The National Comprehensive Cancer Network (NCCN) has added the combination of TTFields (Optune) and temozolomide (Temodar) to its Clinical Practice Guidelines in Oncology for Central Nervous System Cancers for Category 1 treatment of newly diagnosed glioblastoma multiforme (GBM) following maximal safe resection and completion of radiation therapy. The addition, according to a press release from Novocure, is based on 5-year survival results from the phase III EF-14 trial.
TTFields is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Investigators deliver the treatment through 4 transducer arrays with 9 insulated electrodes each placed on the shaved scalp and connected to a portable device set to generate low-intensity, 200-kHz electric fields within the brain.
“Many physicians look to the NCCN Guidelines as the standard resource when determining the best course of treatment for patients,” Asaf Danziger, Novocure’s CEO, said in a statement. “The introduction of Optune with temozolomide gives newly diagnosed GBM patients the potential for long-term survival. We believe the updated NCCN guidelines will increase physician awareness, particularly in the radiation oncology and medical oncology communities, helping us to reach patients earlier in the course of this aggressive disease.”
Data from the the phase III EF-14 trial, published in Journal of the American Medical Association
in December 2017, showed that the combination extended overall survival (OS) and progression-free survival (PFS) by 37% compared with temozolomide alone.
EF-14 included a total of 695 patients with GBM who enrolled at 83 medical centers worldwide from July 2009 to December 2014. Eligible patients had undergone tumor resection or biopsy, and completed concomitant radiochemotherapy.
Patients were randomly assigned to TTFields plus maintenance temozolomide (n = 466) or temozolomide alone (n = 229). Patients in the TTFields arm received low-intensity alternating electric fields treatment was for ≥18 hours per day. All patients received 6 to 12 cycles of 150 mg/m2
to 200 mg/m2
of temozolomide for 5 days in 28-day cycles.
More than 90% of patients completed the trial by December 25, 2016 data cutoff.
Median PFS was 6.7 months with the combination compared with 4.0 months for the monotherapy (HR, 0.63; 95% CI, 0.52-0.76; P
<.001). Median OS was 20.9 months in the TTFields/temozolomide group versus 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P
In posthoc analyses, TTFields plus temozolomide was associated with an increase in PFS and OS in all subgroups regardless of age, sex, Karnofsky performance score, MGMT promoter methylation status, geographic region, or extent of resection. While Investigators found that the OS benefit associated with the combination was consistent across all patient subgroups including subgroups with the worst prognosis who had less benefit from previous therapies such as patients aged ≥65 years (HR, 0.51; 95% CI, 0.33-0.77) and those with methylated and unmethylated MGMT tumors (HR, 0.66; 95% CI, 0.49-0.85).
In exploratory analyses, 43% (95% CI, 39-48) of patients were alive at 2 years from randomization, 26% (95% CI, 22-31) at 3 years, and 26% and 13% (95% CI, 9-18) at 5 years in the combination arm compared with 31% (95% CI, 25- 38; P
<.001), 16% (95% CI, 12-23; P
= .009), and 5% (95% CI, 2-11; P
= .004) in the temozolomide-only group, respectively.
Six-month PFS was 56% (95% CI, 51- 61) in the combination arm compared with 37% (95% CI, 30-44) with temozolomide monotherapy (P
Investigators did not see an increase in systemic adverse events (AEs) with the combination (48% vs 44%; P
= .58). Patients in the combination arm had a higher number of grade 3/4 AEs, but investigators attributed the difference to the longer duration of temozolomide treatment in this group due to delayed occurrence of progression. These differences disappeared when investigators controlled for duration of treatment except in the case of e higher incidence of localized skin toxic effects beneath the transducer arrays in patients treated with TTFields plus temozolomide. Fifty-two percent of patients experienced mild to moderate skin irritation and 2% experienced grade 3 skin involvement.
At the interim analysis, anxiety, confusion, insomnia, and headaches which were reported more frequently, the difference was statistically nonsignificant, in patients treated with TTFields. Investigators did not observe those AEs in the final analysis.
The incidence of seizures was identical in the 2 groups.
Based on earlier results from the EF-14 trial, the FDA approved a second-generation, lighter version of the device in July 2016. The new version weighs 2.7 lbs, about half the size and weight of the original.
The first-generation of Optune was most recently approved in 2015 for use in combination with adjuvant temozolomide as a treatment for patients with newly diagnosed GBM following surgery, chemotherapy, and radiation therapy. Optune was initially approved in 2011 for the treatment of recurrent GBM after other surgical and radiation options were exhausted.
Stupp R, Taillibert S, Kanner A, et al. Survival in patients with glioblastoma: a randomized clinical trial. JAMA.