Related Experiment Video
Updated: Jul 4, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer
Joris van de Haar1,2,3, Joanne M Mankor4, Karlijn Hummelink5
1Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Purpose:
The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease.
Experimental Design:
To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).
Results:
In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival.
Conclusions:
The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.
Insights
Tumor mutational burden (TMB) combined with STK11, KEAP1, and EGFR alterations can predict immune checkpoint blockade (ICB) response in non-small cell lung cancer (NSCLC). High TMB predicts response even with these biomarkers, avoiding overtreatment.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- The clinical utility of STK11, KEAP1, and EGFR alterations in predicting immune checkpoint blockade (ICB) response in non-small cell lung cancer (NSCLC) is debated.
- Some NSCLC patients with these genetic alterations paradoxically exhibit durable responses to ICB therapy.
- There is a critical need for refined combinatorial biomarker strategies to accurately identify patients likely to benefit from ICB.
Purpose of the Study:
- To develop a more specific combinatorial biomarker approach for predicting ICB unresponsiveness in NSCLC.
- To evaluate the predictive value of STK11, KEAP1, and EGFR alterations in conjunction with tumor mutational burden (TMB) for ICB response.
Main Methods:
- A comprehensive analysis of 254 NSCLC patients treated with PD-L1 blockade monotherapy.
- Utilized whole-genome sequencing (WGS) in a discovery cohort (n=75) and large panel sequencing in a validation cohort (n=169).
- Assessed the specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness across low (<10 muts/Mb) and high (≥10 muts/Mb) TMB strata.
Main Results:
- In low TMB NSCLC, STK11/KEAP1/EGFR alterations were highly specific for ICB resistance (0-2.9% response rate).
- In high TMB NSCLC, a significant proportion of patients with these alterations still showed durable ICB benefit (44-85% response rate).
- Progression-free and overall survival analyses supported these findings.
Conclusions:
- Unexpected ICB responses in patients with STK11, KEAP1, or EGFR alterations were predominantly observed in those with high TMB.
- Integrating TMB with STK11, KEAP1, and EGFR alterations provides a highly specific combinatorial biomarker strategy.
- This approach can help limit overtreatment in NSCLC patients undergoing ICB therapy.
More Related Videos
07:42Patient-Derived Tumor Explants As a "Live" Preclinical Platform for Predicting Drug Resistance in Patients
Published on: February 7, 2021
08:14MicroRNA Based Liquid Biopsy: The Experience of the Plasma miRNA Signature Classifier MSC for Lung Cancer Screening
Published on: October 26, 2017
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:27Tumor Immunotherapy