EGFR突变非小细胞肺癌和软脑膜转移患者应用高浓度伏美替尼：前瞻性真实世界研究

软脑膜转移（LM）是非小细胞肺癌（NSCLC）最严重的并发症之一。伏美替尼是一种泛表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），具有较高的血脑屏障穿透率和较宽的治疗窗口。在这里，我们评估了大剂量伏美替尼对EGFR突变的NSCLC和LM患者的疗效和安全性。

This prospective real-world study included patients with EGFR-mutated NSCLC and LM treated with ahigh-dose furmonertinib (240mg once daily) as a monotherapy or in combination with other treatments. The primary endpoint was overall survival (OS), and the secondary endpoints included time to treatment discontinuation (TTD) and clinical response rate. Additional efficacy evaluations included changes in brain magnetic resonance imaging (MRI) by the RANO-LM radiologic criteria. We also introduced next generation sequencing (NGS)-based assays to evaluate genomic and epigenomic features of cell-free DNA (cfDNA) in patients’ cerebrospinal fluid (CSF) samples and to analyze their associations with patient outcomes.

这项前瞻性的真实世界研究包括接受高剂量伏美替尼（240mg，每日一次）作为单一疗法或与其他疗法联合治疗的EGFR突变NSCLC和LM患者。主要终点是总生存期（OS），次要终点包括停药时间（TTD）和临床反应率。其他疗效评估包括根据RANO-LM放射学标准测定的头颅磁共振（MRI）结果的变化。我们还引入了基于下一代测序（NGS）的检测方法，以评估患者脑脊液（CSF）样本中游离细胞DNA（cfDNA）的基因组和表观基因组特征，并分析其与患者预后的关系。

We enrolled 48 patients, of whom 35 (72.9%) had received third-generation EGFR-TKIs. The median OS was 8.43 months (95%CI, 5.48 to 11.39 months), while the median TTD was 8.27 months (95%CI, 5.40 to 11.14 months), and the clinical response rate was 75%. The LM objective response rate (ORR) and disease control rate (DCR) assessed with RANO-LM radiologic criteria were 50.0% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. Briefly, 22 (45.8%) had adverse events (AEs) possibly related to furmonertinib and three (6.3%) had a grade 3-elevated aminotransaminase or nausea or leucopenia, leading to dose reduction to 160 mg daily. Furthermore, methylation analysis of cfDNA in CSF showed that there was a significant correlation between the changes of aberrant methylated fragments (AMFs) from lung cancer cells and the response of the patients. Meanwhile, the copy number burden (CNB) scores derived from the low-pass whole genome sequencing (LP-WGS) assay may offer another objective and effective method for the diagnosis and evaluation of treatment efficacy in LM.

我们招募了48名患者，其中35名（72.9%）接受了第三代EGFR-TKI治疗。中位OS为8.43个月（95%CI，5.48至11.39个月），中位TTD为8.27个月（95%CI，5.40至11.14个月）。临床反应率为75%。根据RANO-LM放射学标准评估的LM客观反应率（ORR）和疾病控制率（DCR）分别为50.0%和92.1%。不良事件与之前关于伏美替尼的报告一致。简而言之，22例（45.8%）发生了可能与伏美替尼有关的不良事件（AE），3例（6.3%）出现了3级转氨酶升高或恶心或白细胞减少症，导致药物剂量减少至每天160毫克。此外，CSF中cfDNA的甲基化分析表明，癌症细胞异常甲基化片段（AMFs）的变化与患者的反应之间存在显著相关性。同时，低通全基因组测序（LP-WGS）得出的拷贝数负担（CNB）评分可能为LM的诊断和疗效评估提供另一种客观有效的方法。

In the real world, the high-dose furmonertinib-based treatment may potentially have clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients previously treated with other third-generation EGFR-TKIs. Methylation and CNB analysis of cfDNA in CSF may be considered objective indicators for the diagnosis of LM and evaluation of treatment response.

在现实世界中，大剂量伏美替尼治疗可能对EGFR突变的非小细胞肺癌合并LM患者具有潜在的临床疗效和可耐受的安全性，即使在之前接受过其他第三代EGFR TKI治疗的患者中也是如此。CSF中cfDNA的甲基化和CNB分析可被视为LM诊断和治疗反应评估的客观指标。