TPS2096 Background: Glioblastoma remains a lethal disease with limited treatment options. With current standard-of-care, consisting of maximal safe resection followed by radiotherapy with concurrent TMZ, then maintenance TMZ plus TTFields, median overall survival (OS) is 20.9 months, as reported in the pivotal EF-14 trial completed more than a decade ago. While immune checkpoint inhibitors (ICIs) have improved outcomes in multiple malignancies, they have not demonstrated meaningful clinical benefit in glioblastoma, in part because the tumor microenvironment (TME) is typically profoundly immunosuppressive. Strategies that reprogram the TME toward immune activation may therefore enable ICIs to elicit more effective anti-tumor immunity. Beyond antimitotic effects, TTFields have shown preclinical evidence of inducing immunogenic cell death and activating type 1 interferon signaling via DNA sensor inflammasomes, with downstream increases in dendritic cell activation and cytotoxic T cell infiltration. In a single-arm phase 2 study (NCT03405792), TTFields plus TMZ and pembrolizumab was associated with improved progression-free survival (PFS) and OS compared to historical controls in newly diagnosed glioblastoma. Here, we describe the design of a randomized phase 3 trial evaluating this regimen. Methods: EF-41/KEYNOTE D58 is a randomized, double-blind, placebo-controlled, phase 3 study (NCT06556563). Eligible patients have newly diagnosed glioblastoma (WHO 2021 Classification), have completed concurrent chemoradiotherapy, and can initiate treatment 4–7 weeks thereafter. Additional criteria include ECOG performance status 0–1 and availability of tumor tissue for central MGMT methylation analysis. Key exclusion criteria include prior anti-PD(L)1 or anti-PDL2 therapy and ongoing dexamethasone >2 mg/day. Patients are randomized 2:1 to TTFields (200 kHz for ≥18 hours/day) plus maintenance TMZ (150–200 mg/m 2 /day PO, days 1-5 of each 28 day cycle for 6-12 cycles) with either pembrolizumab 200 mg IV Q3W (up to 35 cycles) or matching placebo. TTFields is continued until second progression. At first progression, TTFields therapy is maintained and patients may receive standard salvage therapy, including re-resection and/or radiotherapy as well as systemic therapy. The target enrollment is 741 patients, providing 85% power to detect an OS improvement at a two-sided alpha of 0.05 using a 2-sided log-rank test. The primary endpoint is OS. Secondary endpoints include PFS per RANO 2.0 and RANO, PFS6 and PFS12 rates (RANO 2.0), PFS2 (RANO 2.0), 1- and 2-year survival rates, EORTC QLQ-C30 with BN20 module score, 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. Clinical trial information: NCT03405792 .
Tran et al. (Thu,) studied this question.