Therapeutic Targeting of ALK in Neuroblastoma: Experience of Italian Precision Medicine in Pediatric Oncology

SIMPLE SUMMARY: Approximately 50% of high-risk neuroblastomas (NB) relapse within two years after the end of treatment. The prognosis for relapsed or refractory patients is poor, and additional therapeutic options are needed. The identification of ALK somatic mutations or amplification plays an important role in the treatment of relapsed/refractory patients. The aim of our study was to evaluate the genomic status of patients with relapsed/refractory NB and to employ ALK Tyrosine Kinase Inhibitors (TKIs) in patients with targetable ALK mutations. In the era of precision medicine, ALK inhibitors may play an important role in the treatment of high-risk, ALK-mutated, NB patients. ABSTRACT: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, within the Italian project of PeRsonalizEdMEdicine (PREME), was to evaluate the genomic status of patients with relapsed/refractory NB and to implement targeted therapies in those with targetable mutations. From November 2018 to November 2021, we performed Whole Exome Sequencing or Targeted Gene Panel Sequencing in relapsed/refractory NB patients in order to identify druggable variants. Activating mutations of ALK were identified in 8(28.57%) of 28 relapsed/refractory NB patients. The mutation p.F1174L was found in six patients, whereas p.R1275Q was found in one and the unknown mutation p.S104R in another. Three patients died before treatment could be started, while five patients received crizotinib: two in monotherapy (one with p.F1174L and the other with p.S104R) and three (with p.F1174L variant) in combination with chemotherapy. All treated patients showed a clinical improvement, and one had complete remission after two cycles of combined treatment. The most common treatment-related toxicities were hematological. ALK inhibitors may play an important role in the treatment of ALK-mutated NB patients.