Primary Objective: To evaluate the efficacy of high-dose firmonertinib combined with bevacizumab and intrathecal pemetrexed in EGFR Ex19del/L858R-mutated non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM), as measured by Overall Survival (OS). Secondary Objectives: 1. To assess the efficacy of this regimen in EGFR Ex20ins/PACC/L861Q-mutated NSCLC with LM. 2. To further evaluate therapeutic outcomes across cohorts, including: * Time to Treatment Failure (TTF) * Leptomeningeal Objective Response Rate (ORR-LM) * Clinical Response Rate 3. To analyze the impact of this regimen on \*quality of life\* using standardized metrics: * EORTC QLQ-C30 * EORTC QLQ-LC13 4. To assess safety profiles across cohorts, focusing on: * Incidence and severity of adverse events (AEs) graded per \*CTCAE v5.0\* * Frequency of treatment-related toxicities Exploratory Objectives: To investigate correlations between dynamic changes in: * Plasma-derived circulating tumor DNA (ctDNA) * Cerebrospinal fluid-derived cell-free DNA (cfDNA) and clinical outcomes through comparative analysis of genomic profiling and epigenetic signatures before and after treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
100
high-dose firmonertinib (240 mg, daily), bevacizumab (15 mg/kg, every 3 weeks), and pemetrexed (50 mg, intrathecal chemotherapy C1d1d5, then every 3 weeks)
OS(EGFR Ex19del/L858R)
overall survive time (EGFR Ex19del/L858R)
Time frame: the time between the date of enrollment and the date of death from any cause for EGFR Ex19del/L858R NSCLC with leptomeningeal metastases(up to 36 months)
OS(EGFREx20ins/PACC/L861Q)
overall survive time(EGFREx20ins/PACC/L861Q)
Time frame: the time between the date of enrollment and the date of death from any cause for EGFREx20ins/PACC/L861Q NSCLC with leptomeningeal metastases(up to 36 months)
TTF
time to treatment failure:The time interval from the start of the triple therapy to treatment failure
Time frame: up to 24 months
ORR-LM
Objective Response Rate in Leptomeningeal Metastases:the proportion of patients whose leptomeningeal lesions achieve a complete response (CR) or partial response (PR) during the study period from the first administration of the study drug until leptomeningeal disease progression
Time frame: up to 24 months
CRR
Clinical response rate:the proportion of patients whose CR, OR, or PR lasts for at least one week
Time frame: up to 24 months
Quality of life assessment (EORTC QLQ-C30, EORTC QLQ-LC13)
EORTC QLQ-C30(European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire - 30 items, score:30-126, Higher scores indicate worse quality of life) and EORTC QLQ-LC13(European Organization for Research and Treatment of Cancer Quality of Life Lung Module 13 items) were used to assess the quality of life, scores were normalized to 0-100, with high scores in the symptom domain indicating severe symptoms and high scores in the functional domain indicating good functioning
Time frame: At the end of every 2 cycles(each cycle is 21 days)
AE
AEs (Adverse events)were graded according to CTCAE v5.0 every two cycles after enrollment
Time frame: At the end of every 2 cycles(each cycle is 21 days)
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