Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
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DOI：
10.1200/jco.2014.59.7328
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发表时间：
2015-05-20
影响因子：
45.3
通讯作者：
Riely, Gregory J.
中科院分区：
文献类型：
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作者：
Johnson, Melissa L.;Yu, Helena A.;Riely, Gregory J.
AUY 922是一种热休克蛋白90抑制剂，可降解热休克蛋白伴侣蛋白及其客户蛋白，包括表皮生长因子受体。我们进行了I/II期试验，以评估AUY 922和厄洛替尼与EGFR突变型肺癌和疾病进展的患者在erlotinib treatment.Patients和MethodsAll患者已开发获得性耐药厄洛替尼治疗后，并进行了重复肿瘤活检研究进入前评估EGFR T790 M。在I期，18名患者每周一次静脉注射AUY 922，每天一次厄洛替尼，采用3 + 3剂量递增设计，28天为一个周期。在II期，另外19名患者接受了最大耐受剂量治疗。II期试验的主要终点是完全加部分response rate.ResultsIn阶段I（n = 18），三名患者在每个队列中进行治疗，除了最高剂量队列（AUY 922 70 mg和厄洛替尼150 mg），扩大到6名患者，因为剂量限制性毒性（即交界性心律）。常见的药物相关不良事件为腹泻、皮疹、高血糖和夜盲症。所有接受最大耐受剂量治疗的患者（n = 25）均可评价缓解。部分反应率为16%（4 25例; 95%CI，5%至36%），是独立的肿瘤T790 M status.ConclusionPartial响应观察，但与AUY 922和厄洛替尼治疗的时间是有限的毒性，特别是夜盲症。这项AUY 922和厄洛替尼的II期研究没有达到其主要终点。(C)2015年美国临床肿瘤学会
PurposeAUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment.Patients and MethodsAll patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate.ResultsIn phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junctional cardiac rhythm). Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness. All patients treated at maximum-tolerated dose (n = 25) were evaluable for response. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status.ConclusionPartial responses were observed, but the duration of treatment with AUY922 and erlotinib was limited by toxicities, especially night blindness. This phase II study of AUY922 and erlotinib did not meet its primary end point. (C) 2015 by American Society of Clinical Oncology