A Phase II Study of the Multikinase Inhibitor Ponatinib in Patients With Advanced, RET-Rearranged NSCLC.
A Phase II Study of the Multikinase Inhibitor Ponatinib in Patients With Advanced, RET-Rearranged NSCLC.
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DOI：
10.1016/j.jtocrr.2020.100045
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发表时间：
2020-09
影响因子：
--
通讯作者：
Shaw AT
中科院分区：
文献类型：
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作者：
Gainor JF;Gadgeel S;Ou SI;Yeap B;Otterson GA;Shaw AT
RET重排定义了NSCLC的一个独特分子亚群。多激酶抑制剂泊那替尼在RET重排NSCLC临床前模型中显示出强效活性。在这项单组、多中心、II期试验中，我们评价了泊那替尼在既往接受过治疗的晚期RET重排NSCLC患者中的临床活性（NCT 01813734）。通过荧光原位杂交或下一代测序鉴定RET重排。泊那替尼的给药剂量为30 mg，每日一次。无客观缓解记录的患者有资格将泊那替尼剂量递增至45 mg/天。主要终点为客观缓解率。2014年8月至2017年12月期间，入组了9例患者。中位年龄为58岁（范围49-73岁）。8例患者（89%）有脑转移病史。既往治疗线的中位数为3（范围1-5）。在9例接受评价的患者中，5例（55%）发生肿瘤较基线缩小，但未观察到确认的缓解（客观缓解率0%）。疾病控制率为55%。中位随访时间为9.33个月，中位无进展生存期和总生存期分别为3.80个月（95%CI：1.83-5.30）和17.47个月（95%CI：6.57-19.20）。最常见的治疗相关不良事件为皮疹（n = 5; 56%）、便秘（n = 4; 44%）和腹泻（n = 4; 44%）。未观察到治疗相关血栓栓塞或心脏事件。研究因招募缓慢和缺乏临床活动而提前停止。Ponatinib在RET重排NSCLC患者中的临床活性有限。需要继续开发更有效和选择性的RET抑制剂。
RET rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of RET-rearranged NSCLC. In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, RET-rearranged NSCLC (NCT01813734). RET rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate. Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49–73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1–5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83–5.30) and 17.47 months (95% CI: 6.57–19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity. Ponatinib has limited clinical activity in patients with RET-rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.