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.

Trial registration: ClinicalTrials.gov NCT00939770.

©2021 American Association for Cancer Research.

Figures

Figure 1.. Response characteristics in patients with ALK-mutant or amplified neuroblastoma treated with crizotinib at the recommended phase 2 dose.

This panel shows response onset duration along with exact ALK mutation for patients with neuroblastoma treated with crizotinib. The length of the bar shows the time until the patient had a PR, CR or came off protocol therapy due to disease progression. Therapy duration did not exceed 15 months. PR, partial response; CR, complete response.

Figure 2.. Representative responses to Crizotinib monotherapy in patients with activating Arg1275Gln ALK mutation.

A.Patient 114. Diagnostic CT (upper row) and 123I-MIBG SPECT/CT images (lower row) show response of an enlarged right aortocaval lymph node (arrows) to Crizotinib therapy. Images obtained at baseline and after 5 and 13 cycles of therapy, respectively, show a partial response at RP5, and a complete response at RP13, with no residual lymphadenopathy or MIBG uptake at RP13. A similar pattern of response was also shown for a separate site of retroperitoneal disease (not shown). B. Patient 121. Whole body MIBG planar images (outer panels), axial (inner left panels) and sagittal (inner right panels) fat-suppressed T2 weighted MRI images show partial response of measurable disease by MRI and MIBG-avid evaluable disease to Crizotinib therapy. The pre-sacral mass present at baseline (BL, arrow) has decreased significantly in size, with only a small focus of measurable disease (circle) remaining by RP10. Multiple sites of MIBG avid disease, including the pre-sacral soft tissue mass, left parietal skull, entire vertebral column, proximal humeri, bony pelvis, proximal femurs, distal left femur and proximal left tibia, have either resolved (left parietal skull) or are significantly decreased in signal intensity, with only faint uptake remaining at sites of baseline MIBG avid disease.

Figure 2.. Representative responses to Crizotinib monotherapy in patients with activating Arg1275Gln ALK mutation.

A.Patient 114. Diagnostic CT (upper row) and 123I-MIBG SPECT/CT images (lower row) show response of an enlarged right aortocaval lymph node (arrows) to Crizotinib therapy. Images obtained at baseline and after 5 and 13 cycles of therapy, respectively, show a partial response at RP5, and a complete response at RP13, with no residual lymphadenopathy or MIBG uptake at RP13. A similar pattern of response was also shown for a separate site of retroperitoneal disease (not shown). B. Patient 121. Whole body MIBG planar images (outer panels), axial (inner left panels) and sagittal (inner right panels) fat-suppressed T2 weighted MRI images show partial response of measurable disease by MRI and MIBG-avid evaluable disease to Crizotinib therapy. The pre-sacral mass present at baseline (BL, arrow) has decreased significantly in size, with only a small focus of measurable disease (circle) remaining by RP10. Multiple sites of MIBG avid disease, including the pre-sacral soft tissue mass, left parietal skull, entire vertebral column, proximal humeri, bony pelvis, proximal femurs, distal left femur and proximal left tibia, have either resolved (left parietal skull) or are significantly decreased in signal intensity, with only faint uptake remaining at sites of baseline MIBG avid disease.