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Promising overall response and disease control with tumour treating fields combined with sorafenib in hepatocellular carcinoma

Tumour Treating Fields (TTFields) is an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumour using a portable medical device. The phase II HEPANOVA trial demonstrates that the combined use of these TTFields with sorafenib is safe in patients with hepatocellular carcinoma with encouraging preliminary efficacy.

Most patients with hepatocellular carcinoma (HCC) are not amenable to curative therapies and are treated with best supportive care following failure of loco-regional treatment options. Sorafenib has long been the recommended first line treatment for patients with unresectable HCC. More recently, however, atezolizumab plus bevacizumab challenged this standard by showing a better overall and progression-free survival than sorafenib in this setting. Tumour treating field (TTFields) is an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumour using a portable medical device. TTFields is currently approved by the FDA for the treatment of glioblastoma and malignant pleural mesothelioma. Interestingly, in vitro, and in vivo studies with TTFields at 150kHz showed that this technique reduces the proliferative potential of HCC cell lines. Based on these preclinical findings, the phase II HEPANOVA trial investigates the efficacy and safety of TTFields concomitant with sorafenib in patients with advanced HCC.

HEPANOVA study design

The prospective, phase II, single-arm, HEPANOVA study enrolled 27 HCC patients ineligible for surgery or local therapy (BCLC stages 0-C, Child-Pugh score of 5-8), to receive TTFields (150 kHz) for ≥18 hours a day, combined with 400 mg daily sorafenib (2x 200 mg) until disease progression. Following disease progression, patients were followed up every eight weeks until death. Clinical follow up was performed every four weeks, with CT/MRI scan every twelve weeks. The primary endpoint of this study was investigator-assessed overall response rate (ORR), with secondary objectives consisting of progression-free survival at twelve months, one-year survival rate, one-year distant metastases-free survival rate and safety.


The median age of patients included in this study was 65 years. Most patients (44.4%) had an ECOG PS of 0, with about one out of five patients (22.2%) having an ECOG PS of 2. Furthermore, 37.0% and 14.8% of patients had a Child-Pugh score of 7 or 8, respectively with 77.8% of patients having BCLC stage C disease. The median treatment duration with TTFields and sorafenib was short at only 10 and 9 weeks, respectively. Six patients (22%) survived less than 12 weeks. Out of the 21 patients who had a radiological follow-up and were therefore evaluable, ORR was 9.5% with a disease control rate (DCR) of 76%. However, ORR was numerically better in patients who received TTFields and sorafenib up to or over 12 weeks (ORRs of 18% and DCR of 91%). No complete responses were seen. In total, 73% of patients who received treatment ≥12 weeks experienced stabilisation of disease, while this was only the case for 66.5% of patients who were treated for less than 12 weeks. The median PFS was 5.8 months (95%CI: 3.0-8.9), with a 12-month PFS of 23% (95%CI: 7.0-45.0) and a median time to progression of 8.9 months (95%CI: 3.1- not reached [NR]). In-field control rate of one year was 9.5% and the distant metastases-free survival (DMFS) rate at one year was reported at 26% (95%CI: 8-49). The most common grade 3-4 adverse events (AEs) were gastrointestinal (26%), metabolism-related (19%), respiratory, abnormal laboratory investigations and general disorders/administration site-related (all 15%). Thirteen patients (48%) experienced serious AEs, although none were TTFields-related. Furthermore, eighteen patients (67%) had grade 1-2 TTFields related skin toxicity, and one patient (3%) had a grade 3 skin toxicity.


Even though the HEPANOVA patient population had a very poor prognosis and exposure to study treatment was very low, the ORR and DCR observed were higher than what is reported in literature with sorafenib alone. Furthermore, no serious AEs were associated with TTFields and treatment of TTFields plus sorafenib was found to be safe. The results of this study warrant further investigation of TTFields in a randomised control trial with HCC patients.


Gkika E, et al. HEPANOVA: Final Efficacy and Safety Results From a Phase 2 Study of Tumor Treating Fields (TTFields, 150kHz) Concomitant with Sorafenib in Advanced Hepatocellular Carcinoma (HCC). Presented at the 2021 ESMO World Congress on Gastrointestinal Cancer: Abstract O-16.

Speaker Eleni Gkika

Eleni Gkika

Eleni Gkika, MD, University of Freiburg, Freiburg, Germany


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