Why this matters
Tumor Treating Fields are currently introduced during maintenance temozolomide after completion of radiochemotherapy in newly diagnosed glioblastoma.
TRIDENT tested a straightforward biological hypothesis: if TTFields are active against glioblastoma, starting them earlier and combining them directly with radiotherapy and temozolomide might improve survival.
The phase III answer is negative.
Starting TTFields during radiochemotherapy did not improve overall survival, progression-free survival, or response compared with starting TTFields during maintenance treatment.
Study design
TRIDENT was a global, open-label, randomized phase III trial in adults with newly diagnosed glioblastoma.
Patients were randomized before radiochemotherapy to:
- Early Start: TTFields initiated concurrently with RT and temozolomide
- Maintenance Start: TTFields initiated with maintenance temozolomide after completion of RT/TMZ
TTFields were delivered at 200 kHz.
Patients were stratified according to:
- MGMT promoter methylation
- extent of resection
TTFields were recommended until second disease progression in both groups.
The primary endpoint was overall survival.
Secondary endpoints included:
- progression-free survival
- 1-year survival
- 2-year survival
- 3-year survival
- overall response rate
- safety
A total of 981 patients were randomized:
- 492 to Early Start
- 489 to Maintenance Start
Median age was 60 years.
MGMT promoter methylation was present in 38.9% of patients.
Approximately 25% of patients in both groups did not enter the maintenance phase.
Key results
The primary endpoint was negative.
Median overall survival was:
- 17.7 months with Early Start
- 17.5 months with Maintenance Start
- HR 0.953
- 95% CI 0.82-1.10
- p=0.52
There was therefore no evidence that starting TTFields during RT/TMZ improved survival.
Long-term survival rates were also similar.
At 1 year:
- 70.9% vs 72.0%
At 2 years:
- 33.9% vs 31.6%
At 3 years:
- 22.5% vs 18.4%
None of these differences were statistically significant.
Progression-free survival and overall response rate were also not significantly different between treatment groups.
TTFields exposure
Patients assigned to Early Start received TTFields for a longer median duration:
- 7.7 months with Early Start
- 6.1 months with Maintenance Start
Despite this additional treatment exposure, no significant improvement in the primary or major secondary efficacy endpoints emerged.
That makes the negative result particularly informative: simply extending TTFields exposure earlier into the treatment course did not improve outcomes for the overall randomized population.
Safety
Starting TTFields during radiochemotherapy increased device-related adverse events.
Device-related adverse events occurred in:
- 76.2% with Early Start
- 59.2% with Maintenance Start
These events were predominantly grade 1-2 skin reactions.
The combination of TTFields with RT/TMZ was therefore feasible, but the additional device exposure came with more treatment-related burden without a demonstrated survival benefit.
MGMT-methylated subgroup
A post hoc analysis generated a potentially interesting signal in patients with MGMT-methylated tumors who used the device according to protocol during radiochemotherapy.
Median OS in this subgroup was:
- 33.8 months with Early Start
- 23.8 months with Maintenance Start
- HR 0.683
- 95% CI 0.484-0.963
- p=0.03
The magnitude of the difference is clinically notable.
But the analysis has two important limitations.
First, it was post hoc.
Second, it was restricted to patients with per-protocol device usage rather than the full randomized intention-to-treat population.
That creates the possibility of selection and adherence bias.
The result should therefore be viewed as a biomarker hypothesis for future prospective testing, not as evidence that patients with MGMT-methylated glioblastoma should currently start TTFields during radiochemotherapy.
Interpretation
TRIDENT addresses an important principle in treatment intensification: earlier treatment is not necessarily better treatment.
The trial successfully demonstrated that TTFields can be delivered concurrently with radiotherapy and temozolomide.
But feasibility did not translate into efficacy.
Median survival was essentially identical at 17.7 and 17.5 months.
PFS was unchanged.
Response was unchanged.
Longer TTFields exposure did not translate into better outcomes.
This makes the primary phase III result relatively clear: for the overall newly diagnosed glioblastoma population, there is no demonstrated advantage to moving TTFields forward into the concurrent chemoradiotherapy phase.
The MGMT-methylated signal is more interesting biologically than clinically actionable today.
A nearly 10-month median OS difference deserves further investigation, but the methodological context matters. Subgroup findings become substantially less reliable when they emerge after the primary analysis and are further restricted according to treatment adherence.
A prospective biomarker-stratified study would be required to establish whether MGMT methylation truly identifies patients who benefit from earlier TTFields initiation.
Limitations
TRIDENT was open-label.
Approximately one-quarter of randomized patients did not initiate the maintenance phase, reflecting the clinical attrition typical of newly diagnosed glioblastoma.
Device-related adverse events were substantially more frequent with earlier TTFields exposure.
The MGMT-methylated survival finding came from a post hoc, per-protocol device-use analysis rather than the intention-to-treat population.
The study used WHO 2016 glioblastoma classification, reflecting the diagnostic framework under which the trial was initiated.