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

in Med (New York, N.Y.) by Dongjiang Chen, Son B Le, Ashley P Ghiaseddin, Harshit Manektalia, Ming Li, Adam O'Dell, Maryam Rahman, David D Tran

TLDR

  • Researchers combined TTFields with pembrolizumab and temozolomide to treat newly diagnosed glioblastoma patients and found improved progression-free and overall survival rates.

Abstract

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. 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. 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. These findings demonstrate synergy between TTFields and ICIs, particularly in patients with high tumor burden, and support further study in larger trials. This work was supported by a grant from Novocure.

Overview

  • The study evaluated the synergy between tumor treating fields (TTFields), pembrolizumab, and temozolomide for newly diagnosed glioblastoma patients post-chemoradiation.
  • The primary endpoint was progression-free survival (PFS) compared to case-matched controls treated with TTFields and temozolomide alone.
  • The study aimed to assess the immune correlates and safety of the combination therapy, as well as its effects on overall survival (OS) and response rate.

Comparative Analysis & Findings

  • The median PFS was 12.0 months in patients treated with the combination therapy, compared to 5.8 months in controls (HR 0.377, 95% CI 0.217-0.653; p = 0.0026).
  • The median OS was 24.8 months in patients treated with the combination therapy, compared to 14.6 months in controls (HR 0.522, 95% CI 0.301-0.905; p = 0.0477).
  • Patients undergoing biopsy had longer PFS and OS compared to those who received maximal resection, suggesting a potential benefit of the combination therapy in this subgroup.

Implications and Future Directions

  • The study demonstrates synergy between TTFields and immune checkpoint inhibitors (ICIs), particularly in patients with high tumor burden, and supports further study in larger trials.
  • The combination therapy may improve PFS and OS in glioblastoma patients, suggesting its potential as a promising treatment option.
  • Future studies could investigate the optimal duration and combination of TTFields and ICIs, as well as explore the potential of this therapy in other types of cancers.
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