ARTICLE IN BRIEF
The FDA approved the NovoTFF-100A system, a portable non-invasive medical device designed to deliver alternating low-intensity electrical fields through surface electrodes to disrupt cell division of cancer cells, for use in patients with recurrent glioblastoma multiforme.
The FDA approved the NovoTFF-100A system for the treatment of recurrent glioblastoma multiforme (GBM) April 15, following a recommendation by the Neurological Devices Advisory Panel that the benefits outweigh the risks for patients with GBM. The device has undergone a phase 3 clinical study in the US and Europe.
The NovoTTF-100A is a portable non-invasive medical device designed to deliver alternating low-intensity electrical fields through surface electrodes to disrupt cell division of cancer cells. The alternating energy fields are applied through electrically insulated surface electrodes attached to the scalp and are connected to an external power supply that delivers alternating electrical fields virtually round-the-clock for at least four weeks. The electrodes need replacing once or twice a week.
The FDA panel assessed data collected in an open-label randomized trial of 237 patients with recurrent GBM treated with the NovoTTF-100A device alone compared to chemotherapy. At baseline, more than half of the patients in the trial were at their second or subsequent recurrence of GBM and baseline tumors were very large (diameter > 5cm). [The new data was an update to earlier results presented last June at the annual meeting of the American Society of Clinical Oncology.]
The primary end-point in the phase 3 clinical trial was overall survival. Secondary endpoints included progression-free survival at six months and overall survival at one year. About half of the patients received the TTF treatment and the others were prescribed best standard of care (BSC), any one of several chemotherapy agents currently used to treat GBM.
During the study, patients were seen every month. MRI scans were taken every two months and independent clinicians reviewed the scans. Disease progression was measured by tumor growth of more than 25 percent or the appearance of one or more new tumors or new neurological symptoms that correlated with changes on the MRI scan.
In the study, 30 patients (four in the TTF and 26 in the BSC group) never received treatment. Of those 207 patients who did receive the treatment, 49 had to drop out of the study after one treatment because they were in hospice or too weak to travel to their physicians.
At the end of the study, 19 patients were still living; nine in the TTF group and 10 in the BSC group. While there was no difference in the overall survival — the median survival was 6.3 months for the experimental group; 6.4 months for the BSC arm — the investigators reported that patients with TTF had higher rates of progression-free survival (21 percent) than those in the BSC group (15 percent) at six months. The TTF group also had higher tumor response rates (14 percent) than the BSC group (10 percent). In additional, further analysis showed minor differences by country and region. For example, among the US sites, the NovoTTF-100A group showed a more favorable result — with overall survival at 6.1 months — compared to 5.3 months for the BSC group. In the literature given to the panel, the investigators noted that compared to controls, the results “demonstrated that NovoTTF-100A treatment is significantly more effective than ineffective chemotherapies, and is as effective as (‘non-inferior’ to) BSC treatment in the intention-to-treat population.”
An earlier trial, reported in 2007 in the Proceedings of the National Academy of Sciences, of 10 patients with recurrent GBM found that that the NovoTTF device was effective at prolonging survival over currently used therapies. The median overall survival in the pilot study was 14.7 months compared to six months in an historical control sample (p = 0.002). The progression-free survival at six months was 50 percent compared to 11 to 15 percent in an historical control sample. The median time to progression was 26 weeks compared to the normal time to progression for patients with GBM of 13 weeks. The neuro-oncology world was hoping that this would be the magic bullet for patients with this fatal brain tumor.
But the expanded phase 3 trial didn't prove as successful for the NovoTTF-100A. The advisory committee recommended the device's approval for the treatment — not based on the data on overall survival — but because it concluded that TTF was as effective as the standard of care.
The investigators reported there were significantly less gastrointestinal, hematological and infectious adverse events in the NovoTTF patients. The investigators also reported that there were slightly more neurological adverse events in the NovoTTF-treated group (11 percent) than in the BSC group (8 percent) but the scientists involved in the study — and members of the FDA advisory committee — said that many of the adverse events were CNS-related and were attributable to the disease itself and not the treatment, said Philip H. Gutin, MD, chairman of the Department of Neurosurgery at Memorial Sloan-Kettering Cancer Center and executive co-director of center's Brain Tumor Center. Memorial Sloan Kettering was one of the study sites.
The panel voted unanimously that the data show with “reasonable assurance that the treatment is safe” for use in patients with recurrent GBM. The panel also voted 7-6 that TTF treatment for recurrent GBM is effective.
“In the end, the FDA advisory committee thought that the treatment showed non-inferiority to standard chemotherapy, without the toxicity of those drugs,” said Dr. Gutin. “There was a sub-group analysis conducted and independent assessment of radiological responses, suggesting that it has an anti-tumor effect, at least as good as chemotherapy.”
“It was hoped that this would be a non-toxic way to buy more time for patients,” Dr. Gutin added. “This is a totally fresh look at treating cancer. I wish that this had been a home run but it is difficult to achieve a home run in glioblastoma trials.”
The FDA advisory panel only reviewed data on its use in patients with recurrent GBM. Studies are underway to test its effectiveness in newly diagnosed GBM and in advanced lung cancer together with chemotherapy.
Henry Brem, MD, the Harvey Cushing Professor of Neurosurgery and chief of neurosurgery at Johns Hopkins Medicine — who was responsible for developing gliadel, a paper-thin wafer that delivers chemotherapy to targeted brain tissue at the site of the tumor — said he is not sure what long-term benefit the NovoTTF-100A will have for patients. “But,” he added, “given that there are such devastating outcomes in glioblastoma, no one wants to deprive patients of a tool that is not harmful.” That said, he added, “he would be concerned if a patient chose to do this instead of a more rigorously proven therapies.”
Neuro-oncologists are mixed about whether they would use the device based on the findings from the trial. “I think the device has utility but certainly is not for everyone and requires a discussion with the patient,” said Jeffrey Raizer, MD, director of Medical Neuro-Oncology at Northwestern Memorial Hospital. “Like all treatments, it has pluses and minuses. I can see it as a use in some of my patients, likely those with limited options or those who don't qualify for a clinical trial.” He said that a “more rigorous phase 3 trial would be needed to really prove benefit.”
On the other hand, Gregory Cairncross, MD, professor and head of the department of clinical neurosciences at the University of Calgary, said he would not prescribe it for his patients. “There is no evidence that it works. Just a bit of data to suggest that it is as effective as second and third-line chemotherapy for GBM, which in itself is useless and certainly toxic.” He said that he would not give these chemotherapy agents to his patients with late stage GBM, although he said that his view is not universally accepted. “What is needed is a well-designed study in newly diagnosed patients,” he added.
David Schiff, MD, the Harrison Distinguished Professor at the Neuro-Oncology Center in the Departments of Neurology, Neurological Surgery, and Medicine at the University of Virginia, said that had he been on the federal advisory panel he would have voted that it was safe but not yet proven effective. The University of Virginia participated in the phase 3 study and he enrolled nine patients in the trial.
“The device is safe,” he said. “Its absolute lack of side effects is a plus compared to chemotherapy, since just about everything else we use for recurrent GBM has some common side effect(s).”
Less than 20 percent of the control arm of this study received bevacizumab-based therapy. The suggested chemotherapies for the control arm were drugs temozolomide, nitrosoureas, or procarbazine. Since bevacizumab, at least in the US, seems to be the most effective approved therapy for recurrent GBM, Dr. Schiff said he is not sure that showing equivalent efficacy to the other (generally ineffective therapies) is enough to make me excited about this therapy.
Dr. Schiff added: “The TTF device is either something patients really wanted (because of its safety profile and fact that it's not chemotherapy) or something that appalled them (shaving head, wearing this contraption 22 hours a day).”
The FDA takes advisory committee recommendations seriously and generally leans in the direction of the panel's conclusions.
The company is now testing the device in newly diagnosed GBM patients. Itp will be used in conjunction with temozolomide. It compares patients who receive surgery, radiation and temozolomide to patients who receive surgery, radiation and then temozolomide together with NovoTTF-100A.