Background: Tumor Treating Fields (TTFields) is a novel, anti-mitotic, physical treatment. Alternating electrical fields (TTFields) at an intermediate frequency of 200 MHz (1-3 V/cm) are delivered continuously to the brain by a patient-operated, wearable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) is testing the efficacy of adding TTFields to standard adjuvant temozlomide (TMZ) chemotherapy in newly diagnosed GBM. We report the final and mature results of all 695 patients (pts) enrolled (median follow-up > 3 years, minimum follow-up > 24 months) including five year survival rates.
Methods: Within 7 weeks after the end of concomitant chemo-radiotherapy (TMZ/RT) and stratification for extent of resection and MGMT status, pts were randomized (at a 1:2 ratio) to either standard adjuvant TMZ alone (150-200 mg/m2/d x 5d) or TMZ and TTFields. Eligible pts had a newly diagnosed GBM, non-progressive after TMZ/RT, performance status of ≥70%, adequate hematological, liver and renal function. The primary endpoint is progression free survival (PFS; determined by blinded central radiology review), with overall survival (OS) as a powered secondary endpoint.
Results: 695 pts were randomized (7/09 - 11/14). Patient characteristics are balanced, median age 56 years (range 19-83), 87 % had undergone tumor resection, 13 % a biopsy only. One third of tumors were MGMT methylated. Median time from end of radiotherapy to randomization was 37 days. The median number of adjuvant (maintenance) TMZ cycles was 6 and 5 cycles, for TTFields/TMZ and TMZ alone, respectively. All analyses are intent-to-treat. The median PFS is 6.7 months (95%CI 6.1-8.1) for the pts treated with TTFields/TMZ versus 4.0 months (CI 3.8 - 4.4) for TMZ alone (hazard ratio 0.63, p=0.00005). Median OS from randomization is 20.9 months versus 16 months for the TTFields/TMZ and TMZ alone, respectively, with a hazard ratio of 0.63 (CI 0.53-0.76), p=0.00006. Median time from initial diagnosis until completion of TMZ/RT with subsequent randomization was 3.7 months, equal in both arms. The landmark 2 and 5-year survival rates are 43% (CI 39-48%) vs 31% (CI 25-38) and 13% (CI 9-18) vs 5% (CI 2-11); p=0.0008 and 0.0037, respectively. The significant improvement in OS was seen across all patient subgroups regardless of age, extent of resection, performance status, gender, geography or MGMT methylation status. Only compliance with TTFields treatment was predictive of outcome, with pts who were treated for more than 18 hours/day (monthly average) living significantly longer than pts treated for less than 18 hours/day.
Conclusions: This final analysis of the EF-14 trial demonstrate consistent superior PFS and OS in pts treated with maintenance therapy including both TTFields and TMZ compared with maintenance TMZ alone. With a hazard ratio for survival of 0.63, the magnitude of improvement when adding TTFields is comparable to the benefit observed with TMZ 12 years ago. Tumor Treating Fields are a welcome addition to the treatment armamentarium in GBM, and defines a new standard of care. This innovative regional treatment modality that can due to the absence of overlapping toxicity easily be combined with standard chemotherapy holds promise as a regional tumor treatment modality in other solid tumors.
Citation Format: Roger Stupp, Monika E. Hegi, Ahmed Idbaih, David M. Steinberg, Benoit Lhermitte, William Read, Steven A. Toms, Gene H. Barnett, Garth Nicholas, Chae-Yong Kim, Karen Fink, Andrea Salmaggi, Frank S. Lieberman, Jay-Jiguang Zhu, Lynne Taylor, Giuseppe Stragliotto, Andreas F. Hottinger, Eilon D. Kirson, Uri Weinberg, Yoram Palti, Zvi Ram, on behalf of the EF-14 trial investigators. Tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): Final results of a randomized, multi-center, phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT007. doi:10.1158/1538-7445.AM2017-CT007