Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 have significantly improved outcomes in patients with advanced melanoma. However, the optimal treatment duration remains undefined. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring and surveillance and can predict long-term clinical outcomes.Methods: Clinical and ctDNA data from prospectively enrolled patients with stage IV melanoma treated with anti–PD-1-based therapy at a single academic center were retrospectively analyzed. Of the 56 patients eligible, 28 underwent serial ctDNA testing during ICI treatment and follow-up (median 31 months) using a personalized, tumor-informed assay. Landmark analysis at 6 and 9 months was performed to assess progression-free survival (PFS) based on ctDNA status. Multivariable Cox regression was used to identify independent predictors of long-term outcomes.Results: Pre-ICI treatment, 91.7% (11/12) of evaluable patients were ctDNA-positive. At 6 months, ctDNA negativity or clearance was observed in 47.4% (9/19), and was strongly associated with improved PFS in the landmark analysis (HR: 10.0,p= 0.03; 2-year PFS: 89% in ctDNA-negative versus 30% in ctDNA-positive groups). At 9 months, persistent ctDNA positivity trended toward worse PFS. Multivariate analysis confirmed ctDNA status at the 6-month landmark timepoint to be an independent predictor of long-term benefit.Conclusions: Tumor-informed ctDNA testing is a robust, non-invasive tool to predict long-term benefit from anti–PD-1-based therapy in advanced melanoma. ctDNA clearance or sustained negativity at 6 months may serve as a surrogate for durable response and could inform individualized treatment discontinuation strategies, and minimize toxicity and cost while maintaining efficacy. These findings, derived from a limited single-center cohort, warrant further exploration and validation in larger studies.
背景：靶向PD-1的免疫检查点抑制剂（ICIs）显著改善了晚期黑色素瘤患者的预后，但其最佳治疗持续时间尚未明确。循环肿瘤DNA（ctDNA）已成为治疗反应监测和随访中具有前景的生物标志物，并能预测长期临床结局。 方法：本研究回顾性分析了某单一学术中心前瞻性入组的接受抗PD-1为基础治疗的IV期黑色素瘤患者的临床及ctDNA数据。在符合条件的56例患者中，28例在ICI治疗及随访期间（中位时间31个月）接受了基于个体化肿瘤知情检测方法的系列ctDNA检测。研究在6个月和9个月时间点进行了界标分析，以评估基于ctDNA状态的患者的无进展生存期（PFS）。采用多变量Cox回归分析以确定长期结局的独立预测因素。 结果：在ICI治疗前，可评估患者中91.7%（11/12）为ctDNA阳性。在6个月时，47.4%（9/19）的患者观察到ctDNA转阴或清除，界标分析显示这与PFS改善显著相关（HR：10.0，p=0.03；2年PFS：ctDNA阴性组为89%，而ctDNA阳性组为30%）。在9个月时，持续的ctDNA阳性显示出PFS更差的趋势。多变量分析证实，6个月界标时间点的ctDNA状态是长期获益的独立预测因子。 结论：基于肿瘤知情检测的ctDNA分析是一种可靠、无创的工具，可用于预测晚期黑色素瘤患者接受抗PD-1为基础治疗的长期获益。6个月时ctDNA的清除或持续阴性可作为持久反应的替代指标，可能为个体化治疗中止策略提供依据，在维持疗效的同时最大限度地减少毒性和治疗成本。这些发现来源于有限规模的单中心队列，需要在更大规模的研究中进一步探索和验证。
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