ALK 重排非小细胞肺癌（NSCLC）患者的遗传特征及其对 ASCEND-1 研究中色瑞替尼的应答反应。
Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study.
机构信息
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL)), Heidelberg, Germany.
出版信息
Lung Cancer. 2022 Jan;163:7-13. doi: 10.1016/j.lungcan.2021.11.007. Epub 2021 Nov 20.
OBJECTIVES
To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study.
METHODS
ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg.
RESULTS
NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification.
CONCLUSIONS
This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516.
目的
为了更好地了解克唑替尼的疗效相关基因，对 ASCEND-1 研究中接受克唑替尼（≥300mg 剂量）治疗的间变性淋巴瘤激酶（ALK）重排（ALK+）非小细胞肺癌（NSCLC）患者的肿瘤活检进行了探索性分析。
方法
ASCEND-1 是一项开放标签、多中心、Ⅰ期、剂量递增和扩展研究，评估克唑替尼（空腹）在ALK 抑制剂（ALKi）初治或 ALKi 预处理的局部晚期或转移性 ALK+NSCLC 患者中的疗效。使用 Foundation Medicine 靶向 295 个基因的下一代测序（NGS）检测活检标本。对体细胞改变与临床结果（截止日期：2014 年 4 月 14 日）进行相关性分析。共有 285 例 ALK+NSCLC 患者接受了克唑替尼（≥300mg 剂量）治疗。
结果
对 85 例患者（ALKi 预处理[n=54]；ALKi 初治[n=31]）进行了 NGS 检测，其中 57 例患者在接受任何 ALKi 治疗前采集了标本。85 例患者中有 14 例 NGS 未检测到 ALK 重排；这些 NGS 阴性病例中有几个存在其他驱动基因，例如 EGFR 突变。在 71 例 NGS 证实存在 ALK 重排的活检中，最常见的重排是 EML4-ALK 变体 1（V1）和 EML4-ALK V3（分别占 36.6%[26/71]和 32.4%[23/71]）。21 例 ALKi 预处理患者中有 8 例（6 例克唑替尼预处理，2 例克唑替尼预处理后阿来替尼预处理）携带 ALK TKD 点突变，且在克唑替尼治疗前 1-14 天内采集了活检标本；除了 1 例 G1202R 点突变患者外，所有患者均从克唑替尼治疗中获益。在 14 例 ALKi 初治患者中，几乎所有患者均对克唑替尼有效，包括 1 例同时存在 ERBB4 和 HGF 扩增的患者。
结论
这项探索性分析强调了 NGS 在提高我们对克唑替尼疗效和耐药机制的理解方面的潜在作用。它还表明，克唑替尼对 ALKi 预处理患者中发现的几乎所有 ALK 耐药突变均有活性。
临床试验注册
ClinicalTrials.gov，NCT01283516。注册日期：2011 年 1 月 26 日，网址：https://clinicaltrials.gov/ct2/show/NCT01283516。
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