576P - Clonality of both EGFR and co-occurring TP53 mutations affect the treatment efficacy of the third-generation EGFR-TKIs in advanced-stage EGFR-mutant non-small cell lung cancer

Background

As third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the frontline treatment for advanced EGFR-mutant non-small cell lung cancer (NSCLC), heterogenous responses are commonly observed. This study aimed to investigate the influence of clonal architecture involving EGFR and co-occurring genetic mutations on the response to EGFR-TKIs.

Methods

We gathered a large, homogenous cohort of treatment-naive patients with advanced EGFR-mutant NSCLC who underwent tissue next-generation sequencing (NGS) and received first-line treatment with third-generation EGFR-TKI. Variant allele frequency (VAF) from NGS was normalized based on copy numbers of genes. The VAF of each mutation relative to the maximum VAF in each sample was computed to determine clonality.

Results

A total of 160 eligible patients were enrolled at SYSUCC from January 2019 to January 2023. The aberrant TP53 gene was the most frequent co-alteration, accounting for 68.1% of total cases. EGFR (51.9%) was the most common gene occupying the maximum VAF, followed by TP53 (28.8%), RBM10 (4.4%), RB1 (1.9%), and PIK3CA (1.3%). Both EGFR and TP53 mutations exhibited potential as dominant or subordinate clones in advanced NSCLC. Notably, EGFR-mutant patients receiving first-line third-generation EGFR-TKIs demonstrated significantly prolonged progress-free survival (PFS) when EGFR dominance clone prevailed over EGFR sub-clonal status (median PFS: 22.0m VS. 15.0m, P=0.008). Conversely, TP53 dominance clone correlated with diminished treatment outcomes compared to TP53 sub-clonal cases (median PFS: 15.1m VS. 17.7m, P=0.05). Multivariate analysis confirmed EGFR clonality and TP53 clonality as independent predictors of EGFR-TKI response. Moreover, the clinical impact of EGFR and TP53 clonality was validated in an independent cohort.

Conclusions

Our proof-of-concept study illuminates the clinical significance of both EGFR and TP53 clonality in EGFR-mutant patients with advanced NSCLC who received first-line third-generation EGFR-TKIs. EGFR or TP53 mutations exhibit potential as dominant or subordinate clones, intricately linked to the efficacy of third-generation EGFR-TKIs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.