Nivolumab in patients with advanced solid tumors with ctDNA-defined high blood tumor mutational burden: a phase II trial.
12 affiliations
- 1Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan; Department of Oncology, University of Oxford, Oxford, UK.
- 2Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan.
- 3Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.
- 4Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
- 5Department of Clinical Oncology, Aichi Cancer Center, Nagoya, Japan.
- 6Department of Surgery, NHO Osaka National Hospital, Osaka, Japan.
- 7Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
- 8Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
- 9Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
- 10Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
- 11Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan.
- 12Department 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: [email protected].
Abstract
Background
Tissue-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
We 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
Seventy 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
Nivolumab 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.
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BibTeX
@article{nakamura2026nivolumab,
title = {{Nivolumab in patients with advanced solid tumors with ctDNA-defined high blood tumor mutational burden: a phase II trial.}},
author = {Y Nakamura and T Esaki and T Nishina and E Shinozaki and H Taniguchi and T Kato and Y Komatsu and S Yuki and K Kato and M Wakabayashi and T Ikeno and Y Ishiguro and K Takahashi and Y Ikeda and M Asano and A Sato and T Kuwata and T Yoshino},
journal = {ESMO open},
year = {2026},
month = oct,
doi = {10.1016/j.esmoop.2026.108578},
url = {https://europepmc.org/article/MED/42854587},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Nivolumab in patients with advanced solid tumors with ctDNA-defined high blood tumor mutational burden: a phase II trial.
AU - Y Nakamura
AU - T Esaki
AU - T Nishina
AU - E Shinozaki
AU - H Taniguchi
AU - T Kato
AU - Y Komatsu
AU - S Yuki
AU - K Kato
AU - M Wakabayashi
AU - T Ikeno
AU - Y Ishiguro
AU - K Takahashi
AU - Y Ikeda
AU - M Asano
AU - A Sato
AU - T Kuwata
AU - T Yoshino
PY - 2026
DA - 2026/10/09
JO - ESMO open
DO - 10.1016/j.esmoop.2026.108578
UR - https://europepmc.org/article/MED/42854587
AB - Background Tissue-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 We 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 Seventy 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 Nivolumab 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.
SN - 2059-7029
ER -