DDRE-02. PATIENTS WITH LEPTOMENINGEAL METASTASES FROM NSCLC BENEFITED FROM INTRATHECAL PEMETREXED AFTER FAILURE TO TYROSINE KINASE INHIBITORS: TWO CASE REPORTS

BACKGROUND The incidence of leptomeningeal metastasis (LM) is 3%-5% in NSCLC patients; the incidence is even higher in patients with EGFR mutations or ALK gene rearrangement. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment. METHODS Here we report two cases of patients with leptomeningeal metastases from NSCLC who benefited from intrathecal pemetrexed after failure to tyrosine kinase inhibitors(TKIs). RESULTS A 53-year-old woman, diagnosed with adenocarcinoma of the lung with ALK rearrangement, suffered form right limb weakness, dysphagia after multi-line targeted therapy and radiotherapy for brain metastases. Evaluation revealed a rapidly progressing right brainstem mass and diffuse leptomeningeal enhanced. And cytological examination of CSF showed neoplastic cells, which definitely diagnosed as LM. After first intrathecal injection of 30mg pemetrexed every three weeks, the patient's symptoms improved. There were no significant treatment side effects and the quality of life was not affected during the five subsequent treatments. Another patient was a 32-year-old man, diagnosed with adenocarcinoma of the lung with EGFR E24-RAD51E4 fusion mutation with KPS score 30. LM was confirmed after multiline therapy. He suffered form blurred vision and drooping eyelid. Similarly, after first intrathecal injection of 20mg pemetrexed every week, the patient's symptoms improved and KPS score increased gradually. And level II leukopenia was detected during subsequent treatments. Combined with intrathecal pemetrexed progression-free survival (PFS) were 3 months in two NSCLC patients with LM harboring ALK/EGFR mutation . And the quality of life of patients were effectively increased. CONCLUSION Combination therapy third generation EGFR/ALK agents with intrathecal chemotherapy might be benefited in overall survival.

DDRE-04. EFFECTIVENESS AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH LEPTOMENINGEAL METASTASES FORM NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

BACKGROUND the FLAURA study established Osimertinib to be the priority choice for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring mutated epidermal growth factor receptor (EGFR). However, like many previous studies, the FLAURA study excluded patients with symptomatic CNS metastases. Hence, we performed a systematic review and meta-analyses of studies to assess the efficiency and safety of Osimertinib for the treatment of NSCLC with leptomeningeal metastases (LM). METHODS We included studies published between 2010 and 2021 that evaluated the efficacy and toxicity of Osimertinib in NSCLC patients with LM. We searched PubMed, Embase, and oncology meeting abstracts (ASCO, ESMO and WCLC). Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate. We used the random-effects model to generate pooled estimates for proportions. Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence. RESULTS Twelve studies reporting on 367 patients were included in the meta-analysis. Most patients (≥90%) received Osimertinib as at least second line of treatment. The objective response rate was 42% (95% CI, 24%-59%; n = 184), and CNS disease control rate was 90% (95% CI, 85%-94%; n = 154). Intracranial progression free survival and overall survival ranged from 3.7 to 15.6 months, and 11.0 to 18.8 months, respectively. Adverse events were similar with previous studies and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates was acceptable. CONCLUSION This meta-analysis confirmed that for advanced NSCLC with LM harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity and acceptable toxicity.

NIMG-01. INTEROBSERVER VARIABILITY OF THE REVISED IMAGING SCORECARD FOR LEPTOMENINGEAL METASTASIS: A JOINT EORTC BRAIN TUMOR GROUP AND RANO EFFORT

BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

Comprehensive RNA analysis of CSF reveals a role for CEACAM6 in lung cancer leptomeningeal metastases

Non-small cell lung cancer (NSCLC) metastatic to the brain leptomeninges is rapidly fatal, cannot be biopsied, and cancer cells in the cerebrospinal fluid (CSF) are few; therefore, available tissue samples to develop effective treatments are severely limited. This study aimed to converge single-cell RNA-seq and cell-free RNA (cfRNA) analyses to both diagnose NSCLC leptomeningeal metastases (LM), and to use gene expression profiles to understand progression mechanisms of NSCLC in the brain leptomeninges. NSCLC patients with suspected LM underwent withdrawal of CSF via lumbar puncture. Four cytology-positive CSF samples underwent single-cell capture (n = 197 cells) by microfluidic chip. Using robust principal component analyses, NSCLC LM cell gene expression was compared to immune cells. Massively parallel qPCR (9216 simultaneous reactions) on human CSF cfRNA samples compared the relative gene expression of patients with NSCLC LM (n = 14) to non-tumor controls (n = 7). The NSCLC-associated gene, CEACAM6, underwent in vitro validation in NSCLC cell lines for involvement in pathologic behaviors characteristic of LM. NSCLC LM gene expression revealed by single-cell RNA-seq was also reflected in CSF cfRNA of cytology-positive patients. Tumor-associated cfRNA (e.g., CEACAM6, MUC1) was present in NSCLC LM patients’ CSF, but not in controls (CEACAM6 detection sensitivity 88.24% and specificity 100%). Cell migration in NSCLC cell lines was directly proportional to CEACAM6 expression, suggesting a role in disease progression. NSCLC-associated cfRNA is detectable in the CSF of patients with LM, and corresponds to the gene expression profile of NSCLC LM cells. CEACAM6 contributes significantly to NSCLC migration, a hallmark of LM pathophysiology.