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Published on: February 17, 2022
Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group
Jennifer H Foster1, Stephan D Voss2, David C Hall3
1Baylor College of Medicine; Texas Children's Cancer and Hematology Centers, Houston, Texas.
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.
Insights
Crizotinib showed limited activity in neuroblastoma patients with anaplastic lymphoma kinase (ALK) alterations. The drug was most effective in patients with the ALK Arg1275Gln mutation, suggesting higher drug concentrations may be needed.
Area of Science:
- Pediatric Oncology
- Molecular Targeted Therapy
- Neuroblastoma Research
Background:
- Anaplastic lymphoma kinase (ALK) aberrations represent a significant therapeutic target in neuroblastoma.
- Identifying effective treatments for patients with relapsed/refractory neuroblastoma and ALK alterations is critical.
Purpose of the Study:
- To assess the antitumor activity of the first-generation ALK inhibitor crizotinib in patients with neuroblastoma and activating ALK alterations.
- To evaluate the correlation between ALK status and treatment response.
Main Methods:
- A Phase II trial involving twenty patients with relapsed/refractory ALK-positive neuroblastoma.
- Crizotinib was administered at a dose of 280 mg/m².
- A Simon two-stage design was employed to evaluate response, with evaluations at specified intervals.
Main Results:
- The objective response rate was 15% (2 partial, 1 complete response), exclusively in patients with the ALK Arg1275Gln mutation.
- Two patients with the ALK Arg1275Gln mutation achieved prolonged stable disease.
- Patients with ALK Phe1174 mutations or ALK amplification showed limited or no response.
Conclusions:
- Crizotinib demonstrated limited efficacy in this cohort, likely due to insufficient drug concentrations to overcome ATP competition.
- The ALK Arg1275Gln mutation appears to be the most sensitive to crizotinib inhibition in neuroblastoma.
