Phase 1B study of avelumab and whole brain radiotherapy (WBRT) in patients with leptomeningeal disease (LMD) from epithelial carcinomas: Final results and molecular analyses with single cell RNA sequencing

2598 Background: Leptomeningeal disease (LMD) from epithelial cancer has a dismal prognosis with median overall survival (OS) of 3-4 months (mo) using PD-1 axis blocking therapy. Preclinical studies showed that this combination promotes antigen presentation within the CSF compartment, increases BBB permeability and increases ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab in combination with WBRT in patients with LMD (NCT0371768). Methods: Patients received concurrent Avelumab 800 mg IV q2 weeks for up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy in 10 daily fractions. Primary endpoints were safety/DLTs and 3-month OS. Secondary endpoints included CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6 mo were excluded. Results: 15 patients were enrolled with disease sites that included breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). Patients were 87% female, median age 59 range 32-82. One patient did not complete WBRT. Two of 15 patients had grade 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related