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

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-06-03 DOI:10.1016/j.medj.2025.100708

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

{"title":"Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study.","authors":"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","DOIUrl":null,"url":null,"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.","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100708"},"PeriodicalIF":12.8000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2025.100708","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

辅助TTFields联合派姆单抗和替莫唑胺治疗新诊断的胶质母细胞瘤的有效性和安全性：一项2期研究

背景：免疫检查点抑制剂（ICIs）在胶质母细胞瘤治疗中的效果有限，这是由于肿瘤的深度免疫抑制微环境。肿瘤治疗场（TTFields）是一种非侵入性电场疗法，通过DNA传感器依赖性炎症小体激活I型干扰素（T1IFN）途径，促进对胶质母细胞瘤的原位免疫。方法：在这项2期研究中（该研究已在ClinicalTrials.gov注册：NCT03405792）， 31名新诊断的胶质母细胞瘤患者在放化疗后入组，以评估TTFields、派姆单抗和替莫唑胺之间的协同作用。主要终点是与单独使用TTFields和替莫唑胺治疗的病例匹配对照组相比的无进展生存期（PFS）。次要终点包括通过血液和肿瘤样本的单细胞转录组学和T细胞克隆分型评估的总生存期（OS）、反应率、安全性和免疫相关因素。结果：在26例按方案治疗的患者中，中位PFS为12.0个月，对照组为5.8个月(HR 0.377, 95% CI 0.217-0.653；p = 0.0026)，中位OS分别为24.8个月和14.6个月(HR 0.522, 95% CI 0.301-0.905；P = 0.0477)。接受活检的患者PFS更长(27.2个月vs 9.6个月；Hr 0.37, 95% ci 0.16-0.85；p = 0.014)和OS (31.6 vs. 18.8个月；Hr 0.4, 95% ci 0.17-0.92；P = 0.023)。严重不良事件占治疗相关毒性的7.5%。TTFields通过t1ifn驱动的轨迹促进克隆T细胞扩增，而pembrolizumab支持这些克隆的适应性替代，维持T细胞激活和记忆形成，特别是在仅活检的患者中。结论：这些发现证明了TTFields和ICIs之间的协同作用，特别是在高肿瘤负荷患者中，并支持进一步的大规模试验研究。经费：这项工作得到了Novocure的资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.