ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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28 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- First-line PD-1/PD-L1 inhibitors plus chemotherapy vs. chemotherapy alone in stage IIIB-IV non-squamous NSCLC: an updated meta-analysis of phase 3 RCTs.BMC cancer · 2025Pooled it
- SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma.Translational oncology · 2026Article
- Systematic identification of genomic nonresponse biomarkers to cancer therapies.ESMO real world data and digital oncology · 2026Article
- Clinical attribute-based risk matrix for prognostication in immunotherapy-treated non-small cell lung cancer.Nature communications · 2026Article
- Blood-based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage NSCLC: the prospective IOpener study.Journal for immunotherapy of cancer · 2026Article
- Advances in translational lung cancer research in 2025: a narrative review.Translational lung cancer research · 2026Review
- Real-world clinical utility of tumor whole-genome sequencing in solid cancers.Nature medicine · 2026Article
- Discovery of predictive biomarkers for cancer therapy through computational approaches.Nature reviews. Clinical oncology · 2026Review
- Integrating WGCNA and machine learning algorithm to identify ACSM5 as a prognostic biomarker and therapeutic target for predicting immunotherapy efficacy in non-small cell lung cancer.Translational cancer research · 2026Article
- Artificial intelligence in digital pathology diagnosis and analysis: technologies, challenges, and future prospects.Military Medical Research · 2026Review
- Targetable driver gene-tumor immune microenvironment axis in non-small cell lung cancer: from molecular pathological mechanisms to precision immunotherapy stratification strategies.Frontiers in immunology · 2026Review
- Prognostic significance of continuing immunotherapy beyond progression in unresectable lung adenocarcinoma.Frontiers in immunology · 2026Article
- Categorizing immunotherapy resistance mechanisms in non-small cell lung cancer: how can we perform better?Journal for immunotherapy of cancer · 2025Review
- Article
- Clinical utility of liquid biopsy next-generation sequencing for advanced non-small cell lung cancer in the Netherlands.Scientific reports · 2025Article
- Overcoming immunotherapy resistance in non-small cell lung cancer: a narrative review of related factors.Immunotherapy · 2025Review
- PD-L1 Expression and Comprehensive Genomic Profiling in Advanced NSCLC: A Single-Centre Experience.International journal of molecular sciences · 2025Article
- Very Early Health Technology Assessment for Potential Predictive Biomarkers in the Treatment of Advanced Non-Small Cell Lung Cancer.PharmacoEconomics - open · 2025Article
- Novel immune checkpoint inhibitor strategies in advanced non-small cell lung cancer: towards biomarker-driven therapies?Translational lung cancer research · 2025Article
- To be or low TMB (tumor mutational burden).Translational cancer research · 2025Article
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Authors and funding
9 authors at 6 institutions in 1 country.
Funding
Abstract
purposeThe 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
designTo 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).
resultsIn 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.
conclusionsThe 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.