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Crizotinib对进展性ROS1阳性非小细胞肺癌有良好抗肿瘤活性

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发布日期:2012-07-06 16:24 文章来源:丁香园
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研究人员报道,14名在接受crizotinib(Xalkori)治疗的患者中,有8名患者对该药物反应,还有4名患者病情得到稳定控制,而该药物瞄准的突变位点ROS1突变发生在1%到2%的非小细胞肺癌患者中。

该药物使用的最常见的副作用是轻度的视力障碍,而轻度的视力障碍这个副作用发生在几乎所有的患者中。总之,本研究中crizotinib的药物副作用与其他有关crizotinib的临床评估相一致。波士顿马萨诸塞州总医院的Shaw说,ROS1的重排导致了一个特殊亚型的非小细胞肺癌的出现。Crizotinib表明标志着进展性ROS1阳性非小细胞肺癌患者的抗肿瘤活性。这些研究数据证实了ROS1在肺癌治疗中的治疗目标。

Shaw补充道,一些患者具有戏剧性的反应,与之相关的是治疗开始时的症状的改善以及随后几周患者肿瘤组织的减少。rizotinib除了抑制ROS1外,还抑制MEK和ALK。ROS1最近才被看做是一个特殊亚型的非小细胞肺癌。该药物已经获准用于局部进展性和转移性ALK阳性的非小细胞肺癌患者。

Shaw说:“尽管将ROS1与非小细胞肺癌相联系还是最近刚发生的事,但是对于ROS1的认识却在20年前就已经开始。但是对于ROS1的正常功能还不是十分清楚。在细胞水平上,ROS1激活信号通路也是通过与其他络氨酸激酶受体共享实现的。在肿瘤患者中,染色体的重排是ROS1活化的首要机制。原癌基因形式的ROS1被看做是激活与恶性肿瘤形成相关的下有信号通路物质。

crizotinib起初是作为cMET的抑制剂,接着发现其抑制活性同样也可以抑制其他几个络氨酸激酶,其中就包括ROS1。在临床前期的研究中,crizotinib显示出对抗ROS1驱动的肿瘤细胞的活性,证实了其进行1期临床试验的可行性。通过荧光原位杂交法分析,研究人员筛选出ROS1阳性的转移性非小细胞肺癌患者,并且给予初始剂量为250mgbid的标准治疗从而又鉴别出了ALK阳性的肿瘤患者。

Shaw说,迄今已治疗15例患者,目前还有12名患者在治疗中,还有14名患者在评价治疗反应。所有的这些患者都有腺癌的组织学报告,但是其中有一名患者不吸烟,还有12名患者因为转移瘤接受了1次或多次的治疗。队列研究显示对药物反映的患者占到57.1%,并且治疗的中位时间为25.7周。疾病的控制率为79%,这其中包括4名病情已经稳定达到或超过8周的患者。除了轻微的视力障碍外,最常见的不良反应(≥10%的患者)是一过性的肝酶升高,腹泻,低磷血症,血管神经性水肿,味觉异常,恶心,呕吐,碱性磷酸酶升高,中性粒细胞减少,窦性心动过缓。

在ASCO的另一项研究报告(ASCO2012. Abstract 7505)中指出,研究结果补充了有关非小细胞肺癌突变的另一项难题,而有关非小细胞肺癌的难题包括MEK,ALK,FGFR1PTEN,PIK3CA以及DDR2.总之,63%的鳞状细胞癌患者自身的突变位点可以看做是治疗的靶点。

在Shaw的演讲的讨论中,医学博士GregoryRiely谈到非小细胞肺癌从一个单一的实体正在像一种异质性疾病相关的多个基因突变的改变,而这种改变也发生在临床实践中。在纽约纪念斯隆- 凯特琳癌症中心工作的Riely说:“我们很难通过吸烟史,种族,年龄等因素鉴别出这些患者。我们真的需要去筛选测试所有的患者。引用研究中“显著性”反应的比率,Riely说,他有意对每个ROS1阳性的患者使用crizotinib治疗。Riely还说,“我希望保险公司可以参与其中,因为很显然,这些数据是正确的。”

摘要号:7508

题目:Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement


Crizotinib在具有ROS1基因重排的非小细胞肺癌(NSCLC)中的临床活性

摘要:

Background:
Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 rearrangements lead to expression of oncogenic ROS1 fusion kinases and sensitivity to ROS kinase inhibition. We examined the efficacy and safety of crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS, in patients with advanced, ROS1-rearranged NSCLC.

Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of a phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST 1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at 8 weeks.

Results: Thirteen patients within the ROS expansion cohort received crizotinib and all were evaluable for response. The median age was 47 yrs (range 31–72), and all but one of the patients were never-smokers. All patients had adenocarcinoma histology. 12/13 patients were tested for ALK rearrangement and all were negative. The median number of prior treatments was 1 (range 0–3). To date, the ORR is 54% (7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration of treatment was 20 wks (range 4+–59+). All responses are ongoing, and 12 patients continue on study. One patient had disease progression at first restaging and was discontinued from the study. The pharmacokinetics and safety profile of crizotinib in this group of patients were similar to that observed in patients with ALK-positive NSCLC.

Conclusions: Crizotinib demonstrates marked antitumor activity in patients with advanced NSCLC harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation of NSCLC patients for whom crizotinib therapy may be highly effective. This study represents the first clinical validation of ROS as a therapeutic target in cancer.

编辑: xy 作者:丁香园通讯员

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