Background: Diagnosis of Leptomeningeal Metastases (LM) from Non-Small Cell Lung Cancer (NSCLC) is usually based on clinical symptoms, Cerebral-Spinal Fluid (CSF) cytology, and neuro-imaging. However, early diagnosis of LM in NSCLC is challenging due to the low sensitivity of these approaches. The Next-Generation Sequencing (NGS) using CSF could help improve the diagnosis of LM and guide its treatment options.

Case Presentation: We report a 39-year-old male NSCLC patient with negative molecular testing results in the lung cancer tissue sample. The patient developed symptoms of LM with the negative CSF cytology and MRI; however, the NGS analysis of CSF revealed an EGFR exon 19 del mutation. The patient attained 6 months of Progression-Free Survival (PFS) by treating with erlotinib and anlotinib before the neurological symptoms appeared again. EGFR Thr790Met was positive in the CSF but negative in his plasma. The patient was then treated with osimertinib therapy and the response was maintained for more than 1 year.

Results & Discussion: This case is the first study reporting the clinical benefit of using the combination of erlotinib and anlotinib for the treatment of LM with the EGFR 19 del, osimertinib with EGFR T790M mutation in CSF, but negative gene mutation in the blood or lung tumor biopsy specimens. Our results support that genetic analysis should be performed with CSF samples in all cases of suspected LM when the results of testing for EGFR/ALK/ROS1 mutation in blood samples or tumor biopsy specimens are negative, as these patients could benefit from treatment of TKIs in a poor prognostic setting.

Conclusion: In parallel to current patents, NGS could be applied as a novel strategy in the managing of NSCLC patients with LM.

背景：非小细胞肺癌 (NSCLC) 软脑膜转移 (LM) 的诊断通常基于临床症状、脑脊液 (CSF) 细胞学和神经影像学。然而，由于这些方法的敏感性低，NSCLC 中 LM 的早期诊断具有挑战性。使用 CSF 的下一代测序 (NGS) 可以帮助改善 LM 的诊断并指导其治疗方案。

病例介绍：我们报告了一名 39 岁男性非小细胞肺癌患者，肺癌组织样本的分子检测结果呈阴性。患者出现 LM 症状，脑脊液细胞学和 MRI 均呈阴性；然而，CSF 的 NGS 分析显示 EGFR 外显子 19 del 突变。在神经系统症状再次出现之前，患者通过厄洛替尼和安罗替尼治疗获得了 6 个月的无进展生存期 (PFS)。EGFR Thr790Met 在脑脊液中呈阳性，但在血浆中呈阴性。该患者随后接受了奥希替尼治疗，反应维持了 1 年以上。

结果与讨论：本病例是首个报告使用厄洛替尼和安罗替尼联合治疗具有 EGFR 19 del 的 LM、CSF 中具有 EGFR T790M 突变但血液或肺中基因突变为阴性的奥希替尼的临床获益的研究肿瘤活检标本。我们的结果支持在所有疑似 LM 的病例中，当血液样本或肿瘤活检标本中 EGFR/ALK/ROS1 突变的检测结果为阴性时，应该对 CSF 样本进行基因分析，因为这些患者可以从 TKI 治疗中受益预后不良。

结论：与目前的专利并行，NGS 可以作为一种新的策略应用于管理 LM 的 NSCLC 患者。