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 <grade 3 AEs, including hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). There were no grade 5 toxicities. Median follow up was 3.7 mo (range, 0.9-36.8 mo; 95% CI 1.3-14.7 mo). The median follow-up time for survival analyses of the study was 19.8 mo. Ten out of 15 patients (66.7%) were alive at 3 mo. Median OS was 10.5 (95% CI 1.2 - 19.8 mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3 mo (95% CI, 0.9-15.2 mo), Fig. 3B. Two patients remain alive and clinically well. ScRNAseq analyses are underway; signatures correlated with outcomes in short versus long term survivors. Conclusions: The combination of Avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short versus long term survivors should be further explored. Clinical trial information: NCT03719768.