The percentage of patients alive at 2 years in the TTFields together with temozolomide arm was 43% compared to 29% in the temozolomide alone arm. The pre-specified, interim analysis of EF-14 trial data was conducted on the first 315 patients, representing approximately 50 percent of the targeted study population. The data show that: • Patients treated with TTFields together with temozolomide demonstrated a significant increase in progression free survival compared to temozolomide alone (median PFS of 7.1 months compared to 4.0 months, respectively, hazard ratio=0.63, p=0.001). • Patients treated with TTFields together with temozolomide demonstrated a significant increase in overall survival compared to temozolomide alone (median OS of 19.6 months compared to 16.6 months, respectively, hazard ratio=0.75, p=0.034). • The percentage of patients alive at 2 years in the TTFields together with temozolomide arm was 43% compared to 29% in the temozolomide alone arm. Based on the interim analysis results, the Independent Monitoring Committee (IDMC) for the EF-14 trial recommended that the trial be stopped early and that Novocure provide access to TTFields for patients on the temozolomide alone arm. Novocure is in discussions with the United States (U.S.) Food and Drug Administration (FDA) regarding the regulatory pathway for TTFields in newly diagnosed GBM. “These results are spectacular,” said Dr. Roger Stupp, M.D., Director of the University Hospital Cancer Center at the University of Zurich, Zurich, Switzerland and EF-14 Principal Investigator. “A new standard of care for patients suffering from glioblastoma is born.” https://s21.q4cdn.com/825405078/files/doc_news/2014/201408-EF14-Trial-Results-Press-Release.pdf
In November 2014, the trial’s independent data monitoring committee concluded that the study met its endpoints at its pre-specified interim analysis of the first 315 patients with 18 months or more of follow-up. The committee recommended that the trial be terminated early for success and that all control patients be offered TTFields therapy even prior to progression.
Of particular interest was the decision not to include a sham device or placebo control in EF-14. The roundtable participants agreed that one the most common criticisms of the trial is the lack of a sham device or double-dummy design to control for potential placebo effects. Dr. Stupp reported that during the design phase, he and other trial participants agreed that it would not have been ethical or practical to include a sham device to control for possible placebo effects, given the burden of carrying a device which would have no potential for therapeutic benefit.
While the positive results associated with TTFields in EF-14 might be due to placebo effects, the panel agreed that seemed unlikely—particularly with respect to objective endpoints like OS which is a categorical event. Also, the magnitude of benefit observed with TTFields was robust (HRs of 0.69 and 0.75 for PFS and OS, respectively), typically beyond what one usually expects with a placebo effect.
A concern was also raised by the expert panel about the recommendation by the IDMC to terminate the trial and allow control patients to cross-over and receive TTFields based on the early interim analysis of the study data. Although this analysis was pre-specified, it occurred after only 50% of overall study events occurred. The roundtable attendees cited narrowing of the Kaplan-Meier curves noted with further follow-up of the study data presented at ASCO 2015, relative to the data presented approximately six months earlier, as a concern that the IDMC recommendation may have been premature, although the p values for both endpoints remained unchanged. The panel categorically supported continued and long term follow-up of all of the EF-14 trial participants, with a clear intent to track the percentage of control patients who cross over to start TTFields therapy following the IDMC recommendation and clarification of their outcome relative to the control patients who opted not to cross-over.
As a group, the roundtable participants agreed that the appropriately 3-month gain in the intent-to-treat (ITT) population for median PFS [7.1 months in the TTFields plus TMZ arm vs 4.0 months in the TMZ alone arm; 95%CI, HR, 0.62; p = 0.0013)]; and in that same ITT patient population, the median OS [19.6 months in the TTFields plus TMZ alone vs 16.6 months in the TMZ alone arm; 95%CI, HR, 0.744; p = 0.0038]; are in a range generally considered highly significant and clinically meaningful for cancer therapies (Fig. 2). When examined based on time of diagnosis (adding 4 months for completion of radiotherapy before randomization), the median PFS for patients treated with TTFields plus TMZ was 11.1 months and the median OS was 23.4 months. The participants also agreed that the improvement in 2-year survival rate with TTFields Therapy (43 vs. 29%) is notable, and likely to be considered clinically meaningful by the patient and his or her family.
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