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<p>This study evaluated the clinical efficacy and safety of lorlatinib in 25 patients with anaplastic lymphoma kinase (ALK) -driven neuroblastoma. Among 17 evaluable patients, the objective response rate (ORR) was 64.7% (11/17). All six newly diagnosed high-risk patients who received lorlatinib in combination with induction chemotherapy achieved an objective response. Marked response heterogeneity was observed according to molecular profile: patients with ALK hotspot mutations alone achieved an ORR of 100%, whereas those with concurrent MYCN amplification, rare ALK mutations, or ALK amplification demonstrated significantly reduced efficacy (ORR 25.0%, p = 0.006). Acquired resistance was associated with potential bypass pathway alterations, including BRAF fusions, MET amplification, and NF1 mutations; however, functional validation of these mechanisms is still required. Pulmonary toxicity was observed in patients receiving lorlatinib combined with anti-GD2 immunotherapy or chemotherapy. These preliminary findings suggest potential efficacy of frontline lorlatinib in ALK-driven neuroblastoma, highlight molecular determinants of sensitivity, and reveal challenges of resistance and treatment-related toxicity.</p>

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Lorlatinib monotherapy or combination therapy in anaplastic lymphoma kinase–driven high-risk neuroblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Weiji Xie,
  • Yu Zhang,
  • Suying Lu,
  • Feifei Sun,
  • Jia Zhu,
  • Yi Que,
  • Junting Huang,
  • Mengjia Song,
  • Zijun Zhen,
  • Juan Wang,
  • Yizhuo Zhang

摘要

This study evaluated the clinical efficacy and safety of lorlatinib in 25 patients with anaplastic lymphoma kinase (ALK) -driven neuroblastoma. Among 17 evaluable patients, the objective response rate (ORR) was 64.7% (11/17). All six newly diagnosed high-risk patients who received lorlatinib in combination with induction chemotherapy achieved an objective response. Marked response heterogeneity was observed according to molecular profile: patients with ALK hotspot mutations alone achieved an ORR of 100%, whereas those with concurrent MYCN amplification, rare ALK mutations, or ALK amplification demonstrated significantly reduced efficacy (ORR 25.0%, p = 0.006). Acquired resistance was associated with potential bypass pathway alterations, including BRAF fusions, MET amplification, and NF1 mutations; however, functional validation of these mechanisms is still required. Pulmonary toxicity was observed in patients receiving lorlatinib combined with anti-GD2 immunotherapy or chemotherapy. These preliminary findings suggest potential efficacy of frontline lorlatinib in ALK-driven neuroblastoma, highlight molecular determinants of sensitivity, and reveal challenges of resistance and treatment-related toxicity.