ALK 驱动的神经母细胞瘤患者可能对酪氨酸激酶抑制剂有反应，但会出现治疗耐药性，并且目前用于检测残留疾病的方法敏感性有限。在这里，我们提出了一个由 5 名患有复发性或难治性 ALK 驱动的神经母细胞瘤患者组成的未经选择的全国队列，这些患者接受了 lorlatinib 作为单一疗法的治疗，并测试了靶向循环肿瘤 DNA (ctDNA) 分析作为这些患者治疗决策指南的潜力。我们开发了一个测序面板，用于超灵敏检测与神经母细胞瘤或酪氨酸激酶抑制剂耐药相关的 ALK 突变，并将其用于从 4 名携带体细胞 ALK 突变的患者纵向收集的 83 个血浆样本中进行 ctDNA 分析。所有四名 ALK p.R1275Q 患者均出现重大缓解，并在开始 lorlatinib 后存活 35-61 个月。第五名 ALK p.F1174L 患者最初有部分缓解，但治疗 10 个月后复发。在所有病例中，ctDNA 在劳拉替尼单药治疗开始时均被检测到，并逐渐下降，与临床反应相关。在两名出现复发的患者中，ctDNA 分别在临床检测疾病进展前九个月和三个月增加。在一名复发肿瘤中携带 HRAS p.Q61L 的患者中，回顾性 ctDNA 分析显示，在接受 lorlatinib 治疗八个月后，该突变从头出现。我们的结论是，一些复发或难治性高危神经母细胞瘤患者对劳拉替尼单药治疗表现出持久的反应，靶向 ctDNA 分析可有效评估 ALK 驱动的神经母细胞瘤的治疗和早期检测复发。

Patients with ALK-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy, and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35-61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA was increased nine and three months before clinical detection of disease progression, respectively. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after eight months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma.