Risk-adapted therapy guided by human papillomavirus (HPV) circulating tumor DNA in HPV-positive oropharyngeal cancer (ReACT 1.0): an exploratory phase II trial.

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.