\*\*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.
Parallel
proton craniospinal irradiation
RadiationPhase 1: Intrathecal pemetrexed 40 mg, biw, q3w, for 2 cycles (via Ommaya reservoir). CSF ctDNA (maxVAF) tested at baseline (C0) and post-induction (C1) for risk stratification: Low-risk: ΔctDNA \> 80% reduction or clearance. Intermediate-risk: ΔctDNA 20%-80% reduction. High-risk: ΔctDNA \< 20% reduction. Phase 2: Low-risk: Pemetrexed 40 mg, q3w, 4 cycles (no randomisation). Intermediate/High-risk - Cohort A (Control): Pemetrexed 40 mg, q3w, 4 cycles. Intermediate/High-risk - Cohort B (Experimental): Intermediate: Proton craniospinal irradiation (pCSI) 30 GyE/10 fractions. High: pCSI 30 GyE/10 fractions + concurrent low-dose intrathecal pemetrexed 30 mg (days 1 \& 8) as radiosensitizer. Phase 3: Pemetrexed 40 mg, q4w, until intracranial progression. Supportive/Concomitant: Mandatory folic acid and vitamin B12 premedication for pemetrexed; background systemic EGFR-TKI therapy p
Intrathecal pemetrexed
Drughe 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.
Intracranial progression-free survival (iPFS)
Intracranial progression-free survival (iPFS) is defined as the time from enrollment to the date of intracranial progression or death from any cause, whichever occurs first.For subjects without observed intracranial progression or death, iPFS will be censored at the time of the last valid and adequate intracranial tumour assessment. iPFS analysis will be based on the Full Analysis Set (FAS). The median iPFS and its 95% CI will be estimated using the Kaplan-Meier method, and progression-free survival curves will be generated. Treatment group comparison will be performed using stratified log-rank test, and hazard ratio (HR) with 95% CI will be estimated using the Cox proportional hazards model.
Overall survival (OS)
Overall Survival (OS) is defined as the time from enrollment to death from any cause. For subjects not followed up to death, OS will be censored at the time of the last valid survival follow-up. OS analysis will be based on the Full Analysis Set (FAS). The median OS (if applicable) and its 95% CI will be estimated using the Kaplan-Meier method, and survival curves will be plotted. Treatment group comparison will be performed using stratified log-rank test, and HR with 95% CI will be estimated using the Cox proportional hazards model.
The lead time from achieving a 20% change in CSF ctDNA to radiographic progression per RANO-LM criteria
This endpoint is defined as the time interval from the first detection of a ≥20% change (increase or decrease) in CSF ctDNA maxVAF relative to the preceding baseline value to the date of subsequent radiographic intracranial progression confirmed by independent review committee (IRC) per RANO-LM criteria. This analysis will be performed only in subjects with both baseline and at least one on-treatment paired CSF sample and who achieve a ≥20% ctDNA change during treatment. The median lead time and its 95% CI will be estimated using the Kaplan-Meier method, with ctDNA change date as time zero and radiographic progression as the event. If the distribution is skewed, the lead time will be presented descriptively as median with interquartile range.
Incidence and Severity of Adverse Events, Serious Adverse Events, Treatment-Related Adverse Events, Immune-Related Adverse Events, and Laboratory Abnormalities
The number and percentage of participants experiencing adverse events (AEs), serious adverse events (SAEs), treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), and clinically significant laboratory abnormalities will be assessed. Events will be summarized by type, frequency, severity grade, seriousness, and relationship to study treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 6.0.
Change from Baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Global Health Status/Quality of Life Score
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life scale consists of 2 items. The raw score is linearly transformed to a score ranging from 0 to 100. Higher scores indicate better global health status and quality of life.Change from baseline will be assessed at each scheduled post-baseline visit. Changes will be summarized descriptively by treatment group. Between-group differences will be evaluated using a mixed-effects model for repeated measures, including baseline score, treatment group, visit, and treatment-by-visit interaction.
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Shuanghu Yuan
Lead sponsor
Anhui Provincial Cancer Hospital
Sponsor institution
