Abstract
Abstract INTRODUCTION TTFields induce anti-tumor immunity via the STING and AIM2 inflammasomes. Thus, TTFields-treated GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients. METHODS We enrolled 26 ndGBM patients in a pilot study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from pembrolizumab, TTFields starts at cycle 1 of TMZ while pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS versus a case-matched cohort of 56 patients from the EF-14 study. Secondary endpoints include OS, toxicity, and mechanism of response by multiomics of PBMCs and tumors. RESULTS The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in controls (HR = 0.377; 95CI: 0.217-0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95CI: 0.301-0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common SAEs were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses confirmed robust T cell activation by TTFields via T1IFN-dependent plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014). Successful clonal replacement of the most expanded T cell clones after pembrolizumab strongly predicted objective responses to the triple combination in a Cox HR fit model (concordance rate = 0.876; P = 0.031). CONCLUSIONS The triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated
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