NVTG-05 Longitudinal Observation of the Treatment Response to Intrathecal Chemotherapy With Pemetrexed via Circulating Tumor Dna From Cerebrospinal Fluid of Non-Small Cell Lung Cancer Leptomeningeal Metastases

Abstract Approximately 5% of patients with advanced non-small cell lung cancer may develop leptomeningeal metastasis (LM). 1,2 Patients with LM may have a poor prognosis; the median overall survival (OS) of LM NSCLC patients was only 3.6 to 11 months2,3. Although targeting therapies, particularly tyrosine-kinase inhibitors (TKI), are effective against primary tumors, the blood-brain barrier may limit their intracranial performance, resulting in variable patient survival outcomes. 4 LM patients have been shown to benefit from a variety of treatments, including surgery, radiation, systematic chemotherapy, targeted chemotherapy, immunotherapy, and intrathecal injection, but there is still a lack of conventional treatment paradigms for LM patients’ care. In patients with NSCLC, intrathecal administration, which delivers medications directly into the subarachnoid space via cerebrospinal fluid (CSF), was reported to be highly effective in controlling LM. 5,6 However, evaluating the efficacy of treatment for LM remains difficult and lacks standardization. Due to the diffusion of LM lesions, it is challenging to quantify tumor size using imaging techniques. Karnofsky performance score (KPS) is a commonly used assessment tool for functional impairment of LM 7, but it cannot disclose the tumor change in a quantifiable manner. Response Assessment in Neuro-Oncology (RANO) is a generally accepted response criterion that evaluates treatment response by incorporating a novel radiographic scorecard, CSF cytology or flow cytology, and neurological examination, while it was limited on measuring lesions for response assessment. 8,9 Recent research has demonstrated that circulating tumor DNA released by tumor apoptosis can be used as a biomarker to track treatment responses and tumor evolution. 10 Ct-DNA from cerebrospinal fluid (CSF) has also demonstrated superior intracranial response prediction performance compared to plasma. 11 In this study, patients with leptomeningeal metastasis (LM) who had undergone multiple courses of therapy received intrathecal pemetrexed (IP). Then, we monitored the dynamic changes in CSF-ctDNA to assess their response.