William Maisel, MD, MPH
The FDA has approved Optune (formally the NovoTTF-100A System) in combination with adjuvant temozolomide as a treatment for patients with newly diagnosed glioblastoma multiforme (GBM) following surgery, chemotherapy, and radiation therapy, based on an improvement in survival in the EF-14 trial.
In an analysis of 695 patients enrolled in the phase III EF-14 study, the median overall survival (OS) was 19.4 months with Optune compared with 16.6 months with temozolomide alone. Additionally, progression-free survival (PFS) was improved by approximately 3 months, according to the FDA.
“Patients newly diagnosed with this challenging and aggressive form of brain cancer now have another treatment option available,” William Maisel, MD, MPH, acting director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health, said in a statement. “While the treatment is not a cure, it can increase survival by several months.”
Optune is a portable, noninvasive, battery-operated device that attaches directly to the patient’s head to deliver tumor-treating fields to the brain. The device is thought to slow or reverse tumor growth by inhibiting mitosis during metaphase, anaphase and telophase.Â
The FDA initially approved Optune in 2011 as a monotherapyÂ for adult patients with GBM that recurred or progressed after chemotherapy. The agency reviewed the extended indication under its priority review program.Â With the expanded approval, the system can be used as part of a standard upfront treatment for GBM in combination with temozolomide, which is a standard adjuvant therapy.
Interim results from the EF-14 study were presented at the 2014 Society for Neuro-Oncology Annual Meeting. Based on an early assessment of the first 315 patients enrolled in the study, an Independent Data Monitoring Committee recommended that the trial should be stopped early to allow those in the control arm to cross over to receive Optune.
The phase III study had randomized patients in a 2:1 ratio to receive adjuvant therapy with Optune plus temozolomide or temozolomide alone. Patients were enrolled following completion of standard radiotherapy with concomitant temozolomide.
At the interim analysis, data were analyzed for 210 patients treated with the Optune combination and 105 with temozolomide alone. The primary endpoint of the study was PFS, with OS as a secondary outcome measure.
Patient characteristics were well balanced between the two arms. The median age of patients was 57 and 58 years, the tumor was resected for 89% and 90%, and 39% and 41% had MGMT promoter methylation, in the combination and control arms, respectively. Karnofsky performance status was 90% in both groups.
After a minimum follow-up of 18 months, the risk of progression or death was reduced by 37% with the addition of Optune to temozolomide. The median PFS was 7.1 months with the combination compared with 4.0 months with temozolomide alone (HR, 0.63; P
At the interim analysis, the median OS with the combination was 19.6 versus 16.6 months with the single-agent (HR, 0.75; P
= .034). The estimated 24-month OS rate was 43% with Optune and temozolomide versus 29% with temozolomide alone.Â
For the full population of the study (N = 700) with longer follow-up, the 24-month OS rate with Optune in combination with temozolomide was 48% compared with 32% with monotherapy (P
= .0058). The median PFS was 7.2 versus 4.0 months with the combination and single-agent, respectively (HR, 0.62, P
= .001). The median OS was 20.5 months with Optune compared with 15.6 months (HR = 0.66, P
Adverse events (AEs) were similar between the arms and were primarily associated with temozolomide. The most common AEs related to Optune were skin irritation, which occurred in 45% of patients utilizing the device. Of these skin complaints, only 2% were labeled "serious." Seizures were seen in approximately 7% of patients treated in each arm. Additionally, as a precaution, the FDA advised against using the device in patients with an active implanted medical device, a skull defect, or a known sensitivity to conductive hydrogels.
“These results are spectacular,” lead investigator Roger Stupp, MD, director of the University Hospital Cancer Center at the University of Zurich, Zurich, Switzerland, said in a statement when the findings were presented. “A new standard of care for patients suffering from glioblastoma is born.”
Clinical trials continue to assess Optune in various combinations for patients with brain cancer, including a phase II study exploring the treatment in combination with bevacizumab and temozolomide for unresectable GBM (NCT02343549). Additionally, a clinical trial is exploring Optune as a treatment for patients with small cell lung cancer with central nervous system metastasis (NCT02425072). The therapy is also being explored in earlier settings in combination with bevacizumab and hypofractionated stereotactic irradiation in bevacizumab-naive patients with recurrent GBM (NCT01925573).
Stupp R, Wong E, Scott C, et al. Interim analysis of the EF-14 trial: a prospective, multicenter trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. Presented at: 19th Annual Meeting of the Society for Neuro-Oncology; November 13-16, 2014: Miami, FL.