Abstract
Circulating tumor DNA (ctDNA) has an expanding role in oncology. It is unknown whether on-treatment ctDNA can be used to personalize radiation dose. This phase 2 exploratory clinical trial enrolled 102 patients with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC). Intermediate-risk patients (T4 disease or >10 pack-year smokers with pre-treatment HPV ctDNA scores >200) were reclassified as low-risk if HPV ctDNA cleared by >95% mid-treatment. All clinically low-risk and reclassified patients received de-intensified (chemo)radiation. The primary outcome was progression-free survival (PFS) among de-escalated patients; secondary outcomes included tolerability, distant metastatic-free, and overall survival. Eighty-nine patients received de-escalated treatment (60 low-risk, 29 reclassified). Two-year PFS among de-escalated patients was 93% (95%CI, 87-99). Post-hoc analyses suggested that intermediate-risk patients reclassified as low-risk and treated with de-escalation had distinct HPV ctDNA dynamics and favorable outcomes. HPV ctDNA is an emerging biomarker that might improve risk stratification for patients with intermediate-risk HPV-positive OPC. Registration number: NCT04900623.
Acknowledgements
This clinical trial was supported by a Dana-Farber Cancer Institute Department of Medical Oncology Clinical Trial Support Award in 2021. We appreciate the in-kind TTMV-HPV DNA (NavDx) testing provided by Naveris, Inc. throughout the study. We appreciate the collaboration and enrollment efforts of our regional network site colleagues: Dr. Mahesh Pandey, Dr. Anita Koshy, Dr. Alexei Shimanovsky, and Dr. Humberto Rossi. We thank our dedicated research team, nurses, and advanced practice providers for their exceptional patient care: Garrett Kearney, Beverly Spicer, Eileen Mann, Kristen Roper, Rhondine King, Katherine Melvin, Jason Glass, and Brenna Newfell. We are most grateful to our patients and their families for their willingness to participate in this important work. This study was supported by a Dana-Farber Cancer Institute Department of Medical Oncology Clinical Trial Support Award in 2021 and a Joint Center for Radiation Therapy Grant in 2024.
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G.J.H., E.M.R., and J.D.S. have received in-kind assay support for research from Naveris and Natera. G.J.H. has served in a consulting and advisory role for Naveris, Natera, and Adela. All remaining authors have declared no relevant conflicts of interest.
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Hanna, G.J., Gupta, T.R., Trippa, L. et al. Risk-adapted therapy guided by human papillomavirus (HPV) circulating tumor DNA in HPV-positive oropharyngeal cancer (ReACT 1.0): an exploratory phase II trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72984-7
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DOI: https://doi.org/10.1038/s41467-026-72984-7
