Tumor-Treating Fields Combined with Radiotherapy and Temzolomide for the Treatment of Newly Diagnosed Glioblastoma: Final Results from a Pilot Study

Abstract

Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low intensity alternating electric fields. In the phase 3 EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields significantly improved survival compared to temozolomide (TMZ). Preclinical data have demonstrated that TTFields increased glioma cell death following radiation therapy (RT), suggesting a radio-sensitizing effect of TTFields. We therefore initiated a pilot study to evaluate the safety and feasibility of administering TTFields concomitant to RT and TMZ in ndGBM patients. Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by maintenance TTFields and TMZ for up to 24 months. TTFields (200 kHz) were delivered for ≥18 hours/day with removal of the transducer arrays during delivery of RT. TMZ was administered at a dose of 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded according to CTCAE V4.0. Ten patients were enrolled at a single center in Israel between April and December 2017. All patients had recovered from maximal debulking surgery or biopsy. Five patients (50%) had undergone gross total resection while the rest had biopsy only. Median age was 59 and median KPS was 80. Median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity, reported in 4 patients (40%), all of which were Grade 1–2 in severity. Two patients reported serious AEs (seizures and general deterioration) that were considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not yet been reached. The proportion of patients with TTFields-related skin toxicity was similar to that reported in ndGBM patients in the randomized phase 3 study (52%). No other TTFields-related toxicities were reported, nor was there an increase in RT- or TMZ-related toxicities as a result of combining TTFields with RT in addition to TMZ. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.