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

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.