CTSI-01 FINAL RESULTS AND MOLECULAR ANALYSES OF THE PHASE IB CLINICAL TRIAL OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD) FROM SOLID MALIGNANCIES.

Abstract BACKGROUND Leptomeningeal disease (LMD) from solid tumors has a dismal prognosis, even following treatment with anti-PD-1 therapy. We performed a phase IB study evaluating the safety of Avelumab with whole brain radiotherapy (WBRT) in LMD (NCT03719768). METHODS Fifteen patients were enrolled with LMD from breast, lung, nasopharyngeal, ovary, and pancreatic tumors. Patients were treated with Avelumab concurrent with WBRT, with the first infusion of Avelumab starting 14 days pre-WBRT and continuing during and post-WBRT for up to 5 cycles (or until disease progression or unacceptable toxicity). Primary endpoints were safety and 3-month OS (OS3). Secondary endpoints included assessment of immune cells in the cerebrospinal fluid (CSF) using single cell RNA-sequencing (scRNA-Seq). RESULTS DLTs occurred in 2 patients, i.e., adrenal insufficiency, hypothyroidism, and pneumonitis. Treatment-related toxicities happened in 5 patients with grade 1/2 and 5 patients with grade 3/4. Immune-related adverse events occurred in 5 patients with grade 1/2 and 3 patients with grade 3/4. No grade 5 toxicities seen. Median-OS was 3.85 months (95%CI: 0.9–34.4 months) and median-PFS 3.85months (95%CI: 0.9–12.1 months). scRNA-Seq analysis of CSF pre- and post-last-treatment showed Avelumab+WBRT stimulated an adaptive immune response associated with decrease regulatory T cells (Tregs), among other changes in the expression of immune checkpoints on CD8+ T cells and macrophages. CONCLUSION The combination of Avelumab and WBRT is safe and demonstrates activity in patients with LMD. The identification of high levels of Tregs and macrophages in the CSF of patients with LMD offers future avenues for therapeutic development.