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EF-14 TTFields

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial

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Year of Publication: 2017

Authors: Stupp R, Taillibert S, Kanner A, ..., Ram Z

Journal: JAMA

Citation: JAMA 2017;318(23):2306-2316

Link: https://doi.org/10.1001/jama.2017.18718

PDF: https://jamanetwork.com/journals/jama/fullarticle/2666504

Clinical Question

Does adding tumor-treating fields to maintenance temozolomide improve survival in newly diagnosed glioblastoma after standard chemoradiation?

Bottom Line

In newly diagnosed glioblastoma after standard chemoradiation, adding tumor-treating fields (TTFields) to maintenance temozolomide significantly improved both progression-free survival (6.7 vs 4.0 months; HR 0.63) and overall survival (median 20.9 vs 16.0 months; HR 0.63; p<0.001) compared to TMZ alone, with 43% vs 31% two-year survival. Adverse events dominated by scalp skin toxicity under the transducer arrays. Established TTFields as a fourth-pillar modality for GBM.

        Major Points
        Phase 3 multinational randomized open-label trial
695 patients with newly diagnosed glioblastoma (post-resection or biopsy and post-concomitant chemoradiation) at 83 centers enrolled July 2009-2014
Randomized 2:1 to TTFields + maintenance temozolomide (466) or maintenance temozolomide alone (229)
TTFields: 200 kHz alternating electric fields, 1-3 V/cm, delivered ≥18 hours/day via 4 transducer arrays on shaved scalp
Maintenance temozolomide: 150-200 mg/m² days 1-5 of 28-day cycle for 6-12 cycles
Median time from diagnosis to randomization: 3.8 months (post-concomitant RT+TMZ)
Median follow-up at final analysis: December 2016
Primary endpoint: PFS in per-protocol population
PFS: 6.7 (TTFields+TMZ) vs 4.0 months (TMZ alone); HR 0.63 (95% CI 0.52-0.76); p<0.001
Overall survival: median 20.9 vs 16.0 months; HR 0.63 (95% CI 0.53-0.76); p<0.001
2-year OS: 43% (TTFields+TMZ) vs 31% (TMZ alone)
4-year OS: 17% vs 10%; 5-year OS: 13% vs 5%
Benefit consistent across prespecified subgroups
Scalp skin irritation under transducer arrays: 52% — most mild-to-moderate; rare severe skin breakdown
Systemic AEs comparable between arms
QoL generally preserved; device-wearing compliance >75% required for benefit
FDA approved Optune device for newly diagnosed GBM in 2015; final analysis here published 2017
Durable long-term survivor signal (5-year OS 13% vs 5%)

      

Design

Study Type: Phase 3 international multicenter randomized open-label trial

Randomization: 1

Blinding: Open-label (independent central review of PFS imaging)

Enrollment Period: July 2009 - 2014

Follow-up Duration: Through December 2016

Centers: 83

Sample Size: 695

Analyzed: 695

Analysis: Intention-to-treat primary; per-protocol pre-specified for PFS; stratified Cox proportional hazards

Inclusion Criteria

Adults ≥18 years
Newly diagnosed supratentorial glioblastoma (WHO grade IV)
KPS ≥70
Completion of concomitant radiation therapy + temozolomide (Stupp regimen)
Post-chemoradiation MRI showing no progression

Exclusion Criteria

Infratentorial tumor
Prior gliadel wafers
Implanted electronic medical device or skull defect
Progression during chemoradiation
Inability to shave scalp

Baseline Characteristics

Characteristic	Control	Active
N	229	466
Median age	56	56
Male	68%	68%
KPS ≥90	~55%	~55%
MGMT methylated	~40%	~40%

Arms

Field	Control	TTFields + Maintenance Temozolomide
N	229	466
Intervention	Temozolomide 150-200 mg/m² days 1-5 of 28-day cycle for 6-12 cycles	Continuous TTFields (200 kHz, ≥18 h/day via 4 transducer arrays) + same TMZ regimen
Duration	6-12 cycles	TTFields continuous until 2nd progression or toxicity; TMZ 6-12 cycles

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Progression-free survival (per-protocol; central imaging review)	Primary	Median 4.0 months (TMZ)	Median 6.7 months (TTFields+TMZ)	0.63	p<0.001
Overall survival (median)	Secondary	16.0 mo (TMZ)	20.9 mo (TTFields+TMZ)	HR 0.63 (0.53-0.76)	p<0.001
2-year overall survival	Secondary	31%	43%		Favorable
4-year overall survival	Secondary	10%	17%		Durable benefit
5-year overall survival	Secondary	5%	13%		Long-term survivor benefit
Time to second progression	Secondary	Shorter	Longer with TTFields+TMZ		Consistent
Quality of life (EORTC QLQ-C30)	Secondary	Preserved	Generally preserved		Comparable
Scalp skin irritation (transducer arrays)	Adverse	0%	52%		Device-specific; mostly grade 1-2
Severe scalp skin breakdown	Adverse	0%	<3%		Rare
Temozolomide-related nausea/vomiting	Adverse	~30%	~30%		Similar
Thrombocytopenia (TMZ-related)	Adverse	~12%	~12%		Similar
Headache	Adverse	~15%	~16%		Similar
Seizure	Adverse	~9%	~9%		Similar
Serious AEs	Adverse	~30%	~30%		Comparable
Treatment-related deaths	Adverse	None attributable to TMZ	None attributable to TTFields		None

Subgroup Analysis

TTFields benefit was consistent across prespecified subgroups including age, sex, KPS, extent of resection, MGMT methylation status, and prior treatment response. Benefit also observed in IDH-wildtype subgroup (the majority). Compliance >75% wearing time was associated with the largest benefit; patients with low compliance derived less benefit.

Criticisms

Open-label design (blinding not feasible with a wearable device)
Device-wearing burden (≥18 h/day) limits real-world adoption
Cost and insurance coverage vary significantly across countries
Scalp shaving and skin care requirements affect patient preference
Effect size (4.9-month OS benefit) is modest and similar to other maintenance strategies
Initial peer skepticism about mechanism and placebo-sham feasibility

Funding

Novocure (manufacturer of Optune TTFields device)

Based on: EF-14 TTFields (JAMA, 2017)

Authors: Stupp R, Taillibert S, Kanner A, ..., Ram Z

Citation: JAMA 2017;318(23):2306-2316

Content summarized and formatted by NeuroTrials.ai.

EF-14 TTFields

(2017)

Objective

Tumor-treating fields (TTFields) + maintenance temozolomide — to evaluate whether adding TTFields to maintenance TMZ improves progression-free and overall survival in newly diagnosed glioblastoma after standard chemoradiation.

Study Summary

• TTFields added to maintenance TMZ improved survival in newly diagnosed GBM after standard chemoradiation.
• Median overall survival increased by 4.9 months — 20.9 (TTFields+TMZ) vs 16.0 (TMZ alone); HR 0.63 (95% CI 0.53-0.76); p<0.001.
• Median progression-free survival improved 2.7 months — 6.7 vs 4.0 months; HR 0.63 (0.52-0.76); p<0.001.
• 2-year overall survival jumped from 31% to 43%; 5-year OS 13% vs 5%.
• Scalp skin toxicity under transducer arrays was common (52%) but mostly mild-to-moderate; systemic AEs similar to TMZ-alone.
• Established TTFields as a fourth modality (after surgery, RT, chemotherapy) with FDA approval for newly diagnosed GBM in 2015.

Intervention

Continuous TTFields (200 kHz alternating electric fields) delivered ≥18 hours/day via 4 transducer arrays on the shaved scalp + maintenance temozolomide; compared with maintenance temozolomide alone. All patients had completed standard chemoradiation (Stupp regimen).

Inclusion Criteria

Adults with newly diagnosed glioblastoma, KPS ≥70, completion of concomitant chemoradiation with ≤2 mm residual tumor on post-RT MRI.

Study Design

Arms: TTFields + Maintenance Temozolomide vs Maintenance Temozolomide alone (2:1)

Patients per Arm: TTFields+TMZ 466; TMZ alone 229 (N=695)

Outcome

• Primary (PFS): 6.7 (TTFields+TMZ) vs 4.0 (TMZ) months; HR 0.63 (95% CI 0.52-0.76); p<0.001
• Overall survival: median 20.9 vs 16.0 months; HR 0.63 (95% CI 0.53-0.76); p<0.001
• 2-year OS: 43% vs 31%
• 5-year OS: 13% vs 5%
• QoL comparable between arms
• Scalp skin toxicity: 52% (TTFields) vs 0%; mostly grade 1-2
• No increase in systemic AEs from TTFields

Clinical Question

Does adding tumor-treating fields to maintenance temozolomide improve survival after standard chemoradiation for newly diagnosed glioblastoma?

Bottom Line

Major Points

Phase 3 multinational randomized open-label trial
695 patients with newly diagnosed glioblastoma (post-resection or biopsy and post-concomitant chemoradiation) at 83 centers enrolled July 2009-2014
Randomized 2:1 to TTFields + maintenance temozolomide (466) or maintenance temozolomide alone (229)
TTFields: 200 kHz alternating electric fields, 1-3 V/cm, delivered ≥18 hours/day via 4 transducer arrays on shaved scalp
Maintenance temozolomide: 150-200 mg/m² days 1-5 of 28-day cycle for 6-12 cycles
Median time from diagnosis to randomization: 3.8 months (post-concomitant RT+TMZ)
Median follow-up at final analysis: December 2016
Primary endpoint: PFS in per-protocol population
PFS: 6.7 (TTFields+TMZ) vs 4.0 months (TMZ alone); HR 0.63 (95% CI 0.52-0.76); p<0.001
Overall survival: median 20.9 vs 16.0 months; HR 0.63 (95% CI 0.53-0.76); p<0.001
2-year OS: 43% (TTFields+TMZ) vs 31% (TMZ alone)
4-year OS: 17% vs 10%; 5-year OS: 13% vs 5%
Benefit consistent across prespecified subgroups
Scalp skin irritation under transducer arrays: 52% — most mild-to-moderate; rare severe skin breakdown
Systemic AEs comparable between arms
QoL generally preserved; device-wearing compliance >75% required for benefit
FDA approved Optune device for newly diagnosed GBM in 2015; final analysis here published 2017
Durable long-term survivor signal (5-year OS 13% vs 5%)

Study Design

Study Type: Phase 3 international multicenter randomized open-label trial
Randomization: Yes
Blinding: Open-label (independent central review of PFS imaging)
Sample Size: 695
Follow-up: Through December 2016
Centers: 83

Primary Outcome

Definition: Progression-free survival (per-protocol; central imaging review)

Control	Intervention	HR/OR	P-value
Median 4.0 months (TMZ)	Median 6.7 months (TTFields+TMZ)	0.63 (0.52-0.76)	p<0.001

Limitations & Criticisms

Open-label design (blinding not feasible with a wearable device)
Device-wearing burden (≥18 h/day) limits real-world adoption
Cost and insurance coverage vary significantly across countries
Scalp shaving and skin care requirements affect patient preference
Effect size (4.9-month OS benefit) is modest and similar to other maintenance strategies
Initial peer skepticism about mechanism and placebo-sham feasibility

Citation

JAMA 2017;318(23):2306-2316

View Original Publication →

EF-14 TTFields

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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