Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glio

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.

Med. Volume 6, Issue 9 100708 September 12, 2025 Open access

Context and significance

Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis, and survival for patients with inoperable GBM is especially dismal. While immune checkpoint inhibitors (ICIs) have shown success in other cancers, their effectiveness in GBM has been limited due to the tumor’s profoundly immunosuppressive microenvironment. In this study, the researchers investigate the use of TTFields, an electric field treatment known to induce an in situ immunization effect against GBM, alongside pembrolizumab, an anti-PD-1 ICI, in newly diagnosed GBM patients. This study confirms that the use of TTFields in conjunction with pembrolizumab enhances immune recognition and anti-tumor immunity, significantly improving PFS and OS, particularly in patients with biopsy-only tumor. These findings suggest that TTFields can augment ICI efficacy, offering a promising new treatment strategy for GBM.

Highlights

• TTFields plus pembrolizumab and TMZ improved survival in newly diagnosed GBM

• The triple regimen improved survival in patients with biopsy-only tumor

• The triple regimen enhanced anti-tumor immunity, especially in biopsy-only patients

• The triple regimen was generally well tolerated

Summary

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.