Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial

Abstract

Background: Understudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.

Methods: All 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan-Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.

Results: The PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30-0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33-0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29-50%) versus 27% (95% CI, 15-41%; P=0.072) at 2 years, 19% (95% CI, 11-29%) versus 11% (95% CI, 4-23%; P=0.135) at 3 years, and 15% (95% CI, 7-25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1-2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.

Conclusions: Combining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT00916409, identifier: NCT00916409.

Keywords: TTFields; Tumor Treating Fields; efficacy and safety; elderly patients; newly diagnosed glioblastoma; phase 3 clinical trial; quality-of-life; temozolomide.

Conflict of interest statement

ZR received research grants from and is a paid consultant of Novocure. AH received a research grant from Novocure, paid to the institution. AI received research grants and travel funding from Carthera, Leo Pharma and Novocure, research grants from Air Liquide, Nutritheragene, Sanofi, and Transgene, and travel funding from Leo Pharma, and served on received honorarium for advisory boards from Novocure and Leo Pharma. J-JZ received funding paid to the institution from Boston Biomedical Sumitomo Dainippon Pharma Global Oncology, Novocure, Inc., and NRG consortium of National Cancer Institute (NCI) and an honorarium from the Hong Kong Precision Oncology Society. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Novocure. The funder had the following involvement with the study: design and conduct of the study; collection, management, analysis, andinterpretation of the data; and preparation and review of this manuscript.

Copyright © 2021 Ram, Kim, Hottinger, Idbaih, Nicholas and Zhu.

Figures

Figure 1

CONSORT Diagram. Updated from Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma a randomized clinical trial. JAMA. (2017) 318:2306–16. TMZ, temozolomide; TTFields, Tumor Treating Fields.

Figure 2

Kaplan–Meier curves of (A) PFS and (B) OS of elderly patients ≥65 years of age who were treated with TTFields plus TMZ combination (blue line) compared to TMZ monotherapy (red line). CI, confidence interval; mo, month; no, number; OS, overall survival; PFS, progression-free survival; TMZ, temozolomide; TTFields, Tumor Treating Fields.

Figure 3

Kaplan–Meier curves of (A) median PFS and (B) median OS of TTFields plus TMZ combination with TTFields daily usage of ≥75% (purple lines) compared to TTFields daily usage of <75% (green lines) and TMZ alone (red lines).(C) Baseline age and KPS of patients ≥65 years of age with TTFields daily usage of ≥75% and <75%. CI, confidence interval; KPS, Karnofsky Performance Status; mo, month; no, number; OS, overall survival; PFS, progression-free survival; TMZ, temozolomide; TTFields, Tumor Treating Fields.

Figure 4

(A) Median deterioration-free survival and (B) median time to deterioration for health-related quality-of-life domains in patients ≥65 years of age who received TTFields plus TMZ combination compared with TMZ monotherapy. DFS, deterioration-free survival; HR, hazard ratio; NR, not reached; TMZ, temozolomide; TTD, time-to-deterioration; TTFields, Tumor Treating Fields. aAt the time of this analysis, median TTD was not reached for global health status and physical functioning in the TTFields plus TMZ combination group or pain and financial difficulties in the TMZ monotherapy group.