Dynamic circulating tumor DNA-driven, risk-adapted systematic therapy in nasopharyngeal carcinoma: The EP-STAR trial.

Abstract

6010 Background: Circulating tumor-derived Epstein-Barr virus (EBV) DNA (ctDNA) during treatment has been established as a biomarker in nasopharyngeal carcinoma (NPC). However, how this information would facilitate individualized management remains unknown. We designed EP-STAR, a multicentre, phase II, adaptive trial to investigate whether the dynamic on-treatment ctDNA-driven, risk-adapted treatment strategy improved survival for NPC patients. Methods: Locoregionally advanced NPC (stage III-IVA) with detectable pretreatment EBV DNA (excluding T3N0 with EBV DNA<2000 copy/mL), who received gemcitabine plus cisplatin induction chemotherapy (IC) concurrently with longitudinal on-treatment EBV DNA monitoring were enrolled and classified into different ctDNA risk subgroups. Low-risk patients (EBV DNA post-IC1-3 =0) did not undergo treatment adaptation and continued standard therapy (chemoradiotherapy, CCRT) (No_adaptive_Arm-control). At-risk patients (intermediate/high-risk) underwent risk-based treatment adaptation (Adaptive population): intermediate-risk patients (EBV DNA post-IC1 >0, EBV DNA post-IC3 =0 or EBV DNA post-IC1 =0, EBV DNA post-IC2 >0, EBV DNA post-IC3 =0) started treatment intensification with addition of adjuvant metronomic capecitabine to CCRT (650 mg/m² orally twice daily) (Adaptive_Arm-I_cap); high-risk patients (EBV DNA post-IC1 >/=0, EBV DNA post-IC3 >0) started treatment intensification with addition of 12 cycles sintilimab to CCRT (anti-PD-1 drug, 200 mg intravenously every three weeks) (Adaptive_Arm-II_sin). Primary endpoint was failure-free survival (FFS) of adaptive population; co-primary endpoint was FFS of Adaptive_Arm-II. Results: A total of 142 patients were enrolled (58 in Adaptive_Arm-I, 52 in Adaptive_Arm-II, 32 in No_adaptive_Arm-control). Primary endpoint was met, 3-year FFS of adaptive population was 89.0% (88.4–89.6%) at a median follow-up of 41.5 months (Table 1). Data compared favorably with historic cohort of the similar populations but did not undergo adaptive therapy (3-year FFS: 74.7% [68.8–80.6%]), Table 1). Toxicity was manageable with grade 3-4 adverse events recorded in 56.1% and 59.6% patients in Adaptive_Arm-I/II during adaptive phase, respectively; no treatment-related death was observed. Conclusions: The ctDNA-driven, risk-adapted paradigm was highly likely to result in improved survival outcomes than conventional unchanging treatment strategy in NPC. Clinical trial information: NCT04072107 . Summary of FFS in EP-STAR and the similar population in historic control. EP-STAR Historic control( Prospective, Cancer Cell, 2024 ) Recruitment year 2020-2021 2019-2021 3-year FFS Intermediate & high-risk patients with or without adaptive therapy 89.0% (88.4–89.6%) 74.7% (68.8–80.6%) High-risk patients with or without adaptive therapy 86.5% (77.3–95.7%) 64.8% (55.0–74.6%) Low-risk patients 93.8% (91.0–100.0%) 90.8% (85.9–95.7%)