CTIM-05. FINAL RESULTS OF 2-THE-TOP: A PILOT PHASE 2 STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)

Abstract

Abstract INTRODUCTION TTFields induce anti-tumor immunity via type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes. Thus, TTFields may synergize with immune checkpoint inhibitors to prolong survival in GBM. METHODS We enrolled 26 ndGBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance TMZ. Primary endpoints were PFS versus case-matched controls of TTFields plus TMZ in the EF-14 study and immune signatures by multiomics of PBMCs and tumors. Secondary endpoints included toxicity and OS. 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. As of 2/16/22, 7 (27%) were progression-free and 14 (54%) were alive with median follow-up of 16.8 months. Median PFS was 12.1 months versus 7.9 months in a case-matched control cohort of 26 patients (HR = 0.456; 95% CI: 0.222-0.937; P = 0.015). Twelve-month PFS was 52.4% (95% CI: 31.4-69.6%) versus 20.4% (95% CI: 5.5-41.7%) in controls; P = 0.012. Six of 15 (40%) patients with measurable disease achieved partial or complete response. Median OS was 25.2 months versus 15.9 months in controls (HR = 0.382; 95% CI: 0.168-0.861; P = 0.078). Two-year OS was 57.8% (95% CI: 33.7-75.9%) versus 19.2% (95% CI: 7.0-36.0%) in controls; P = 0.002. In a Cox regression analysis adjusting for key prognostic factors, P-value reached 0.033 for PFS and 0.020 for OS. Molecular analyses confirmed robust T cell activation via the T1IFN trajectory, which highly correlated with TCRαβ clonal expansion (Spearman coefficient = -0.8; P = 0.014), and defined a T cell-based gene signature of TTFields effects. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (8%) patients, respectively. CONCLUSIONS The triple combination demonstrated acceptable toxicity and promising efficacy in ndGBM. Survival and molecular data will be updated.