Risk Stratification and Strategies Towards Front-Line Therapy of EGFR-Mutant NSCLC: A Narrative Review

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treatment is rapidly advancing.
• Heterogeneous outcomes in EGFR-mutant NSCLC are influenced by mutations, CNS involvement, and tumor burden (ctDNA).

Purpose of the Study:

• To review risk stratification frameworks for EGFR-mutant NSCLC.
• To evaluate treatment intensification and adverse effect management.
• To explore the role of circulating tumor DNA (ctDNA) in personalized therapy.

Main Methods:

• Comprehensive literature search of major medical databases.
• Review and quality assessment of relevant studies on EGFR-mutant NSCLC workup and management.

Main Results:

• Co-alterations (TP53, RB1) and CNS involvement predict poorer outcomes, suggesting treatment intensification.
• Combination therapies (osimertinib + chemo/amivantamab) improve PFS and delay CNS progression versus osimertinib alone.
• Treatment intensification increases toxicity (dermatologic, infusion reactions); ctDNA is a prognostic marker, with predictive roles under investigation.

Conclusions:

• EGFR-mutant NSCLC treatment is shifting towards integrated approaches considering molecular features, CNS status, and ctDNA response.
• Intensified regimens offer efficacy but require proactive toxicity management.
• ctDNA-guided therapy escalation/de-escalation is a promising frontier for personalized lung cancer treatment.