Post Hoc Analyses of Intention-to-Treat Population in Phase III Comparison of NovoTTF-100A™ System Versus Best Physician’s Choice Chemotherapy

Abstract

We performed a treatment-based analysis of data from the pivotal phase III trial of the NovoTTF-100A System™ versus best physician's choice (BPC) chemotherapy in patients with recurrent glioblastoma multiforme (GBM), with particular focus on efficacy in patients using NovoTTF Therapy as intended. Median overall survival (OS) was compared for recurrent GBM patients receiving at least one full cycle of treatment with NovoTTF-100A System or BPC chemotherapy (modified intention-to-treat [mITT] population) in the recently reported phase III trial. The relationship between NovoTTF-100A System compliance and OS was evaluated in the ITT population. Kaplan-Meier analyses examined treatment-related differences in OS for various patient subgroups. Median OS was significantly higher in patients receiving≥1 course of NovoTTF Therapy versus BPC (7.7 v 5.9 months; hazard ratio, 0.69; 95% confidence interval [CI], 0.52-0.91; P = .0093). Median OS was also significantly higher in patients receiving NovoTTF Therapy with a maximal monthly compliance rate≥75% (≥18 hours daily) versus those with a<75% compliance rate (7.7 v 4.5 months; P = .042), and Kaplan-Meier analysis demonstrated a significant trend for improved median OS with higher compliance (P = .039). Additional post hoc analysis showed significantly higher median OS with NovoTTF Therapy than with BPC for patients with prior low-grade glioma, tumor size≥18 cm(2), Karnofsky performance status≥80, and those who had previously failed bevacizumab therapy. When used as intended in mITT patients with recurrent GBM, NovoTTF Therapy provides an OS benefit compared with chemotherapy in patients with recurrent GBM. This contrasts with the equivalent efficacy reported previously based on analysis of all randomized ITT subjects, including many who did not receive a full cycle of treatment. Higher NovoTTF Therapy compliance corresponds with greater survival benefit in the present study.

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

“…The compliance with TTFields therapy in the clinical trials was tightly linked to the survival outcomes; monthly compliance above 75% was associated with higher overall survival 9,10,31 . Our cell culture experiments revealed that the surviving cells recover with a delay of 24 h after end of TTFields application.…”

“…For clinical use they are applied at tumor specific frequencies via ceramic electrodes, so-called transducer arrays, adhered to the shaved scalp of the patient. The therapy compliance was tightly linked to the outcome and monthly compliance above 75% was associated with higher overall survival 9,10 . In addition, this important development in the treatment of GBM patients, the therapy may be further improved by its combination with synergistic therapies.…”

The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes

“…Importantly, median OS and PFS6 were significantly longer in these 93 patients who completed the full cycle compared with those patients receiving chemotherapy. 27,80 Interestingly, in a post-hoc analysis conducted on this randomized clinical trial, compliance in patients below 60 years of age was statistically higher compared with those above 60 (80% vs 74%, respectively; p = 0.043). 26 The importance of patient compliance cannot be overstated, as the results of the original randomized trial, 65 as well as those of a previously mentioned pilot trial, 30 demonstrated that the duration of AEF therapy was highly correlated with survival (r 2 = 0.92).…”

“…For example, it has been shown that patients with favorable prognostic characteristics (such as age less than 60 years or Karnofsky Performance Scale score greater than 80%), as well as patients with tumors refractory to bevacizumab treatment, had significantly greater OS with AEF therapy in comparison with standard chemotherapy. 26,27,53 Moreover, when excluding patients who did not receive a complete cycle of treatment with AEFs, patients in the AEF cohort showed improved survival in comparison with physician's best choice chemotherapy. 80 A survival benefit was also noted when comparing AEF monotherapy to those patients receiving bevacizumab.…”

“…54 Interestingly, certain tumor characteristics were also associated with improved OS with AEFs, including prior low-grade glioma, refractory response to bevacizumab, and tumor size greater than 18 cm 2 . 26,27 case reports…”