Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management

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.

Keywords: activating mutations; epidermal growth factor receptor (EGFR); non‐small cell lung cancer (NSCLC); tyrosine kinase inhibitors (TKIs).

FIGURE 1

Structural and functional organization of the EGFR protein. EGFR exists as an inactive monomer embedded in the cell membrane. Upon ligand binding (e.g., epidermal growth factor), the receptor dimerizes, transitioning to an activated state. This activation triggers intracellular signaling cascades, such as MAPK, PI3K‐AKT‐MTOR, which regulate cellular proliferation, survival, and differentiation. Mutations in the kinase domain of EGFR can lead to a constitutive and ligand‐independent activation of the protein and downstream pathways. EGFR indicates epidermal growth factor receptor. Created in BioRender (Maxime Borgeaud, and Timothée Olivier, 2025; https://BioRender.com/s16f601).

FIGURE 2

EGFR tyrosine kinase domain mutations. The EGFR gene is located on chromosome 7 (7p11.2). Most frequent mutations within the tyrosine kinase domain in exons 18–21 are shown. Classical‐like mutations include deletions in exon 19, L858R mutations (both are usually referred to as common EGFR mutations), and other rare point mutations. PACC mutations include most other non‐ex20ins and T790M mutations. Insertions in exon 20 represent 8%–9% of EGFR mutations. Most frequent EGFR resistance mutations, acquired after exposure to EGFR TKIs, are shown. T790M represents a resistance mutation to first‐generation or second‐generation TKIs, whereas C797S, G724S, and L718Q represent resistance mutations to third‐generation EGFR TKIs. ex20ins indicates insertion mutation at exon 20; PACC, P‐loop and αC‐helix–compressing; TKIs, tyrosine kinase inhibitors; TM, transmembrane EGFR domain. Created in PowerPoint (Timothée Olivier, 2025).

FIGURE 3

Key clinical data from trials in the first‐line metastatic setting of EGFR‐mutant NSCLC. *The IPASS trial included 10 patients with uncommon EGFR mutations. **The LASER301 trial only reported treatment‐related grade 3 or greater adverse events. AE indicates adverse events; Chemo, chemotherapy; ex20ins, insertion mutation at exon 20; Mo, months; NR, not reached; NSCLC, nonsmall cell lung cancer. Created in PowerPoint (Timothée Olivier, 2025).

FIGURE 4

(A, B) This figure illustrates key resistance mechanisms to third‐generation TKIs in EGFR‐mutant NSCLC. On‐target resistance occurs through secondary EGFR mutations, such as C797S and G724S, or through EGFR amplification. Cell cycle alterations, including the loss of CDKN2A/B or amplification of CDK4/6 and CCND1, drive uncontrolled proliferation. Resistance can also arise from bypass pathway activation, such as MET or HER2 amplification, or oncogenic mutations in KRAS, BRAF, or PIK3CA. In addition, histologic transformation enables tumor cells to evade therapy by transforming into small cell or squamous cell carcinoma. ctDNA+ indicates circulating tumor DNA‐positive; NSCLC, nonsmall cell lung cancer; TKIs, tyrosine kinase inhibitors. Created in BioRender (Maxime Borgeaud and Timothée Olivier, 2025; https://BioRender.com/s16f601).

FIGURE 5

Clinical and molecular poor prognostic factors. PFS outcomes are shown for different treatments groups from the MARIPOSA and FLAURA2 trials. This figure combines subgroup and exploratory analyses from two separate clinical studies to provide a comprehensive overview; however, caution is warranted when performing cross‐trial comparisons. Ami‐laz indicates amivantamab plus lazertinib; HR, hazard ratio; NE, not estimable; Osi, osimertinib; Osi‐CT, osimertinib plus chemotherapy; PFS, progression‐free survival. Created in BioRender (Maxime Borgeaud, 2025; https://BioRender.com/s16f601).