cohort A), and 48 patients who received the same treatment as second-line therapy (cohort B) were selected using 1:1 propensity score matching and served as control group.

Results

Thirty-nine unique EGFR 19delins genotypes were identified, with L747_P753delinsS (34.0 %), L747_A750delinsP (18.1 %), and E746_S752delinsV (9.8 %) being the top three variants. Patients with EGFR 19delins had significantly shorter median PFS compared with patients with common exon19del (first-line, 12.9 vs. 19.7 months, p = 0.0039; second-line, 7.9 vs. 10.5 months, p = 0.0387). Exploratory analyses indicated that L747_P753delinsS might be associated with poorer prognosis, while E746_S752delinsV appeared to show better outcomes with third-generation EGFR-TKIs, findings that require further validation.

Conclusion

These findings show real-world evidence that patients with EGFR 19delins derive limited clinical benefit from third-generation EGFR-TKI therapy compared to those with common EGFR 19del mutations, suggesting the need for optimal treatment regimen in this patient population.