NovoTTF-100A, a device for treatment of glioblastoma multiforme from Novocure, a subsidiary of Jersey Isle-based Standen Ltd., received FDA approval following a clinical trial and an agency panel recommendation. The device creates an electric field at the tumor site, preventing cancer cells from dividing and the tumor from growing. The system is indicated for patients following tumor recurrence after receiving chemotherapy.
NovoTTF-100A is a portable, non-invasive medical device designed for continuous use throughout the day by the patient. The device has been shown in in vitro studies to slow and reverse tumor growth by inhibiting mitosis, the process by which cells divide and replicate. The NovoTTF-100A device, which weighs about six pounds (three kilograms), creates a low intensity, alternating electric field within the tumor that exerts physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cancer cell death prior to division. Novocure currently has U.S. and European marketing approvals for the NovoTTF-100A.
The FDA approval was based on data from a randomized pivotal trial of 237 patients with Glioblastoma Multiforme (GBM) brain tumors that had recurred or progressed despite previous surgical, radiation and chemotherapy treatments. Patients treated with the NovoTTF alone achieved a comparable overall survival time to patients treated with the physician’s choice of the best chemotherapy. The rate of progression free survival at six months (PFS6) was 21 percent in the NovoTTF group compared to 15 percent in chemotherapy patients. Also, patients treated with the NovoTTF had a 14 percent tumor response rate (RR) compared to 10 percent in chemotherapy treated patients in the trial, and three complete radiographic responses were observed in the NovoTTF group compared to none in chemotherapy patients. NovoTTF treated patients reported better quality of life scores and fewer side effects during the trial compared to patients treated with chemotherapy. Specifically, quality of life using the device was better than that of chemotherapy patients in the following subscale domains: vomiting, nausea, pain, diarrhea, constipation, cognitive functioning and emotional functioning, all of which are hallmarks of patient suffering while receiving chemotherapy. The most commonly reported side effect from NovoTTF treatment was a mild-to-moderate rash beneath the electrodes.
Electric fields exert forces on electric charges similar to the way a magnet exerts forces on metallic particles within a magnetic field. These forces cause movement and rotation of electrically charged biological building blocks, much like the alignment of metallic particles seen along the lines of force radiating outwards from a magnet.
Electric fields can also cause muscles to twitch and if strong enough may heat tissues. TTFields are alternating electric fields of low intensity. This means that they change their direction repetitively many times a second. Since they change direction very rapidly (200 thousand times a second), they do not cause muscles to twitch, nor do they have any effects on other electrically activated tissues in the body (brain, nerves and heart). Since the intensities of TTFields in the body are very low, they do not cause heating.
The breakthrough finding made by NovoCure was that finely tuned alternating fields of very low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are multiplying, TTFields cause the building blocks of these cells to move and pile up in such a way that the cells physically explode. In addition, cancer cells also contain miniature building blocks which act as tiny motors in moving essential parts of the cells from place to place. TTFields cause these tiny motors to fall apart since they have a special type of electric charge.
As a result of these two effects, cancer tumor growth is slowed and can even reverse after continuous exposure to TTFields.
Other cells in the body (normal healthy tissues) are affected much less than cancer cells since they multiply at a much slower rate if at all. In addition TTFields can be directed to a certain part of the body, leaving sensitive areas out of their reach.
In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very few side effects and promising affectivity in slowing or reversing this disease.
The device is also notable for the responses it elicits from professionals, according to Zvi Ram, MD, professor and chair of neurosurgery at Tel-Aviv Sourasky Medical Center in Israel.
To date, reports about the electrical device have elicited both antagonistic and enthusiastic reaction from oncologists, with "neither the enthusiasts nor the antagonists having significant bases for either kind of acute reaction," Dr. Ram told Medscape Medical News after his presentation.
Dr. Ram did not dwell on the antagonism. "It's human nature," he said about such audience reactions.
Traditional approaches to glioblastoma have a lot of room for improvement, explained Dr. Ram. "We're used to hurting the brain all the time. I operate on these patients; I take chunks of the brain out. Oncologists give toxins and irradiate the brain. That's what we're used to. Now somebody is thinking far outside the box with a new modality that's noninvasive."
Another neuro-oncology expert confirmed that NovoTTF is effective.
"There is little doubt that this device has an antitumor effect and the toxicity profile is nonexistent. The next few years will tell us where NovoTTF will fit into the treatment of glioblastoma and a variety of other difficult tumors," said Philip H. Gutin, MD, chair of the Department of Neurosurgery and Fred Lebow Chair in Neuro-Oncology at Memorial Sloan-Kettering Cancer Center in New York City.
The NovoTTF device delivers low-amplitude "tumor treatment fields," ranging from 100 to 300 kHz, which have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to a press release from NovoCure, the manufacturer of the device and sponsor of the trial.
The press release states that "alternating electric fields within the tumor exert physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cell death prior to division."
The portable device weighs about 2.75 kg, is connected to a battery pack, and is designed to be worn almost constantly, with a target of at least 20 hours each day.
Some Glioblastoma Results Not Seen "Anywhere"
In a randomized phase 3 clinical trial presented earlier this year at the American Society of Clinical Oncology annual meeting, an intent-to-treat analysis comparing NovoTTF with the best available chemotherapy found no statistical difference in 1-year overall survival in 237 recurrent glioblastoma patients between treatments.
However, a per protocol analysis (which included only patients who wore the device for 70% of the recommended time during the first month) showed a statistically significant benefit with NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs 19.1%; hazard ratio, 0.64; P = .01).
Now, a post hoc analysis of several subgroups in the study has found some additional advantages, reported Dr. Ram.
One subgroup of 110 "good prognosis" patients (younger than 60 years and with a Karnofsky Performance Scale score of more than 80) showed a "more robust" survival benefit than was seen in the overall intent-to-treat analysis, he said.
In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, compared with 6.6 months for those treated with chemotherapy (P < .01). This compares to 6.6 months and 6.0 months in the overall intent-to-treat group, he explained.
Moreover, 1-year overall survival in this subgroup was 35.2% with NovoTTF group, compared with 20.8% with chemotherapy (P < .01), which is an improvement over the nonsignificant difference between the 2 groups (23.6% vs 20.7%) in the larger analysis.
Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (roughly 20% of the entire cohort). Both an intent-to-treat analysis and a per protocol analysis showed significant overall survival advantages for NovoTTF, said Dr. Ram.
Among 44 patients in the intent-to-treat group, median overall survival with NovoTTF was 4 months and with chemotherapy was 3.1 months (hazard ratio, 0.43; P < .02). Among 29 patients in the per protocol analysis, median overall survival was 6.3 months with NovoTTF and 3.3 months with chemotherapy (hazard ratio, 0.21; P = .02).
"You don't see this anywhere," he told Medscape Medical News. "There's no drug in the world that could produce such a response in patients who had already failed [bevacizumab]."
The investigators also analyzed a surgery-naive group. "You know these are going to be poor responders, almost identical to bevacizumab failure," said Dr. Ram.
In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF and 5.5 months with chemotherapy.
Finally, an analysis using the Quality of Life Symptom Scale, measured prospectively during the study, showed significant differences between the 2 groups, with NovoTTF-treated patients having more favorable constipation scores (-34 vs -35) and diarrhea scores (+77 vs +50) than chemotherapy-treated patients.
Nausea and vomiting scores were -15 for the NovoTTF group and -61 for the chemotherapy group, and pain scores were -1 and +63, respectively.
A quality-of-life analysis using the EORTC QLQ-C30 showed scores of in favor of NovoTTF for cognitive functioning (+14 vs -7) and for emotional functioning (+7 vs +1).
"We do this to all our patients; we intoxicate them," said Dr. Ram about the adverse effects of chemotherapy. "Even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], then it may still improve quality of life."
Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase 2 study followed some of them for 59 months. "Seventy percent are still alive - that's unheard of," he remarked.
"There were concerns that patients might have more headaches or seizures, but there were none," he said.
Dr. Ram reported that the rate of adverse events related to the central nervous system (CNS) was similar for NovoTTF and chemotherapy (66% vs 67%), as were serious CNS adverse events (21% vs 22%), seizures (15% vs 12%), and headaches (18% vs 13%).
"There are no real concerns that this does anything hazardous to the brain," he said.
Dr. Ram also presented evidence suggesting that NovoTTF therapy has benefits in other forms of cancer.
A study reported by his colleagues earlier this year at the European Society for Medical Oncology Congress showed that NovoTTF therapy combined with chemotherapy resulted in significant prolongation of survival in patients with NSCLC, compared with historic controls, he said.
"If this kind of therapy acts against brain cancer cells, it should act also against other tumor types," he reasoned.
In the study, which looked at 42 NSLC patients, NovoTTF was delivered with newly designed electrodes placed on the chest and neck of patients with locally advanced metastatic stage IIIb and IV disease, he explained.
Overall survival was better with the combination of NovoTTF plus pemetrexed than with pemetrexed alone (13.8 vs 8.3 months), as was the rate of 1-year survival rate (57% vs 30%).
"We're talking about something that appears to be acting against cancer cells, regardless of origin," said Dr. Ram. "Action in the lung seems similar to what has been seen in [glioblastoma multiforme] - a slow resolution of malignant pleural effusion and masses within the chest over time."
"It's very interesting and exciting, even if we do not yet have enough definitive data," said Alba B. Brandes, MD, moderator of the session and chair of medical oncology at Azienda USL, a group of 9 hospitals in and around Bologna, Italy.
The study investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per protocol results that show significance, she said.
"An intention-to-treat population and per protocol population are 2 different things and, from a statistical point of view, it is sometimes difficult for the oncologic community to accept."
However, she said, the per protocol observations should not be dismissed, because when looked at this way, the results become "not a little significant, but highly significant," she said.
"I was really surprised to see what happened in the lung cancer. I am a medical oncologist and I have never seen that complete a response. It's surprising. We have to wonder if all that we know about the treatment of tumors is correct."
Dr. Ram acknowledged that the per protocol analysis of the findings is unconventional, but that "there is no precedent for this kind of therapy. I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions that we were traditionally using."
NovoCure announced today that it presented the results from a single-arm pilot trial evaluating the Novo-TTF, a non-invasive portable medical device, combined with neo-adjuvant chemotherapy for the treatment of patients with locally advanced breast cancer. Tumor volume shrank by 86-100 percent in the first four patients treated with the combined therapy, and one patient has experienced a complete response.
The data, which was presented during the annual meeting of the American Association for Cancer Research, also indicated that the Novo-TTF device can be safely combined with chemotherapy. It should be noted that these results are preliminary and the study is ongoing. In addition, NovoCure presented in vitro data from studies of the Novo-TTF treatment combined with chemotherapy to treat breast cancer and non-small cell lung cancer cells in culture, as well as animal data from VX2 tumors. The in vitro data demonstrated that the combination of chemotherapy with the Novo-TTF may produce additive as well as synergistic effects of one treatment plus the other.
“We are delighted that the American Association of Cancer Research gave us the opportunity to present publicly, for the first time, preliminary human data related to the combination of low intensity, intermediate frequency, alternating electric fields and chemotherapy agents for breast cancer patients,” said Professor Yoram Palti, M.D., Ph.D. and NovoCure founder. “These results add to the growing body of evidence that the Novo-TTF may be a valuable option for patients with solid tumor cancer.”
NovoCure also continues to develop the Novo-TTF as a treatment for glioblastoma multiforme (GBM) brain tumors. NovoCure recently published data from its human pilot study for patients with GBM tumors that recurred after surgery and radiation. The results of this study preliminarily indicate that the Novo-TTF more than doubled the median overall survival rates for recurrent GBM patients relative to historical data.
NovoCure is currently conducting a Phase III clinical trial at more than 20 centers in the US and Europe for patients with recurrent glioblastoma. Please refer to www.novocuretrial.com or call 1 (800) 978-0265 for more information on this trial.
AACR STUDY DETAILS
NovoCure presented data at the AACR from studies of the effect of combining the Novo-TTF with chemotherapy for the treatment of cancer tumors. The data included results for both safety and efficacy endpoints. An in vitro study determined the cell growth rates in human breast and non-small cell lung carcinoma cultures treated with the Novo-TTF, paclitaxel, doxorubicin and cyclophosphamide separately and in combination. The results varied from a simple additive effect (TTFields and doxorubicin) to an enhanced, synergistic effect (Novo-TTF and cyclophosphamide; Novo-TTF and paclitaxel). The study also showed that when the Novo-TTF was combined with all these agents, significantly less chemotherapy was needed to achieve the same beneficial effect as when chemotherapy was used alone. NovoCure then replicated the in vitro studies in an animal model by implanting VX2 tumors under the kidney capsule of rabbits. This in vivo study demonstrated similar outcomes to the in vitro study.
NovoCure built upon the animal and laboratory work with a single-arm human pilot trial to determine the safety and efficacy of the Novo-TTF with neo-adjuvant chemotherapy (doxorubicin or epirubicin together with docetaxel) in locally advanced breast cancer patients. This study is under way. Neo-adjuvant refers to chemotherapy delivered in advance of surgery in an effort to shrink the tumor so as to improve operative outcomes. The early results from the first four patients with combined therapy to date indicate that tumor volume shrank significantly by 86%, 89% and 96% and an additional patient has experienced a complete response.
The Novo-TTF is currently being studied in patients with brain cancer and breast cancer. Treatment related toxicity is a major limitation of all current cancer treatments and often prevents the delivery of effective doses. No clinically significant side effects due to the Novo-TTF have been seen throughout these trials to date. The only device-related side effect observed was a mild to moderate contact dermatitis beneath the electrodes, which responded well to the application of topical cream and periodic electrode relocation. - Edelman Public Relations
Novocure Limited is a private oncology company pioneering a novel therapy for solid tumors. Novocure's worldwide headquarters is located in the Jersey Isle. Novocure's U.S. operations are based in Portsmouth, NH and the company's research center is located in Haifa, Israel. For additional information about the company, please visit www.novocure.com.
Frank Leonard, Novocure
List of Clinical trial sites and contact information in the US. : http://clinicaltrials.gov/ct2/show/study/NCT00916409?show_locs=Y#locn