1386P - Prognostic value of EGFR A859S alteration in advanced NSCLC patients treated with third-generation EGFR-TKI

Background

The EGFR A859S alteration, a rare variant in non-small cell lung cancer (NSCLC), is located between A859 and L858 in proximity to the classic EGFR L858R driver mutation. The clinical significance A859S alteration and its effect on EGFR activity remains unclear. Therefore, this study aimed to explore the clinical and genomic features of NSCLC patients with EGFR A859S mutations.

Methods

Fifteen NSCLC patients carrying the EGFR A859S alteration were included in this study. Clinical and survival data were collected for analysis. Genomic profiling was conducted using next-generation sequencing.

Results

Common co-mutations with EGFR A859S were identified as EGFR L858R (73.3%), TP53 (40%), and STK11 (20%) mutations, with significant co-occurrence between TP53 and STK11 mutations. Notably, A859S alterations co-existing with L858R mutations were more likely to involve rare base changes at the c.2574 position rather than the classic c.2573 T>G transversion in single L858R mutations (P<0.001). Additionally, A859S-positive (A859S+) patients were older than EGFR L858R-positive (L858R+) patients (median age 68 versus 60 years, P=0.015). Moreover, we observed cases of A859S co-occurring with other driver mutations, such as EGFR 19 exon deletion and KRAS G12V mutation, as well as cases of squamous NSCLC harboring single A859S alterations. Survival analysis revealed a median progression-free survival (PFS) of 21.5 months and a median overall survival of 22.0 months for A859S+ patients with advanced NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy. Notably, longer PFS was observed particularly in patients receiving third generation TKIs, potentially attributable to higher binding affinities between these TKIs and A859S-mutated EGFR, as suggested by docking simulations. Further research is necessary to validate these findings.

Conclusions

This study identified the clinical and genomic characteristics of NSCLC patients with EGFR A859S mutations, contributing to an enhanced understanding of this rare alteration for the optimization of treatment strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

B.X. Li.

Funding

Has not received any funding.

Disclosure

Y. Ma, C. Wang, J. Yin, J. Pang, Q. Ou: Non-Financial Interests, Institutional, Full or part-time Employment: Nanjing Geneseeq Technology Inc. All other authors have declared no conflicts of interest.