{ "abstract": "Background\n\nTissue-based tumor mutational burden (TMB) is a biomarker for immune checkpoint inhibitors; however, data on circulating tumor DNA (ctDNA)-based blood TMB (bTMB) are limited.Patients and methods\n\nWe conducted an amended phase II basket study enrolling patients with gastrointestinal (GI) cancers with high bTMB identified using Guardant360® CDx (cohorts 1 and 2) and patients with GI cancers with ultrahigh bTMB identified using Guardant360® CDx (Ultrahigh TMB GI cohort; top 2% within each GI tumor type). After early discontinuation of the Ultrahigh TMB GI cohort, the bTMB-High cohort enrolled patients with solid tumors across cancer types with bTMB score ≥14, as measured by FoundationOne® Liquid CDx. Nivolumab 360 mg was administered intravenously every 3 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) and hypothesis testing was prespecified for the bTMB-High cohort.Results\n\nSeventy patients were treated (cohort 1, n = 28; cohort 2, n = 4; Ultrahigh TMB GI cohort, n = 19; bTMB-High cohort, n = 19). The ORR was 14.3%, 0%, 21.1%, and 21.1%, respectively. In the bTMB-High cohort, the lower bound of the 90% confidence interval (CI) exceeded the prespecified 5% threshold, meeting the primary endpoint. Treatment-related grade ≥3 adverse events occurred in 8.6% of patients. Early ctDNA decline at week 3 was associated with longer progression-free survival (hazard ratio 0.51, 95% CI 0.29-0.87). Baseline bTMB did not clearly distinguish responders from nonresponders, whereas higher baseline ctDNA concentrations were associated with a lower ORR.Conclusions\n\nNivolumab showed activity in patients with ctDNA-defined bTMB-High cancers. Absolute bTMB alone did not reliably identify benefits, whereas baseline ctDNA concentrations and early ctDNA decline provided additional insight into response. These findings provide a preliminary signal supporting the prospective evaluation of ctDNA-based bTMB selection in a tumor-agnostic setting and warrant further validation in larger, randomized trials.", "abstract_shown": true, "affiliations": [ "Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan; Department of Oncology, University of Oxford, Oxford, UK.", "Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan.", "Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.", "Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.", "Department of Clinical Oncology, Aichi Cancer Center, Nagoya, Japan.", "Department of Surgery, NHO Osaka National Hospital, Osaka, Japan.", "Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.", "Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.", "Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.", "Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.", "Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan.", "Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Division of Drug and Diagnostic Development Promotion, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: tyoshino@east.ncc.go.jp." ], "article_type": "research article", "arxiv": null, "author_total": 18, "authors": [ { "affs": [ 0 ], "name": "Y Nakamura" }, { "affs": [ 1 ], "name": "T Esaki" }, { "affs": [ 2 ], "name": "T Nishina" }, { "affs": [ 3 ], "name": "E Shinozaki" }, { "affs": [ 4 ], "name": "H Taniguchi" }, { "affs": [ 5 ], "name": "T Kato" }, { "affs": [ 6 ], "name": "Y Komatsu" }, { "affs": [ 7 ], "name": "S Yuki" }, { "affs": [ 8 ], "name": "K Kato" }, { "affs": [ 9 ], "name": "M Wakabayashi" }, { "affs": [ 9 ], "name": "T Ikeno" }, { "affs": [ 9 ], "name": "Y Ishiguro" }, { "affs": [ 9 ], "name": "K Takahashi" }, { "affs": [ 9 ], "name": "Y Ikeda" }, { "affs": [ 9 ], "name": "M Asano" }, { "affs": [ 9 ], "name": "A Sato" }, { "affs": [ 10 ], "name": "T Kuwata" }, { "affs": [ 11 ], "name": "T Yoshino" } ], "bibtex": "https://research.draconitic.com/paper/2sv2ry3j24m8r.bib", "cited_by": 0, "doi": "10.1016/j.esmoop.2026.108578", "fulltext_url": "https://europepmc.org/articles/PMC13677574", "id": "2sv2ry3j24m8r", "issns": [ "2059-7029" ], "landing_url": "https://europepmc.org/article/MED/42854587", "language": "eng", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Cancer Immunotherapy and Biomarkers" ] ], "openalex": "W7221169589", "pdf_url": "https://europepmc.org/articles/PMC13677574?pdf=render", "pmcid": "PMC13677574", "pmid": "42854587", "published": "2026-10-09", "publisher": null, "ris": "https://research.draconitic.com/paper/2sv2ry3j24m8r.ris", "sources": [ { "first_seen": "2026-10-30T12:18:12Z", "native_id": "MED:42854587", "source": "europepmc", "url": "https://europepmc.org/article/MED/42854587" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers", "subfield": "oncology" } ], "title": "Nivolumab in patients with advanced solid tumors with ctDNA-defined high blood tumor mutational burden: a phase II trial.", "title_text": "Nivolumab in patients with advanced solid tumors with ctDNA-defined high blood tumor mutational burden: a phase II trial.", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:12Z", "url": "https://research.draconitic.com/paper/2sv2ry3j24m8r", "venue": "ESMO open", "versions": [] }