A1 Refereed original research article in a scientific journal
Blood-based tumor mutational burden as a biomarker in unresectable non-small cell lung cancer treated with chemoradiotherapy and durvalumab
Authors: Horndalsveen, Henrik; Haakensen, Vilde Drageset; Madebo, Tesfaye; Grønberg, Bjørn Henning; Halvorsen, Tarje Onsøien; Koivunen, Jussi; Oselin, Kersti; Cicenas, Saulius; Helbekkmo, Nina; Aanerud, Marianne; Ahvonen, Jarkko; Silvoniemi, Maria; Bjaanæs, Maria Moksnes; Farooqi, Saima; Nebdal, Daniel; Dalsgaard, Astrid Marie; Danielsen, Britina Kjuul; Børve, Mari; Dalen, Tonje Sofie; Öjlert, Åsa Kristina; Helland, Åslaug
Publisher: Frontiers Media SA
Publication year: 2025
Journal: Frontiers in Oncology
Article number: 1681420
Volume: 15
ISSN: 2234-943X
eISSN: 2234-943X
DOI: https://doi.org/10.3389/fonc.2025.1681420
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.3389/fonc.2025.1681420
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505283038
Introduction: Chemoradiotherapy followed by durvalumab is a potentially curative treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), but clinical outcomes remain highly variable. Identifying robust biomarkers is essential to refine treatment selection and enable risk-adapted strategies.
Methods: In this multicenter, prospective cohort study, 86 patients with unresectable stage III NSCLC were treated with chemoradiotherapy followed by durvalumab. Baseline plasma samples underwent genomic profiling and blood tumor mutational burden (bTMB) assessment using targeted next-generation sequencing. Associations between bTMB, circulating tumor DNA (ctDNA) alterations, PD-L1 expression, and progression-free survival (PFS) were evaluated using a one-sided significance threshold of p < 0.10.
Results: Median PFS was 18.9 months (95% CI: 14.7-not reached), and median bTMB was 6.6 mutations/megabase. In univariable analysis, high bTMB was associated with longer PFS using both the prespecified 8.5 mut/Mb cut-off (HR: 0.65; p = 0.088) and the median 6.6 mut/Mb cut-off (HR: 0.52; p = 0.016). PD-L1 ≥ 1% was associated with longer PFS (HR: 0.38; p = 0.0003), while STK11, KEAP1, or NFE2L2 mutations in ctDNA were linked to shorter PFS (HR: 1.84; p = 0.040). In multivariable analysis, PD-L1 remained significantly associated with PFS in both models, while bTMB and STK11/KEAP1/NFE2L2 mutations were significant using the 6.6 mut/Mb cut-off.
Conclusion: High bTMB, PD-L1 expression ≥ 1%, and absence of STK11/KEAP1/NFE2L2 mutations were associated with longer PFS. These findings support integrating multiple biomarkers to improve risk stratification and personalize treatment in unresectable stage III NSCLC.
Clinical trial registration: The study is registered on www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT04392505).
Keywords: TMB; biomarker; circulating tumorDNA; immunotherapy; locally advanced NSCLC.
Copyright © 2025 Horndalsveen, Haakensen, Madebo, Grønberg, Halvorsen, Koivunen, Oselin, Cicenas, Helbekkmo, Aanerud, Ahvonen, Silvoniemi, Bjaanæs, Farooqi, Nebdal, Dalsgaard, Danielsen, Børve, Dalen, Öjlert and Helland.
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Funding information in the publication:
The author(s) declare financial support was received for the research and/or publication of this article. This study was researcher-initiated and funded by grants from the South-Eastern Norway Regional Health Authority (grant no: 2019119 and 26011) and AstraZeneca. The authors declare that this study received funding from AstraZeneca. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
