*July 2025*
Abstract
The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR-mutant non-small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression-free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co-mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR-mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.
INTRODUCTION
The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene introduced the concept of actionable alterations in nonsmall cell lung cancer (NSCLC) and paved the way for precision medicine in lung cancer. Mutations in the tyrosine kinase domain of EGFR represent one of the most common druggable alterations in NSCLC. EGFR kinase domain mutations are found almost exclusively in lung adenocarcinomas (LUADs), with a prevalence ranging from 15% to 50% depending on ethnicity.1 They occur more commonly in patients with no smoking history, females, and patients of Asian ethnicity.2, 3 Among patients with NSCLC of East Asian genomic ancestry—determined by a single-nucleotide variant approach—the prevalence of EGFR mutations is approximately 50.3% versus 34.2%, 26.8%, 14%, and 13% for patients of South Asian, admixed American, African, and European genomic ancestry, respectively.4, 5
EGFR-mutant NSCLC represents an important health issue worldwide. Although the incidence of smoking-related lung cancers, such as squamous cell carcinoma or small cell lung cancer, is decreasing,6 LUAD, which affects both individuals with and without a history of smoking, has become the most common histologic subtype of lung cancer worldwide. LUAD is frequently associated with oncogenic driver alterations such as EGFR mutations, particularly in the absence of a smoking history. Exposure to air pollution has been associated with an increased risk of LUADs, notably EGFR-mutant NSCLC,7 and might contribute to their high incidence. Diagnosis of lung cancer in young and never-smoking patients, often thought to be at low risk of cancer, can be challenging and contributes to delayed diagnosis. Furthermore, despite improvements in survival with tyrosine kinase inhibitors (TKIs) and combination therapies and a better prognosis than that for nononcogene-addicted NSCLC, EGFR-mutant NSCLC remains a challenging disease, particularly in the metastatic setting, in which long-term disease control remains elusive. Recognizing the heterogeneity of EGFR-mutant NSCLC and the expanding number of treatment options, risk stratification and personalized strategies are relevant clinical questions.
In this review, we aim to provide a comprehensive clinical overview of the management of patients with EGFR-mutant NSCLC. Unless explicitly stated otherwise, the studies and results discussed in this report apply to the common L858R and exon 19 deletions (ex19del) EGFR mutations. The treatment of insertion mutations in exon 20 (ex20ins) is not covered in this review because ex20ins represents a distinct disease subtype with unique biology, prognosis, and therapy response.
BIOLOGY OF EGFR-MUTANT NSCLC
Functional consequences of EGFR kinase domain mutations
EGFR is a transmembrane protein localized at the cellular surface and a member of the ERBB family of tyrosine kinase receptors (Figure 1). EGFR is commonly expressed by various epithelial tissues, such as skin, lung, or gastrointestinal mucosa, in which it plays a role in regulating tissue regeneration and wound healing. In normal conditions, the EGFR protein is activated through binding of its ligand, mainly epidermal growth factor and TGF-α. Ligand binding induces dimerization of the receptor and triggers activation of the intracellular kinase domain, which then activates intracellular pathways implicated in the survival, growth, and proliferation of the cell, such as the MAP kinase and PI3K/AKT/MTOR pathways (Figure 1).8 EGFR mutations occurring in exons 18 through 21 often lead to constitutive activation of the tyrosine kinase domain. Read more.
