Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).
Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).
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DOI：
10.1158/1078-0432.ccr-20-4224
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Mossé YP
中科院分区：
文献类型：
--
作者：
Foster JH;Voss SD;Hall DC;Minard CG;Balis FM;Wilner K;Berg SL;Fox E;Adamson PC;Blaney SM;Weigel BJ;Mossé YP
间变性淋巴瘤激酶（ALK）畸变是神经母细胞瘤患者的一个有希望的靶点。我们评估了第一代ALK抑制剂克唑替尼在没有已知治愈治疗方法和肿瘤具有活化ALK改变的患者中的活性。20例复发/难治性alk阳性神经母细胞瘤患者以推荐的2期剂量280 mg/m2/剂量接受克唑替尼治疗。采用Simon两阶段设计来评价克唑替尼单药治疗的抗肿瘤活性。在第1、3、5、7个周期后进行反应评估，然后每3个周期进行一次。ALK状态与反应的相关性是该研究的次要目的。神经母细胞瘤患者的客观缓解率为15% (95% CI: 3.3%,34.3%): 2例部分缓解，1例完全缓解。所有3例患者都有体细胞ALK Arg1275Gln突变，这是在神经母细胞瘤中观察到的最常见的ALK热点突变，也是唯一预测对克唑替尼抑制ALK敏感的突变。2例患者病情长期稳定（分别为10和13个周期）；都携带ALK Arg1275Gln突变。3例ALK Phe1174Leu突变患者在第1周期治疗期间进展，1例ALK Phe1174Val患者在疾病进展前接受了3个周期治疗。两例ALK扩增患者无反应。最常见的不良反应是中性粒细胞计数减少。尽管在本试验中观察到有限的活性，但我们得出结论，这更可能是由于无法达到克服竞争性ATP亲和力所需的更高浓度的克唑替尼。
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.
影响因子：
3.7
作者：
George RE;Attiyeh EF;Li S;Moreau LA;Neuberg D;Li C;Fox EA;Meyerson M;Diller L;Fortina P;Look AT;Maris JM
通讯作者：
Maris JM