Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial
Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial
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DOI：
10.1200/jco.2018.77.9777
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发表时间：
2018-08-20
影响因子：
45.3
通讯作者：
Kris, Mark G.
中科院分区：
文献类型：
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作者：
Li, Bob T.;Shen, Ronglai;Kris, Mark G.
目的人表皮生长因子受体2（HER 2，ERBB 2）激活突变发生在2%的肺癌中。我们评估了活性的ado-曲妥珠单抗emtansine，HER 2靶向抗体药物偶联物，在一个队列的HER 2突变型肺癌患者作为第二阶段篮trial.Patients和MethodsPatients的一部分，接受ado-曲妥珠单抗emtansine在3.6毫克/公斤静脉注射每3周，直到进展。主要终点是使用实体瘤疗效评价标准（RECIST）第1.1版的总体缓解率。采用Simon两阶段优化设计。其他终点包括无进展生存期和毒性。HER 2检测肿瘤组织进行下一代测序，荧光原位杂交，免疫组化，和蛋白质massspectrometry.ResultsWe治疗18例晚期HER 2突变型肺腺癌。既往全身治疗的中位次数为2次（范围：0 - 4次既往治疗）。部分缓解率为44%（95%CI，22%-69%），符合主要终点。在HER 2 20号外显子插入和激酶、跨膜和细胞外结构域点突变的患者中观察到缓解。在2例患者中观察到并发HER 2扩增。HER 2免疫组化范围为0至2+，不能预测缓解，通过质谱法测量的缓解者的HER 2蛋白表达较低。中位无进展生存期为5个月（95% CI，3 - 9个月）。毒性包括1级或2级输注反应、血小板减少症和肝转氨酶升高。没有病人停止治疗的毒性或死亡的study. Conclusion曲妥珠单抗-美坦新偶联物是一种活性药物，在HER 2突变型肺癌患者。这是第一个积极的试验，在这个分子亚型的肺癌。对该药剂的进一步使用和研究是必要的。
PurposeHuman epidermal growth factor receptor 2 (HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial.Patients and MethodsPatients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry.ResultsWe treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study.ConclusionAdo-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.