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

Abstract

INTRODUCTION: Emerging data indicate that TTFields, the new antimitotic 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.