Abstract 4607: A translational study of Tumor Treating Fields in non small cell lung cancer
Authors: Pless Miklos , Weinberg Uri , Betticher Daniel , Giladi Moshe , von Moos Roger , Schneiderman Rosa , Droege Cornelia , Itzhaki Aviran , Mordechovich Daniel , Porat Yaara , Salzberg Marc , Kirson Eilon D. , Palti Yoram 
Published: August 2012

Abstract
Background Lung cancer is the second most common cancer and the leading cause of cancer related death in the US. Non-small-cell-lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. Prognosis of NSCLC remains poor despite extensive research. Tumor Treating Fields (TTF, TTFields) are low intensity, intermediate frequency alternating electric fields that have been demonstrated to disrupt cancer cell replication. A phase III clinical trial has previously demonstrated the efficacy of TTF in glioblastoma patients. Objectives This study was designed to test the effects of TTF in NSCLC, both as a single therapy and in combination with chemotherapies, from bench to the bedside. Methods H1299 (Human NSCLC) and LLC1 (murine Lewis lung carcinoma) cells were cultured while being subjected to different frequencies of low intensity (1-2 V/cm) TTF alone or in combination with different chemotherapies (cisplatin, pemetrexed, erlotinib and paclitaxel). An autologous model of C57BL/5 mice bearing LLC1 tumors was used to test the in vivo application of continuous TTF. A phase II clinical trial of TTF in combination with pemetrexed (standard regimen) was performed in 42 stage IIIB and IV NSCLC patients following progression after at least one line of chemotherapy. Treatment was made using 2 pairs of insulated, non-invasive transducer arrays applied to the skin of the thorax. Results In-vitro: The treatment of H1299 and LLC1 cultures with TTF for 72 hours had a significant inhibitory effect on proliferation in both cell lines, compared to control cultures. The optimal frequency for culture growth inhibition was 150 kHz. The combination of optimal frequency-TTF with different concentrations of chemotherapeutic agents led to further decrease in culture growth rate, compared to TTF-naïve cultures. In-vivo: TTF resulted in a significant reduction of approximately 30% in tumor volume and weight in mice bearing NSCLC tumors, as a monotherapy. This therapeutic effect almost doubled in mice that were treated with pemetrexed concomitant to the TTF. No pathological changes could be demonstrated in healthy tissues excised from TTF-treated animals. Clinical: NSCLC human patients with advanced-stage disease were treated with TTF (median of 11.2 hours/day) using the NovoTTF-100L System (NovoCure Ltd.) in combination with pemetrexed. Median progression-free survival was 23 weeks, median overall survival was 13 months and 1-year-survival was 54% - an improvement over pemetrexed-treated historical controls. The only device-related adverse event was mild to moderate contact dermatitis. Conclusions The inhibitory effect of TTF in different NSCLC models was demonstrated both as a single treatment and in combination with chemotherapies. The promising efficacy and low toxicity of TTF therapy combined with pemetrexed in NSCLC patients should lead to further clinical investigation of TTF as a potential treatment for NSCLC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4607. doi:1538-7445.AM2012-4607