Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

Abstract

PURPOSE:

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.

PATIENTS AND METHODS:

Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor 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.

RESULTS:

The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (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 three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count.

CONCLUSIONS:

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.See related commentary by Schulte and Eggert, p. 3507.

• Authors: Jennifer H Foster, Stephan D Voss, David C Hall, Charles G Minard, Frank M Balis, Keith Wilner, Stacey L Berg, Elizabeth Fox, Peter C Adamson, Susan M Blaney, Brenda J Weigel, Yael P Mossé
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 13 Pg. 3543-3548 (07 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33568345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Crizotinib
• Anaplastic Lymphoma Kinase

Topics

• Anaplastic Lymphoma Kinase (genetics)
• Child
• Crizotinib (therapeutic use)
• Humans
• Lung Neoplasms (drug therapy)
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Neuroblastoma (drug therapy, genetics)
• Protein Kinase Inhibitors (adverse effects)