AUTHOR=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 

TITLE=Blood-based tumor mutational burden as a biomarker in unresectable non-small cell lung cancer treated with chemoradiotherapy and durvalumab

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1681420

DOI=10.3389/fonc.2025.1681420

ISSN=2234-943X

ABSTRACT=IntroductionChemoradiotherapy 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.MethodsIn 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.ResultsMedian 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.ConclusionHigh 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 RegistrationThe study is registered on www.clinicaltrials.gov  (ClinicalTrials.gov identifier: NCT04392505).