CTIM-04. UPDATES FOR A PHASE 2 OPEN-LABELED STUDY OF PEMBROLIZUMAB PLUS TTFIELDS PLUS MAINTENANCE TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (2-THE-TOP)

Abstract INTRODUCTION Tumor-treating fields (TTFields) are a new standard anti-mitotic treatment for newly diagnosed glioblastoma (ndGBM). Emerging data indicate that TTFields also stimulate innate immunity, leading to adaptive immunity. We hypothesize that immune checkpoint inhibitors synergize with TTFields to promote anti-tumor immunity in ndGBM. METHODS 24 adult patients with ndGBM will be enrolled following radiotherapy with concurrent temozolomide. To identify TTFields-induced immune effects that are augmented by pembrolizumab, TTFields (200 kHz) is started with cycle 1 of maintenance TMZ while pembrolizumab (200mg Q3W) is added at cycle 2 and continued up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint is PFS vs. historical controls (JAMA, 318:2306–2316). Secondary endpoints include toxicity/tolerability and immune activation by TTFields before and after pembrolizumab as determined by single-cell analysis of peripheral blood mononuclear cells. RESULTS As of 06/19/2020, there are 17 evaluable patients. The median follow-up is 12.2 months from cycle 1 of maintenance TMZ. 10 (59%) patients are progression-free, and 13 (76%) are alive. Of 9 patients with follow-up > 12 months, the median PFS is at least 11.2 months vs. historical median PFS of TTFields plus maintenance TMZ of 6.7 months. The most common serious adverse events are pain, weakness, lymphatic swelling, and metabolic disturbances observed in 3 (18%), 2 (12%), 2 (12%), and 1 (6%) patients, respectively. In response to TTFields, we detect a 2.26 (p=0.01) and 5.2-fold (p=0.07) mean increase in the number of classical and plasmacytoid dendritic cells (DC), respectively. Network analysis shows wide-spread pathway upregulation in responders, especially type 1 interferon response genes in DC (FDR=0.02) and cytotoxicity genes in CD8 T cells (FDR=0.03). CONCLUSIONS Pembrolizumab in combination with TTFields plus maintenance TMZ is generally well tolerated in patients with ndGBM. Preliminary data demonstrates activation of adaptive immunity and improved efficacy and will be updated.