The Efficacy And Safety Of Third-generation EGFR-TKIs Combined With Bevacizumab And Intrathecal Pemetrexed In The Treatment Of Leptomeningeal Metastasis With EGFR Mutant Non-small Cell Lung Cancer

ObjectiveLeptomeningeal metastasis(LM)is one of the most devastating complications of advanced malignant tumors.Due to the unclear pathogenesis of LM and the presence of the blood-brain barrier,most drugs cannot reach effective concentrations within the skull.Therefore,the treatment of LM in clinical practice remains a challenging problem.This study aims to observe the efficacy and safety of third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)combined with bevacizumab and intrathecal pemetrexed in the treatment of EGFR-mutant non-small cell lung cancer(NSCLC)with LM.Methods:A retrospective analysis was conducted on patients diagnosed with NSCLC LM in the Oncology Department of the Second Affiliated Hospital of Nanchang University from June 2020 to November 2022.Twenty EGFR-mutation-positive NSCLC LM patients were selected to explore the efficacy and safety of the treatment plan with third-generation EGFR-TKIs combined with bevacizumab and intrathecal pemetrexed.The primary endpoint was overall survival(OS)of LM,and secondary endpoints were progression-free survival(PFS),objective response rate(ORR),and safety.Results:Among the 20 patients,there were 8 males(40%)and 12 females(60%),with a male-to-female ratio of 1:1.5.The average age was 55 years old.Thirteen patients received Osimertinib treatment,and seven patients received Almonertinib treatment.A total of 185 intrathecal chemotherapy were administered,with a median of 7injections(range 2-25).The minimum intrathecal dose of pemetrexed was 10 mg,and the maximum dose was 40 mg.The median PFS of LM was 9.4 months(95% CI:4.8-14.0),and the median OS of LM was 13.2 months(95% CI: 10.5-15.9).In the evaluation of LM-related neurological symptoms,14 patients(70%)improved,4patients(20%)remained stable,and 2 patients(10%)progressed.Cranial MRI evaluation showed improvement in 12 patients(60%)and stability in 8 patients(40%).Among the 20 patients,12(60%)were considered to have a clinical response,with an ORR of 60%(12/20).Most adverse reactions were mild(grade 1-2).Grade 3or higher adverse reactions were mainly concentrated in hematological toxicity,and two patients had adverse reactions of grade 4 leukopenia and thrombocytopenia at the same time,which were considered related to intrathecal treatment.Conclusion:The combination of third-generation EGFR-TKIs,bevacizumab,and intrathecal pemetrexed is a potential treatment option for advanced EGFR-mutant NSCLC patients with LM,and the adverse reactions are manageable.In the future,more groups need to be included,and randomized controlled studies with larger sample size and more centers need to be carried out for further confirmation.