Multicenter phase 2 trial of risk-adaptive therapy guided by dynamic ctDNA in nasopharyngeal carcinoma

Despite promising data showing the ctDNA dynamics during treatment can inform real-time tumor response and recurrence risk, how best to translate these insights into actionable clinical decision-making remains unclear. The multicenter phase 2 EP-STAR trial in China investigated whether a risk-adaptive treatment (RAT) strategy guided by on-treatment ctDNA dynamics can meaningfully improved survival, using nasopharyngeal carcinoma (NPC) as a model. Patients began treatment with standard-of-care gemcitabine-cisplatin neoadjuvant chemotherapy (GP-NAC), followed by RAT or standard-of care chemoradiotherapy guided by ctDNA clearance trajectory during GP-NAC. Protocol-eligible patients who did not receive RAT served as a non-randomized control cohort. The primary endpoint was failure-free survival (FFS) in the RAT group. After a median follow-up of 47.3 months, the 3-year FFS rate was 89.1% in the RAT group (n=110). Patients who received RAT showed significantly improved FFS compared with the no-RAT external cohort (HR 0.41; p=0.004). The RAT strategy was well-tolerated with no treatment-related deaths. The authors conclude that a ctDNA-drive RAT paradigm could be a promising strategy to improve survival.