LBA 04 - TRIDENT: Phase 3 Trial of Tumor Treating Fields (TTFields) Therapy Concurrent with Temozolomide (TMZ) Radiochemotherapy Followed by Maintenance TMZ and TTFields for Newly Diagnosed Glioblastoma (ndGBM)

02:15pm - 02:25pm ET

Room 210

Presenter(s)

Wenyin Shi, MD, PhD - Thomas Jefferson University, Philadelphia, PA

W. Shi¹, M. Glas², S. Lapointe³, F. Iwamoto^4,5, K. Wang⁶, J. J. Zhu⁷, A. Demopoulos⁸, R. M. Graham⁹, S. Gupta-Burt¹⁰, F. Ducray¹¹, F. Bokstein¹², S. Jeyapalan¹³, S. Nagpal¹⁴, S. A. Goldlust¹⁵, M. Williams¹⁶, S. E. Combs¹⁷, K. Mishima¹⁸, D. Roberge¹⁹, R. Grossman²⁰, and E. Cohen-Jonathan Moyal²¹; ¹Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, ²Department of Neurology and Neurooncology, St. Marien Hospital Lünen, Lünen, Germany, ³Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada, ⁴Columbia University, New York, NY, ⁵Department of Neurology, Neuro-Oncology,Stanford University, Palo Alto, CA, ⁶Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, ⁷Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, ⁸Hartford Healthcare Medical Group, Hartford, CT, ⁹Tennessee Oncology, Chattanooga, TN, ¹⁰Department of Radiation Oncology, The University of Kansas Medical Center, Kansas City, KS, ¹¹Service de Neuro-Oncologie, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France, ¹²Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, ¹³Tufts Medical Center, Boston, MA, ¹⁴Department of Neurology, Neuro-Oncology, Stanford University, Palo Alto, CA, ¹⁵Alexion Pharmaceuticals, Boston, MA, ¹⁶Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom, ¹⁷Department of Radiation Oncology, Technical University Munich, Munich, Germany, ¹⁸Saitama Medical University International Medical Center, Hidaka, Japan, ¹⁹Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada, ²⁰Brain Tumor Center, Department of Neurosurgery, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel, ²¹20. Université de Toulouse, Oncopole Claudius Regaud, IUCT-Oncopole, Touloise, France

Purpose/Objective(s):

Standard treatment for newly diagnosed glioblastoma (ndGBM) is maximal safe resection followed by radiotherapy (RT) with temozolomide (TMZ) then maintenance TMZ and TTFields therapy. TRIDENT evaluated whether earlier initiation of TTFields therapy concurrently with RT/TMZ improves survival compared with current utilization.

Materials/Methods:

TRIDENT (NCT04471844) was a randomized, open-label, global phase 3 clinical trial. Adults with ndGBM (WHO 2016 classification) were randomized 1:1 prior to RT/TMZ to receive TTFields (200 kHz) initiated concurrently with RT/TMZ (Early Start arm) or with adjuvant TMZ (Maintenance Start arm). Patients (pts) were stratified by MGMT promoter methylation status and extent of resection. TTFields were recommended until second disease progression in both arms. Key inclusion criteria: recovered from maximal safe resection (biopsy allowed); KPS =70; and planned initiation of RT/TMZ <8 weeks after surgery. Primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 1-, 2-, and 3-year survival rate, overall response rate (ORR), and safety. Survival data were compared using the Kaplan-Meier method and a stratified log-rank test.

Results:

A total of 981 pts were randomized Dec 2020–Jan 2024 globally to the Early Start (n=492) or Maintenance Start (n=489) arms. Baseline characteristics were balanced (overall: median age 60 [22–86] years, 65.1% male, 38.4% KPS =80, 38.9% MGMT methylated, 5.4% IDH mutant). ~25% of pts did not initiate the maintenance phase across both arms. Median duration of TTFields use was 7.7 months (m) (0-49) and 6.1 m (0-43) with Early and Maintenance Start, respectively. In the intention to treat (ITT) population, there was no significant difference in median OS (mOS). mOS (95% CI) was 17.7 m (16.0–18.8 ) with Early Start vs 17.5 m (15.9–19.0 ) with Maintenance Start, (HR 0.953 [95% CI 0.82–1.10]; p=0.52). 1, 2, and 3-year survival rates were 70.9% vs 72.0%, 33.9% vs 31.6%, and 22.5% vs 18.4%, respectively (all NS). PFS and ORR were not significantly different between arms. Device-related adverse events (AEs) occurred in 76.2% of Early Start pts vs. 59.2% of Maintenance Start pts but remained mostly grade 1-2 skin-related. In post hoc analysis of pts with per protocol device usage during RT/TMZ, pts with MGMT-methylated tumors showed a significant survival benefit with Early Start (mOS of 33.8 m vs 23.8 m; HR 0.683 [95% CI 0.484–0.963]; p=0.03).

Conclusion:

TTFields concurrent with RT/TMZ was feasible and safe. Although earlier TTFields initiation did not improve survival in the ITT population, durable long-term survival was observed regardless of TTFields start time. Post hoc analyses identified a clinically meaningful survival benefit from early TTFields initiation in pts with MGMT-methylated tumors.