The landscape of metastatic non-small cell lung cancer (mNSCLC) treatment continues to evolve, with biomarker testing playing an increasingly crucial role in treatment decisions. Despite recent advances in survival rates, lung cancer remains the leading cause of cancer-related deaths in the United States, with NSCLC accounting for 80-85% of all cases.
Current State of Biomarker Testing
"As precision medicine expands in oncology, biomarker testing becomes more essential to tailor treatment plans based on a patient's unique genetic profile," explains Dr. Kristen A. Marrone of Johns Hopkins University School of Medicine. More than half of patients with metastatic adenocarcinoma NSCLC may have genetic alterations that are actionable across various treatment lines.
The National Comprehensive Cancer Network® (NCCN®) recommends comprehensive molecular profiling for mNSCLC patients, including testing for EGFR, KRAS G12C, ALK rearrangement, ROS1 rearrangement, BRAF, NTRK1/2/3 gene fusion, MET exon 14 skipping, RET rearrangement, HER2, and PD-L1 expression status.
Emerging Biomarkers and Treatment Implications
Several novel biomarkers are under investigation for their potential role in predicting treatment outcomes:
- STK11: A tumor-suppressor gene mutation associated with rapid tumor progression and poor prognosis
- KEAP1: Mutations may impact tumor growth and resistance to various anticancer therapies
- SMARCA4: Shows complex interactions with KRAS mutations that may influence immunotherapy response
- KRAS: The most common oncogene, representing approximately 30% of NSCLC cases
Role of PD-L1 in Immunotherapy Selection
PD-L1 testing remains a critical biomarker for immunotherapy decision-making, particularly for first-line treatment in patients without EGFR mutations or ALK alterations. Tumors expressing high PD-L1 levels (≥50%) typically show better responses to immune checkpoint inhibitors (ICIs).
However, Dr. Marrone notes limitations in current biomarker approaches: "We are looking to determine if we can identify novel biomarkers to help us inform disease management plans, particularly in PD-L1 negative tumor space, which remains an area of unmet need."
Future Directions in Biomarker Research
Recent research indicates that co-occurring mutations, particularly combinations of STK11, KEAP1, and SMARCA4, may significantly impact treatment outcomes. One study found that more than 95% of high-risk NSCLC tumors showed mutations in both STK11 and KEAP1, highlighting the importance of comprehensive genetic profiling.
As the field advances, the integration of next-generation sequencing (NGS) testing becomes increasingly vital for identifying rare molecular changes and emerging biomarkers. This comprehensive approach to molecular profiling will be crucial for optimizing treatment selection and improving patient outcomes in mNSCLC.
