Abstract 576P
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.
Resources from the same session
238P - Enfortumab-vedotin for metastatic urothelial carcinoma refractory to platinum-based chemotherapy and immune checkpoint inhibitors: A single institution experience
Presenter: Yuki Endo
Session: Poster Display
Resources:
Abstract
239P - Elevated baseline C-reactive protein is a prognostic indicator for OS in patients with metastatic non clear cell renal cell carcinoma treated with systemic therapy
Presenter: Ryuichi Mizuno
Session: Poster Display
Resources:
Abstract
240P - Efficacy and safety of first-line combination therapy with ipilimumab + nivolumab for metastatic renal cell carcinoma in a single institution in Japan
Presenter: Naoya Nagaya
Session: Poster Display
Resources:
Abstract
241P - First-line cabozantinib in metastatic renal cell carcinoma (mRCC): A real-world exploratory study from eastern India
Presenter: Tamojit Chaudhuri
Session: Poster Display
Resources:
Abstract
244P - Clinicopathologic feature and treatment outcome of metastatic non clear cell kidney cancer: A single centre experience from India
Presenter: Somnath Roy
Session: Poster Display
Resources:
Abstract
245P - The role of TGF-β in the formation of the protumor phenotype of circulating neutrophils at different stages of renal cancer
Presenter: Ilseya Myagdieva
Session: Poster Display
Resources:
Abstract
246P - Impact of renal impairment on first-line treatment in metastatic urothelial cancer
Presenter: Stephanie Wakeling
Session: Poster Display
Resources:
Abstract
247P - Adjuvant chemoradiotherapy in the management of bladder adenocarcinoma compared to multiple treatment modalities
Presenter: Othman Mohammed
Session: Poster Display
Resources:
Abstract
248P - Screening zinc homeostasis-related genes identifies metallothionein 1H (MT1H) as a potential prognostic biomarker in clear cell renal cell carcinoma (ccRCC)
Presenter: Eyad Al Masoud
Session: Poster Display
Resources:
Abstract
249P - The prognostic utility of Progestogen associated Endometrial protein (PAEP) gene expression in clear cell renal cell carcinoma (ccRCC)
Presenter: Leen Lataifeh
Session: Poster Display
Resources:
Abstract