\*\*Brief Summary (English)\*\*
The goal of this clinical trial is to learn if a risk-adaptive consolidation therapy, guided by cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clearance kinetics after induction intrathecal pemetrexed, can improve intracranial progression-free survival (iPFS) compared to standard intrathecal pemetrexed consolidation in patients with leptomeningeal metastasis (LM) from EGFR-mutant non-small cell lung cancer (NSCLC) that has progressed on third-generation EGFR-TKIs. It will also learn about the safety and tolerability of proton craniospinal irradiation (pCSI) in this setting.
The main questions it aims to answer are:
* Does risk-adaptive consolidation therapy (pCSI with or without concurrent low-dose intrathecal pemetrexed) prolong iPFS compared to standard intrathecal pemetrexed consolidation? * What medical problems do participants have when receiving pCSI or intrathecal pemetrexed?
Researchers will compare the experimental arm (risk-adaptive consolidation: pCSI for intermediate-risk, or pCSI with concurrent low-dose intrathecal pemetrexed for high-risk patients) to the control arm (standard intrathecal pemetrexed consolidation) to see if the adaptive strategy improves survival outcomes.
Participants will:
* Receive induction intrathecal pemetrexed (40 mg, biw, q3w for 2 cycles) via Ommaya reservoir. * Undergo CSF collection at baseline and after induction for ctDNA (maxVAF) analysis to determine risk stratification (low, intermediate, high). * If stratified as intermediate or high risk, be randomly assigned to either standard intrathecal pemetrexed consolidation or risk-adaptive consolidation (pCSI 30 GyE/10f for intermediate-risk; pCSI 30 GyE/10f with concurrent intrathecal pemetrexed 30 mg on d1, d8 for high-risk). * Receive maintenance intrathecal pemetrexed (40 mg, q4w) until intracranial progression. * Undergo regular efficacy assessments (contrast-enhanced MRI of brain and whole spine) every 8 weeks, and complete neurocognitive and quality-of-life questionnaires.
Voluntary participation with written informed consent obtained prior to any study-specific procedures, and willingness and ability to comply with scheduled visits, the treatment plan, laboratory tests, and other study requirements.
Male or female patients aged between 18 and 75 years (inclusive) at the time of signing informed consent.
Primary tumour confirmed as non-small cell lung cancer (NSCLC) by cytology or histology, harbouring EGFR-sensitive mutations (including 19del and exon 21 L858R). Testing reports for EGFR mutation status must be available; if no prior report exists, submission of archived tissue or baseline biopsy for assessment is mandatory.
Leptomeningeal metastasis (LM) diagnosed according to the EANO-ESMO guidelines, based on cerebrospinal fluid (CSF) cytology and/or imaging evidence of leptomeningeal enhancement or ventriculomegaly.
Patients with concurrent primary tumors of the brain or spinal cord.
Patients with severe central nervous system diseases (including severe cerebral herniation or coma).
Patients with life-threatening or uncontrolled systemic diseases, such as uncontrolled hypertension or active bleeding tendency.
Patients with other concurrent malignancies, except for basal cell carcinoma of the skin and carcinoma in situ.
Shuanghu Yuan
Lead sponsor
Anhui Provincial Cancer Hospital
Sponsor institution