Cancer Drug Development in Never-Smoker Lung Cancer: Targeted and Immune-Based Therapeutic Strategies

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Lung cancer in never-smokers (LCINS) is a distinct subtype of non-small cell lung cancer.
• LCINS is driven by specific oncogenic alterations, not tobacco use.
• Understanding the molecular profile of LCINS is crucial for effective treatment selection.

Purpose of the Study:

• To review current and emerging targeted and immune-based therapeutic strategies for LCINS.
• To highlight how molecular features influence treatment response and resistance in LCINS.
• To discuss novel therapeutic approaches for addressing treatment gaps in LCINS.

Main Methods:

• Literature review of evidence published in the past five years.
• Focus on targeted therapies for specific genetic alterations in LCINS.
• Analysis of immune-based strategies and their efficacy in LCINS.

Main Results:

• Key driver alterations in LCINS include EGFR, ALK, ROS1, RET, MET, HER2, BRAF V600E, and NTRK.
• Third-generation tyrosine kinase inhibitors improve response rates but face acquired resistance, especially in the CNS.
• Immune checkpoint inhibitors show limited efficacy due to low mutational burden and immune activation in LCINS.

Conclusions:

• Targeted therapies are advancing treatment for specific LCINS subgroups, but resistance mechanisms require further investigation.
• Novel therapeutic strategies including antibody-drug conjugates, bispecific antibodies, and cellular therapies are under evaluation.
• Addressing CNS drug exposure and acquired resistance is critical for improving long-term outcomes in LCINS.