Glecirasib treatment in KRAS G12C-positive non-small cell lung cancer with leptomeningeal metastasis

Background Leptomeningeal metastasis (LM) is associated with poor outcomes in non-small cell lung cancer (NSCLC), and clinical evidence for KRAS G12C inhibition in this setting is limited. We examined clinical outcomes and cerebrospinal fluid (CSF) molecular changes in patients with KRAS G12C -positive LM who received glecirasib. Methods This retrospective case series included patients treated with glecirasib at Affiliated Brain Hospital of Nanjing Medical University between January 2025 and June 2026. Intracranial progression-free survival (iPFS) and overall survival (OS) were summarized descriptively. Exploratory serial CSF circulating tumor DNA (ctDNA) analyses were performed in two selected patients. Results Seven patients were included, with a median observed follow-up of 6.3 months (range, 2.4-9.6). The best overall LM assessment was response in five patients, stable disease in one, and progressive disease in one. Two patients developed LM progression and one patient died; median iPFS and OS were not reached. In the patient with acquired KRAS G12C , CSF ctDNA detected the alteration at LM progression after EGFR-TKI therapy. KRAS G12C variant allele frequency decreased after glecirasib initiation and subsequently increased at progression, accompanied by the emergence of KRAS G12D and increased CDK4/MDM2 amplification. In the patient with primary KRAS G12C , KRAS G12C and TP53 variant allele frequencies initially decreased but later rose at the last CSF assessment, without concurrent radiographic, cytological, or symptomatic evidence of LM progression. Conclusions In this retrospective series of seven patients, glecirasib monotherapy was associated with LM disease control in six patients, suggesting possible activity in KRAS G12C-positive NSCLC with LM.