Gainor Justin F, Gadgeel Shirish, Ou Sai-Hong I, Yeap Beow, Otterson Gregory A, Shaw Alice T
Department of Medicine, Center for Thoracic Cancers, Massachusetts General Hospital, Boston, Massachusetts.
Department of Medicine, Division of Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
JTO Clin Res Rep. 2020 Apr 24;1(3):100045. doi: 10.1016/j.jtocrr.2020.100045. eCollection 2020 Sep.
rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of -rearranged NSCLC.
In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, -rearranged NSCLC (NCT01813734). 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 -rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.
重排定义了非小细胞肺癌（NSCLC）的一个独特分子亚群。多激酶抑制剂波纳替尼在RET重排的NSCLC临床前模型中显示出强大活性。
在这项单臂、多中心、II期试验中，我们评估了波纳替尼在晚期、先前接受过治疗的RET重排NSCLC患者中的临床活性（NCT01813734）。通过荧光原位杂交或二代测序鉴定RET重排。波纳替尼以每日一次30mg的剂量给药。未记录到客观缓解的患者有资格将波纳替尼剂量增加至每日45mg。主要终点是客观缓解率。
2014年8月至2017年12月期间，9例患者入组。中位年龄为58岁（范围49 - 73岁）。8例患者（89%）有脑转移病史。既往治疗线数的中位数为3（范围1 - 5）。在9例评估患者中，5例（55%）出现肿瘤较基线缩小，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%）。未观察到治疗相关的血栓栓塞或心脏事件。由于入组缓慢且缺乏临床活性，该研究提前终止。
波纳替尼在RET重排的NSCLC患者中的临床活性有限。需要继续研发更有效和更具选择性的RET抑制剂。
