18 TTFields with maintenance temozolomide/pembrolizumab versus TTFields with maintenance temozolomide/placebo for newly diagnosed glioblastoma: the phase 3 EF-41/KEYNOTE D58 trial

Abstract Introduction With the current standard-of-care for glioblastoma (maximal safe resection followed by radiotherapy with concurrent TMZ, then maintenance temozolomide/TTFields), median overall survival (OS) is approximately 21 months. Immune checkpoint inhibitors have not demonstrated meaningful clinical benefit in glioblastoma, partly because the tumor microenvironment is immunosuppressive. Preclinically, TTFields can induce immunogenic cell death and activate type 1 interferon signaling, with downstream increases in dendritic cell activation and cytotoxic T-cell infiltration. In a phase 2 study in newly diagnosed glioblastoma (NCT03405792), TTFields plus temozolomide/pembrolizumab improved progression-free survival (PFS) and OS compared with historical controls. Methods EF-41/KEYNOTE D58 is a randomized, double-blind, placebo-controlled phase 3 study (NCT06556563). Eligibility: newly diagnosed glioblastoma (WHO 2021 Classification); completed chemoradiotherapy and able to initiate treatment 4–7 weeks thereafter; ECOG performance status 0–1; tumor tissue for central MGMT methylation analysis; no prior anti-PD(L)1 or anti-PDL2 therapy; ongoing dexamethasone ≤2 mg/day. Patients are randomized 2:1 to TTFields (200 kHz, ≥18 hours/day) plus maintenance temozolomide (150-200 mg/m2/day PO, days 1-5 Q28 days for 6–12 cycles) with either pembrolizumab 200 mg IV Q3W (≤35 cycles) or placebo. TTFields is continued until second progression. At first progression, TTFields is maintained and patients may receive salvage therapy, including re-resection, radiotherapy and systemic therapy. Results Target enrollment is 741 patients, providing 85% power to detect OS improvement (two-sided alpha 0.05, 2-sided log-rank test). Primary endpoint: OS. Secondary endpoints include PFS, PFS2, quality of life, and safety. MRI assessments are performed every 9 weeks and evaluated per RANO 2.0. Adverse events are monitored throughout the study. Enrollment is ongoing. Conclusions EF-41/KEYNOTE D58 will determine whether maintenance TTFields plus temozolomide/pembrolizumab improve OS in patients with newly diagnosed glioblastoma.