Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.
Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.
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DOI：
10.1016/j.jtho.2016.02.016
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Kobayashi SS
中科院分区：
文献类型：
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作者：
Costa DB;Jorge SE;Moran JP;Freed JA;Zerillo JA;Huberman MS;Kobayashi SS
涉及erb-b2受体酪氨酸激酶2 （ERBB2）的基因组畸变是约2%的肺腺癌的驱动癌基因。然而，ERBB2酪氨酸激酶抑制剂（TKIs）（包括阿法替尼）的每日剂量的使用一直充满血浆浓度，几乎无法达到临床前模型抑制，患者报告的显着毒性和有限的临床活性。我们假设替代给药策略可以提高耐受性和疗效。我们分析了肺癌细胞系对TKIs的影响，并回顾性评估了ERBB2突变肺癌患者对脉冲阿法替尼（每周280mg一次）的毒性/反应。ERBB2外显子20插入突变的肺癌细胞系对阿法替尼的抑制浓度比报道的阿法替尼40mg /天的血浆浓度高50%。3例晚期ERBB2突变肺腺癌患者接受超说明书脉冲阿法替尼治疗。每周280毫克的剂量耐受性良好，没有皮疹和轻微腹泻的报告。一名TKI-naïve患者获得了5个月的部分缓解，另一名患者病情稳定了11个月。每周给药的脉冲阿法替尼在ERBB2外显子20插入突变的肺腺癌中诱导抗肿瘤活性。未来的临床试验中，ERBB TKIs作为单一疗法或与其他疗法联合治疗ERBB2突变肿瘤是有必要的。
Genomic aberrations involving erb-b2 receptor tyrosine kinase 2 (ERBB2) are driver oncogenes in ∼2% of lung adenocarcinomas. However, the use of daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs) - including afatinib - has been fraught by plasma concentrations that barely achieve preclinical model inhibition, significant patient-reported toxicities and limited clinical activity. We hypothesized that alternative dosing strategies could improve tolerability and efficacy. We profiled lung cancer cell lines against TKIs and retrospectively evaluated the toxicity/response to pulse afatinib (280mg once weekly) in lung cancers with ERBB2 mutations. An ERBB2 exon 20 insertion mutated lung cancer cell line had 50% inhibitory concentration to afatinib higher than the reported plasma concentration of afatinib 40mg daily. Three patients with advanced ERBB2 mutated lung adenocarcinomas were treated with off-label pulse afatinib. The 280mg weekly dose was well tolerated with no reported rash and minimal diarrhea. One TKI-naïve patient achieved a partial response for 5 months and another stable disease for 11 months. Pulse afatinib at a weekly dosing scheme induced anti-tumor activity in ERBB2 exon 20 insertion mutated lung adenocarcinomas. Future clinical trials of alternative dosing schemes of ERBB TKIs as monotherapy or in combination with other therapies are warranted for ERBB2 mutated tumors.