In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.

Abstract

551 Background: Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Sorafenib (oral multikinase inhibitor) is approved in patients with advanced HCC, yet survival benefit is limited. Tumor Treating Fields (TTFields) are an effective, anti-neoplastic treatment modality delivered via noninvasive, low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. The study aim was to explore in vitro and in vivo effects of TTFields alone and combined with sorafenib for HCC treatment. Methods: HCC (HepG2 and Huh-7D12) cells were TTFields treated with at frequencies of 100-400 kHz for 72 hr using the inovitro system. Efficacy of TTFields and sorafenib combined treatment was tested at optimal frequency with various sorafenib concentrations. Cell counts, apoptosis induction, and clonogenic potential were determined. Healthy rats were used to assess safety of TTFields applied to the abdomen. N1S1 HCC cells were injected into the left hepatic lobe of Sprague Dawley rat; after 1 week, TTFields (1.2 V/cm) and sorafenib (10 mg/kg) were applied for 6 days. Tumor growth was evaluated using MRI. Results: The optimal TTFields frequency was 150 kHz in HepG2 and Huh-7D12 HCC cells. TTFields 150 kHz treatment (1.0 - 1.7 V/cm, 72 hr) led to cell count reductions (53-55%) and further decreases in clonogenic potential (65-69%). TTFields and sorafenib combination treatment led to a significant reduction in cell count (2-way ANOVA, P < 0.05) vs either treatment alone. Also, tumor growth was significantly reduced in the combined treatment group vs the control group (student t test, P < 0.01). Tumor volume (fold increase) in the combination treatment group (1.6) was significantly lower vs control (5.9, P < 0.0001), TTFields alone (3.3, P < 0.01), and sorafenib alone (2.3, P < 0.05) groups. Safety studies did not reveal any TTFields related adverse events with delivery to the rat abdomen. Conclusions: In vitro and in vivo data demonstrated efficacy and safety of TTFields in HCC; and improved efficacy in combination with sorafenib. A phase 2 study (HEPANOVA; NCT03606590) will explore the clinical potential of TTFields 150 kHz plus sorafenib.