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

Henrik Horndalsveen^1,2*Vilde Drageset Haakensen¹Tesfaye Madebo^3,4Bjørn Henning Grønberg^5,6Tarje Onsøien Halvorsen^5,6Jussi Koivunen^7,8Kersti Oselin⁹Saulius Cicenas¹⁰Nina Helbekkmo¹¹Marianne Aanerud^12,4Jarkko Ahvonen¹³Maria Silvoniemi¹⁴Maria Moksnes Bjaanæs¹⁵Saima Farooqi¹Daniel Nebdal¹⁶Astrid Marie Dalsgaard¹⁶Britina Kjuul Danielsen¹⁶Mari Børve¹⁶Tonje Sofie Dalen¹⁶Åsa Kristina Öjlert¹Åslaug Helland^1,2

• ¹Department of Cancer Genetics and Department of Oncology, Oslo University Hospital, Oslo, Norway
• ²Department of Clinical Medicine, University of Oslo, Oslo, Norway
• ³Department of Pulmonology, Stavanger University Hospital, Stavanger, Norway
• ⁴Department of Clinical Science, Universitetet i Bergen, Bergen, Norway
• ⁵Department of Clinical and Molecular Medicine, Norges teknisk-naturvitenskapelige universitet, Trondheim, Norway
• ⁶Department of Oncology, St Olav's Hospital HF, Trondheim, Norway
• ⁷Medical Research Center Oulu, Oulu, Finland
• ⁸Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
• ⁹Oncology and Haematology Clinic, North Estonia Medical Centre, Tallinn, Estonia
• ¹⁰Department of Thoracic Surgery and Oncology, National Cancer Center, Affiliate of Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
• ¹¹Department of Pulmonology, Universitetssykehuset Nord-Norge HF, Tromsø, Norway
• ¹²Department of Thoracic Medicine, Haukeland Universitetssjukehus, Bergen, Norway
• ¹³Tays Cancer Center, Department of Oncology, Tampere University Hospital, Tampere, Finland
• ¹⁴Department of Pulmonary Medicine, Turku University Hospital, Turku, Finland
• ¹⁵Department of Oncology, Oslo University Hospital, Oslo, Norway
• ¹⁶Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway

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. The study is registered on www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT04392505).