Revisiting Biomarker-Guided Therapy in EGFR-Mutant Non-Small Cell Lung Cancer with High PD-L1 Expression.

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• EGFR-mutant NSCLC was considered uniform, sensitive to EGFR TKIs, and resistant to ICIs.
• Emerging data reveal heterogeneity within EGFR-mutant NSCLC.
• High PD-L1 expression correlates with poorer outcomes on EGFR-TKI monotherapy.

Purpose of the Study:

• To review evidence supporting EGFR-mutant NSCLC with high PD-L1 as a distinct biological phenotype.
• To explore the clinical, molecular, and immunologic characteristics of this subtype.
• To discuss therapeutic implications and future strategies.

Main Methods:

• Synthesis of clinical data from retrospective cohorts and real-world analyses.
• Review of translational studies investigating molecular and immunologic features.
• Analysis of treatment outcomes with EGFR-TKIs and ICIs.

Main Results:

• High PD-L1 expression is linked to reduced oncogene addiction and increased genomic complexity.
• Tumor cell plasticity and a dysfunctional immune microenvironment are observed.
• PD-L1 expression marks aggressive biology and early resistance to EGFR-TKIs, not ICI benefit.

Conclusions:

• EGFR-mutant NSCLC with high PD-L1 represents a distinct, aggressive phenotype.
• Biomarker-informed, risk-adapted strategies combining EGFR-TKIs are warranted.
• Careful integration of immunotherapy and prospective validation are crucial.