CTIM-16. PHASE 2 STUDY OF PEMBROLIZUMAB PLUS TTFields PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED glioblastoma (2-THE-TOP)

Abstract

Abstract INTRODUCTION Emerging data indicate that TTFields, the new anti-mitotic treatment for GBM, stimulate immunity via the type-1 interferon (T1IFN) pathway of STING and AIM2 inflammasomes. Thus, we hypothesize that TTFields synergize with immune checkpoint inhibitors to induce anti-tumor immunity in GBM. METHODS We conduct a phase 2 study combining pembrolizumab, TTFields and maintenance TMZ in 25 patients with newly diagnosed GBM (ndGBM). To distinguish immune effects of TTFields from pembrolizumab, TTFields is started at cycle 1 of TMZ and pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS vs. the historical control of TTFields plus TMZ (JAMA/318:2306-2316). Secondary endpoints include toxicity, immune signature of TTFields vs. pembrolizumab by single-cell RNAseq of PBMCs, and OS. RESULTS As of 05/24/2021, 25 patients with a median age of 61 years were enrolled. Eight (32%) and 4 (16%) had biopsy only and partial resection, respectively. Eighteen (72%) had unmethylated MGMT and 3 (12%) had an IDH mutation. The median follow-up was 14.7 months. Twelve (48%) were progression-free, and 15 (60%) were alive. Of 19 patients with follow-up >=9 months, the median PFS was >=11.2 months vs. 6.7 months in the control. Six (24%) patients with measureable tumors achieved partial to complete response. The most common serious adverse events were thrombosis, seizure, and metabolic disturbances in 4 (16%), 3 (12%), and 2 (8%) patients, respectively. We sequenced 193,760 PBMCs in 12 patients before pembrolizumab and detected robust post-TTFields T cell activation in 11 of 12 patients via the T1IFN trajectory with a strong correlation with the TCRab clonal expansion Simpson index (Spearman coefficient r=-0.8, P=0.014). Importantly, we defined a T cell-based gene signature of TTFields effects on TCRab clonal expansion. CONCLUSION The triple combination is well tolerated and shows early evidence of efficacy in ndGBM patients. Survival and molecular data will be updated.