Phase II study of pembrolizumab in leptomeningeal carcinomatosis.

Abstract

2007 Background: Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). Median survival of patients with LMD is approximately 4-6 weeks and there are no effective treatment options. We performed a phase II study of pembrolizumab in LMD from any solid tumor malignancy (NCT02886585). Methods: The primary endpoint is the rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Ten patients were to be enrolled in the first stage. If 2 or more patients were alive at 3 months, an additional 8 patients would be enrolled. If at least 6 patients among the total of 18 patients were alive at three months, then the treatment would be deemed promising in the cohort. Serial CSF, blood samples and tumor samples were collected to elucidate the genomic and transcriptional determinants of immunotherapy response in central nervous system (CNS) lesions. Results: A total of 18 patients were accrued (15 with breast cancer, 2 with lung cancer and 1 with gastric cancer). The median follow-up of patients still alive was 2.9 months (range: 2.2 to 6.3 months). The percentage of patients with one or more grade-3 or higher adverse events that were at least possibly related to treatment is 33.3%. At the time of the data retrieval, eight (8) patients (44%) were alive at three months after enrollment (OS3). Therefore, the study met its primary endpoint. Whole exome sequencing of tissue samples and cell-free DNA from CSF and blood, as well as single-cell RNA sequencing of CSF, were carried out to track the evolution of the tumor and the immune system in the CNS and identify biomarkers of response. Genetic and transcriptomic differences within the CSF were detected between the pre- and post-treatment samples and in patients that reached OS3 compared with those that did not. Conclusions: Pembrolizumab is well-tolerated and has activity in LMD. CSF provides an opportunity to monitor the clonal evolution of tumor and the immune microenvironment in LMD. Clinical trial information: NCT02886585.