Foster JH, Voss SD, Hall DC, Minard CG, Balis FM, Wilner K, Berg SL, Fox E, Adamson PC, Blaney SM, Weigel BJ, Mossé YP. Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group Study (ADVL0912). Clin Cancer Res. 2021 Jul 1;27(13):3543-3548. doi: 10.1158/1078-0432.CCR-20-4224. Epub 2021 Feb 10. PMID: 33568345; PMCID: PMC8254744.
Publication Citation
Abstract
Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase 2 dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the anti-tumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. The objective response rate for patients with neuroblastoma was 15% (95% CI: 3.3%,34.3%): two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received 3 cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.