EF-14
Tumour treating fields plus maintenance temozolomide versus maintenance temozolomide alone after chemoradiation in glioblastoma (EF-14)
Phase 3N = 695NCT00916409
- Population
- Patients with glioblastoma whose tumour was resected or biopsied and who had completed concomitant radiochemotherapy; 695 randomised at 83 centres between July 2009 and 2014 (median age 56 years); randomisation occurred after chemoradiation, not at diagnosis
- Design
- Randomised (2:1), open-label trial in patients who had completed concomitant radiochemotherapy (median 3.8 months from diagnosis to randomisation): TTFields (200 kHz, at least 18 hours a day via 4 transducer arrays on the shaved scalp) plus maintenance temozolomide 150 to 200 mg/m2 for 5 days per 28-day cycle (6 to 12 cycles) versus temozolomide alone; primary endpoint progression-free survival, overall survival a hierarchically tested secondary endpoint (final analysis)
- Primary endpoint
- PFS
- Arms
- TTFields plus temozolomide (experimental, n = 466): TTFields 200 kHz at least 18 hours a day plus maintenance temozolomide 150 to 200 mg/m2 for 5 days per 28-day cycle
- Temozolomide alone (control, n = 229): Maintenance temozolomide 150 to 200 mg/m2 for 5 days per 28-day cycle
- People
- Stupp R, senior author Ram Z
PFSHR 0.62Δ median PFS+3.1 monthsOSHR 0.64Δ median OS+4.9 monthsPFSHR 0.63 (95% CI 0.52–0.76)Δ median PFS+2.7 months
Show the numbers
| Endpoint | Analysis | TTFields plus temozolomide | Temozolomide alone | Effect |
|---|---|---|---|---|
| PFSIntention-to-treat population at the interim analysis (first 315 patients: 210 TTFields plus temozolomide, 105 temozolomide alone) | interimmedian follow-up 38 monthsStupp 2015 | median 7.1 months (5.9–8.2) | median 4 months (3.3–5.2) | HR 0.62P=.001Interim analysis. The hazard ratio is reported with a 98.7% confidence interval of 0.43 to 0.89, not a 95% interval. Significance threshold for the primary endpoint was .01. The trial was terminated based on the results of this planned interim analysis. |
| OSPer-protocol population at the interim analysis (n=280: 196 TTFields plus temozolomide, 84 temozolomide alone) | interimmedian follow-up 38 monthsStupp 2015 | median 20.5 months (16.7–25.0) | median 15.6 months (13.3–19.1) | HR 0.64P=.004Powered secondary endpoint in the per-protocol population (significance threshold .006), not the intention-to-treat population. The hazard ratio is reported with a 99.4% confidence interval of 0.42 to 0.98. |
| PFS | finalStupp 2017 | median 6.7 months | median 4 months | HR 0.63 (95% CI 0.52–0.76)P<.001Final analysis; followed up through December 2016. Primary endpoint tested at alpha .046. |
| OS | finalStupp 2017 | median 20.9 months | median 16 months | HR 0.63 (95% CI 0.53–0.76)P<.001Secondary endpoint tested hierarchically at alpha .048. Systemic adverse events 48% with TTFields plus temozolomide and 44% with temozolomide alone; mild to moderate skin toxicity under the transducer arrays in 52% of patients receiving TTFields and in none receiving temozolomide alone. |
| Endpoint | Analysis | TTFields plus temozolomide | Temozolomide alone | Effect |
|---|---|---|---|---|
| PFSIntention-to-treat population at the interim analysis (first 315 patients: 210 TTFields plus temozolomide, 105 temozolomide alone) | interimmedian follow-up 38 monthsStupp 2015 | median 7.1 months (5.9–8.2) | median 4 months (3.3–5.2) | HR 0.62P=.001Interim analysis. The hazard ratio is reported with a 98.7% confidence interval of 0.43 to 0.89, not a 95% interval. Significance threshold for the primary endpoint was .01. The trial was terminated based on the results of this planned interim analysis. |
| OSPer-protocol population at the interim analysis (n=280: 196 TTFields plus temozolomide, 84 temozolomide alone) | interimmedian follow-up 38 monthsStupp 2015 | median 20.5 months (16.7–25.0) | median 15.6 months (13.3–19.1) | HR 0.64P=.004Powered secondary endpoint in the per-protocol population (significance threshold .006), not the intention-to-treat population. The hazard ratio is reported with a 99.4% confidence interval of 0.42 to 0.98. |
| PFS | finalStupp 2017 | median 6.7 months | median 4 months | HR 0.63 (95% CI 0.52–0.76)P<.001Final analysis; followed up through December 2016. Primary endpoint tested at alpha .046. |
| OS | finalStupp 2017 | median 20.9 months | median 16 months | HR 0.63 (95% CI 0.53–0.76)P<.001Secondary endpoint tested hierarchically at alpha .048. Systemic adverse events 48% with TTFields plus temozolomide and 44% with temozolomide alone; mild to moderate skin toxicity under the transducer arrays in 52% of patients receiving TTFields and in none receiving temozolomide alone. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.63 | 0.52–0.76 |
| OS | 0.63 | 0.53–0.76 |
- TTFields plus temozolomide (experimental)
- Temozolomide alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | TTFields plus temozolomide | Temozolomide alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 4 | 67.7% | 50.0% |
| 9 | 41.5% | 21.0% |
| 13 | 28.1% | 10.5% |
| 18 | 17.3% | 4.4% |
- TTFields plus temozolomide (experimental)
- Temozolomide alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | TTFields plus temozolomide | Temozolomide alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 13 | 64.4% | 56.1% |
| 26 | 41.5% | 31.5% |
| 38 | 27.7% | 18.5% |
| 51 | 17.8% | 10.4% |
Appears in
Sources
Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535-43.
Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017;318(23):2306-2316.