2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12A.23 PD-L1 Induced Resistance to EGFR-TKIs in Lung Adenocarcinoma

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The study investigates how PD-L1 expression induces resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma (LUAD) patients with EGFR mutations. It highlights that PD-L1-positive status in these patients typically reduces the effectiveness of EGFR-TKIs, and aims to uncover the underlying mechanisms and suggest potential treatment strategies.<br /><br />The study involved 103 patients, and data were collected using next-generation sequencing (NGS) to evaluate PD-L1 expression. Various analyses, such as mutational signature analysis and clonality analysis, were employed to distinguish the genetic differences between PD-L1-negative and positive groups and assess tumor mutational burden (TMB) and DNA damage response and repair (DDR) status.<br /><br />Key findings included that the SMO gene alteration was exclusive to PD-L1-positive patients. Also, MET amplification was higher in this group. Signature SBS42, potentially tied to haloalkane exposure, was more frequent among PD-L1-positive patients, while signature SBS31, linked to better response to platinum-based chemotherapy, was prevalent among PD-L1-negative patients.<br /><br />Mechanisms of EGFR-TKI resistance involve divers mutations in downstream pathways, notably PI3K, AKT, mTOR. Clonal RARA and PIK3CA were more common, while TP53 was predominantly subclonal in PD-L1-positive patients, suggesting higher PD-L1 expression. Progression-free survival (PFS) analysis indicated that PD-L1 expression correlates with shorter PFS under EGFR-TKI monotherapy. However, combining EGFR-TKIs with chemotherapy significantly improved PFS.<br /><br />Ultimately, the study proposes that a combined treatment approach with EGFR-TKIs and chemotherapy as a first-line strategy might better counteract PD-L1-induced resistance in patients with concurrent PD-L1 expression and EGFR mutations, providing a potentially more effective therapeutic option.

Asset Subtitle

Guangming Yi

Meta Tag

Speaker Guangming Yi

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

PD-L1 expression

EGFR-TKIs resistance

lung adenocarcinoma

EGFR mutations

next-generation sequencing

tumor mutational burden

DNA damage response

SMO gene alteration

MET amplification

combination therapy