New Adjunctive Therapy Extends Survival in Glioblastoma

Low-intensity, intermediate-frequency, alternating electric fields — a therapy known as tumor-treating fields (TTFields) — used in combination with maintenance temozolomide has been found to increase progression-free survival by three months in newly diagnosed glioblastoma patients treated first with temozolomide and radiotherapy.

TTFields, which is detailed in this earlier Consult QD post, is the first therapy in a decade to improve both progression-free and overall survival in a randomized phase 3 trial of patients with this devastating diagnosis.

In that international study, published in JAMA in December, the addition of TTFields to temozolomide produced a median progression-free survival of 7.1 months, significantly longer than the 4.0 months achieved in patients treated with temozolomide alone (hazard ratio, 0.62 [98.7% CI, 0.43-0.89], P = .001, for intent-to-treat population).

Median overall survival with TTFields was 20.5 months, versus 15.6 months with temozolomide alone (hazard ratio, 0.64 [99.4% CI, 0.42-0.98], P = .004, for per-protocol population).

Positive findings prompt early study termination

These findings were from a planned interim analysis of the first 315 patients enrolled in the trial with at least 18 months of follow-up, 210 of whom were randomized to TTFields plus temozolomide and 105 to temozolomide alone. As a result of the findings, the trial was terminated early and control patients were offered the addition of TTFields therapy.

Later analysis of the intent-to-treat population shortened the overall survival benefit to 19.6 months with TTFields versus 16.6 months with temolozomide alone, but this was still a significant relative improvement.

“This modality offers an additional option for glioblastoma patients with limited therapeutic options,” says Manmeet Ahluwalia, MD, a neuro-oncologist in Cleveland Clinic’s Burkhardt Brain Tumor and Neuro-Oncology Center. Dr. Ahluwalia and study co-author Gene Barnett, MD, MBA, enrolled more than 20 Cleveland Clinic patients in the multicenter trial.

Benefits and limits of TTFields

Having worked with TTFields for more than four years, Dr. Ahluwalia has a good understanding of the benefits and limitations of the therapy, which requires patients to wear transducer arrays (which deliver the alternating electric fields) directly on their shaved scalp (see image at top of post).

“We think it’s a reasonable option, particularly for patients with low blood counts, because the side effects are basically limited to grade 1 or 2 skin irritation at the treatment site,” he says. “There is no overlapping toxicity with the chemotherapies used to treat these patients.”

Dr. Ahluwalia discusses the treatment option with newly diagnosed glioblastoma patients after they finish radiation, and he’s found that some patients are deterred by the need to shave their scalp and wear the device for a minimum of 18 hours a day. “It will be interesting to see the acceptability rates over the next year or so,” he says. “They won’t be 100 percent.”

Cost and coverage questions

In 2012, TTFields was granted FDA approval as monotherapy for recurrent glioblastoma. Yet the Centers for Medicare & Medicaid Services (CMS) has denied coverage for the treatment, deeming it “medically unnecessary.” At $20,000 per month, the treatment is generally unaffordable without insurance coverage — a fact that may further hinder acceptance.

In October 2015, the combination of TTFields and temozolomide studied in the new clinical trial published in JAMA received FDA approval for newly diagnosed glioblastoma. Dr. Ahluwalia thinks CMS will likely reconsider its coverage decision given the survival advantage seen in this recent study in patients with newly diagnosed glioblastoma.

Additional studies underway

The bigger question is whether oncologists will embrace the new treatment option, Dr. Ahluwalia says. “Some physicians feel they need to see more data from other randomized trials, as there was no placebo group or sham device used in this JAMA study,” he explains.

Dr. Ahluwalia and others feel TTFields holds enough promise to merit additional studies. “Preclinical studies have shown an additive or synergistic effect when TTFields is used with chemotherapy in several cancers, as well as in glioblastoma,” he notes. “We are encouraged that it can extend survival and, since its main side effect is local skin reaction, can be combined with the chemotherapies used to treat these patients.”

A number of clinical trials involving TTFields in the treatment of glioblastoma are ongoing. These include a multicenter phase 2 trial combining TTFields with bevacizumab for recurrent glioblastoma; Dr. Ahluwalia serves as principal investigator.

“We are grappling with how to incorporate the findings from this newly published study in ongoing and planned trials of newly diagnosed glioblastoma patients,” he says.

He adds that five additional studies are evaluating TTFields in other forms of cancer, including mesothelioma and ovarian and pancreatic cancers.

Photo courtesy of Novocure.