Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study

Dongjiang Chen; Son B Le; Ashley P Ghiaseddin; Harshit Manektalia; Ming Li; Adam O'Dell; Maryam Rahman; David D Tran

doi:10.1016/j.medj.2025.100708

Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study

Med. 2025 Sep 12;6(9):100708. doi: 10.1016/j.medj.2025.100708. Epub 2025 Jun 4.

Authors

Dongjiang Chen¹, Son B Le¹, Ashley P Ghiaseddin², Harshit Manektalia¹, Ming Li³, Adam O'Dell¹, Maryam Rahman⁴, David D Tran⁵

Affiliations

¹ Division of Neuro-Oncology, Department of Neurosurgery, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90033, USA.
² Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA.
³ Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
⁴ USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Division of Neuro-Oncology, Department of Neurosurgery, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA. Electronic address: david.tran@med.usc.edu.

PMID: 40466642
DOI: 10.1016/j.medj.2025.100708

Abstract

Background: Immune checkpoint inhibitors (ICIs) have shown limited success in glioblastoma due to the tumor's profoundly immunosuppressive microenvironment. Tumor treating fields (TTFields), a non-invasive electric field therapy, activate the type I interferon (T1IFN) pathway via DNA sensor-dependent inflammasomes, promoting in situ immunization against glioblastoma.

Methods: In this phase 2 study (this study was registered at ClinicalTrials.gov: NCT03405792), 31 newly diagnosed glioblastoma patients were enrolled post-chemoradiation to evaluate synergy between TTFields, pembrolizumab, and temozolomide. The primary endpoint was progression-free survival (PFS) compared to case-matched controls treated with TTFields and temozolomide alone. Secondary endpoints included overall survival (OS), response rate, safety, and immune correlates assessed through single-cell transcriptomics and T cell clonotyping of blood and tumor samples.

Findings: Among 26 patients treated per protocol, the median PFS was 12.0 vs. 5.8 months in controls (HR 0.377, 95% CI 0.217-0.653; p = 0.0026), and the median OS was 24.8 vs. 14.6 months (HR 0.522, 95% CI 0.301-0.905; p = 0.0477). Patients undergoing biopsy had longer PFS (27.2 vs. 9.6 months; HR 0.37, 95% CI 0.16-0.85; p = 0.014) and OS (31.6 vs. 18.8 months; HR 0.4, 95% CI 0.17-0.92; p = 0.023) compared to maximal resection. Severe adverse events constituted 7.5% of treatment-related toxicities. TTFields promoted clonal T cell expansion via a T1IFN-driven trajectory, while pembrolizumab supported adaptive replacement of these clones, sustaining T cell activation and memory formation, especially in biopsy-only patients.

Conclusions: These findings demonstrate synergy between TTFields and ICIs, particularly in patients with high tumor burden, and support further study in larger trials.

Funding: This work was supported by a grant from Novocure.

Keywords: DNA sensor inflammasomes; TTFields; Translation to patients; anti-PD1 inhibitors; glioblastoma; immune checkpoint inhibitors; immune monitoring; in situ immunization; multi-omics analysis; pembrolizumab; tumor treating fields.

Publication types

Clinical Trial, Phase II

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized* / administration & dosage
Antibodies, Monoclonal, Humanized* / adverse effects
Antibodies, Monoclonal, Humanized* / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Brain Neoplasms* / mortality
Brain Neoplasms* / therapy
Combined Modality Therapy
Electric Stimulation Therapy* / adverse effects
Electric Stimulation Therapy* / methods
Female
Glioblastoma* / mortality
Glioblastoma* / therapy
Humans
Male
Middle Aged
Progression-Free Survival
Temozolomide* / administration & dosage
Temozolomide* / adverse effects
Temozolomide* / therapeutic use
Tumor Microenvironment

Substances

pembrolizumab
Antibodies, Monoclonal, Humanized
Temozolomide

Associated data

ClinicalTrials.gov/NCT03405792