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Updated: Jun 4, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Clinical perspectives on the value of testing for STK11 and KEAP1 mutations in advanced NSCLC
Michelle Shiller1, Melissa Johnson2, Robert Auber3
1Department of Pathology, Baylor University Medical Center, Dallas, TX, United States.
Abstract:
Standard first-line therapy for patients with metastatic non-small cell lung cancer (mNSCLC) without identified actionable mutations consists of regimens comprising immune checkpoint inhibitors (ICIs), alone or in combination with platinum-based chemotherapy (CTx). However, approximately 20-30% of patients with mNSCLC (including some patients with high tumor programmed cell death ligand-1 expression) display primary resistance to ICIs, either alone or in combination with CTx. Mutations in tumor suppressor genes serine/threonine kinase 11 (STK11), and Kelch-like ECH-associated protein 1 (KEAP1) often detected in patients with Kirsten rat sarcoma virus mutations, are associated with an aggressive disease phenotype and resistance to standard ICI regimens. Consequently, there is an important need for effective treatments for patients with NSCLC with STK11 or KEAP1 mutations. In this article, we describe new data on the prevalence of STK11 and KEAP1 mutations in a large clinical population, consider practicalities around the detection of these mutations using available biomarker testing methodologies, and describe experiences of managing some of these difficult-to-treat patients in our clinical practice.
Insights
Metastatic non-small cell lung cancer (mNSCLC) patients with STK11 or KEAP1 mutations often resist standard therapies. New data and clinical insights are crucial for developing effective treatments for this challenging patient group.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Standard first-line therapy for metastatic non-small cell lung cancer (mNSCLC) involves immune checkpoint inhibitors (ICIs) +/- chemotherapy.
- A significant subset of mNSCLC patients (20-30%) exhibit primary resistance to ICIs.
- Mutations in STK11 and KEAP1 genes are linked to aggressive mNSCLC and resistance to ICIs.
Purpose of the Study:
- To present new data on the prevalence of STK11 and KEAP1 mutations in a large mNSCLC patient cohort.
- To discuss practical aspects of detecting STK11 and KEAP1 mutations using current biomarker testing.
- To share clinical experiences in managing mNSCLC patients with STK11 or KEAP1 mutations.
Main Methods:
- Analysis of mutation prevalence in a large clinical mNSCLC population.
- Review of biomarker testing methodologies for STK11 and KEAP1.
- Retrospective analysis of clinical management strategies for affected patients.
Main Results:
- Detailed prevalence data for STK11 and KEAP1 mutations in mNSCLC.
- Discussion on the feasibility and challenges of molecular testing for these mutations.
- Insights into treatment outcomes and management approaches for patients with STK11/KEAP1 mutations.
Conclusions:
- STK11 and KEAP1 mutations represent a significant challenge in mNSCLC treatment due to ICI resistance.
- Accurate and accessible biomarker testing is essential for identifying these patients.
- Further research and novel therapeutic strategies are urgently needed for this difficult-to-treat population.
