阿来替尼治疗脑转移的 ALK 阳性非小细胞肺癌患者中枢神经系统临床基因组结局的特征。
Characterization of Central Nervous System Clinico-Genomic Outcomes in ALK-Positive Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Alectinib.
机构信息
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States; Albert Einstein College of Medicine, Bronx, NY, United States.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States; Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
出版信息
Lung Cancer. 2023 Apr;178:57-65. doi: 10.1016/j.lungcan.2023.02.005. Epub 2023 Feb 9.
INTRODUCTION
Highly effective brain-penetrant ALK-targeted tyrosine kinase inhibitors (TKIs) have been developed for the management of NSCLC patients with brain metastases (BM). Local therapy (LT) such as SRS or therapeutic craniotomy is increasingly being deferred for such patients. Herein we report detailed patient- and lesion-level intracranial outcomes and co-mutational genomic profiles from a cohort of NSCLC patients with BM treated with alectinib, with or without LT.
METHODS
We retrospectively reviewed ALK fusion-positive NSCLC patients with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. Outcome variables included intracranial progression-free survival (iPFS), overall survival (OS), duration of TKI therapy, and CNS response rates. Genomic characteristics from tumor specimens were assessed with MSK-IMPACT, a next-generation sequencing (NGS)-based genomic profiling assay.
RESULTS
A total of 38 patients with 114 CNS lesions were included. Twelve of these patients also received contemporaneous LT (SRS, WBRT, or surgical resection). Maximal BM diameter in the TKI + LT group was greater (p < 0.003) but despite this difference, iPFS (TKI only, HR 1.21, 95 % CI 0.51-2.89; p = 0.66) and OS (TKI only, HR 5.99, 95 % CI 0.77-46.6; p = 0.052) were similar between groups and trended towards more favorable outcomes with the addition of LT. SMARCA4 co-alterations were associated with inferior OS (HR 8.76, 1.74-44.2; p = 0.009).
CONCLUSIONS
Our study demonstrated that patients with ALK fusion-positive NSCLC treated with TKI + LT had larger BM and higher likelihood of pre-treatment neurologic symptoms. Despite these differences, iPFS was similar between groups. Results should be interpreted with caution as our study was limited by an underpowered sample size. SMARCA4 co-alterations were associated with inferior OS and these findings warrant further investigation.
介绍
已开发出高效穿透血脑屏障的间变性淋巴瘤激酶（ALK）靶向酪氨酸激酶抑制剂（TKI），用于治疗伴有脑转移（BM）的非小细胞肺癌（NSCLC）患者。对于此类患者，局部治疗（LT）如立体定向放射外科（SRS）或治疗性开颅手术正越来越多地被推迟。在此，我们报告了一组接受艾乐替尼治疗的伴有 BM 的 NSCLC 患者的详细患者和病变水平颅内结果和共突变基因组特征，这些患者接受或未接受 LT。
方法
我们回顾性分析了 2012 年 1 月至 2021 年 5 月期间诊断为 BM 的伴有 ALK 融合的 NSCLC 患者，这些患者在 BM 诊断时接受了艾乐替尼治疗。结果变量包括颅内无进展生存期（iPFS）、总生存期（OS）、TKI 治疗持续时间和中枢神经系统（CNS）反应率。通过 MSK-IMPACT（一种基于下一代测序（NGS）的基因组分析检测）评估肿瘤标本的基因组特征。
结果
共纳入 38 例患者的 114 个 CNS 病变。其中 12 例患者还同时接受了同期 LT（SRS、全脑放疗或手术切除）。TKI+LT 组的最大 BM 直径更大（p<0.003），但尽管存在这种差异，iPFS（仅 TKI，HR 1.21，95%CI 0.51-2.89；p=0.66）和 OS（仅 TKI，HR 5.99，95%CI 0.77-46.6；p=0.052）在两组之间相似，并且随着 LT 的加入，趋势更有利于更好的结果。SMARCA4 共改变与 OS 不良相关（HR 8.76，1.74-44.2；p=0.009）。
结论
我们的研究表明，接受 TKI+LT 治疗的 ALK 融合阳性 NSCLC 患者的 BM 更大，且更有可能在治疗前出现神经症状。尽管存在这些差异，两组的 iPFS 相似。由于我们的研究样本量较小，结果应谨慎解释。SMARCA4 共改变与 OS 不良相关，这些发现值得进一步研究。
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