Objective: Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer, linked to asbestos exposure. The prognosis of patients with MPM is poor, with a median overall survival (OS) of ~12 months reported with historical, standard of care (SOC) cisplatin or carboplatin plus pemetrexed. Tumor Treating Fields (TTFields) is an anti-neoplastic treatment delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields and was shown to increase OS to 18.2 months in combination with SOC. Based on these data, TTFields were approved for treatment of unresectable MPM. The aim of this study was to further evaluate the effectiveness and safety of TTFields alone and in combination with SOC for MPM treatment, utilizing in vitro and in vivo models.
Methods: NCI-H2052 and MSTO-211H human MPM cells were treated at various TTFields frequencies (100-400 kHz) for 72 hours using the inovitroTM system to determine optimal frequency. The combination of TTFields with cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency in combination with various concentrations of the chemotherapeutic agents. For TTFields alone, cell counts, clonogenic potential, and induction of apoptosis were determined. Also, cytotoxic, apoptotic, and overall (cytotoxic plus clonogenic) effects were evaluated for cisplatin or pemetrexed alone (at various concentration) and in combination with TTFields. TTFields (1.2 V/cm) were applied for 8 days to rats injected with IL-45 MPM cells to the intrapleural cavity and tumor volume was measured.
Results: The optimal frequency of TTFields was 150 kHz in both MPM human cell lines. TTFields application (1.0 V/cm, 72 hours) alone at 150 kHz led to a 45-51% reduction in cell counts and a 64-76% additional reduction in clonogenic potential. The combined treatment of TTFields with cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis, and reduced clonogenic potential as compared to each modality alone. In vivo, TTFields in combination with pemetrexed plus cisplatin significantly decreased the MPM tumor volume in the rat model compared to the control group (P < 0.006). Safety studies did not reveal any adverse events associated with 150 kHz TTFields application to the rat torso.
Conclusions: These preclinical data demonstrate that TTFields are an effective treatment against MPM and the combination with cisplatin or pemetrexed enhanced treatment effectiveness. Results are consistent with the recent phase 2 STELLAR study (EF-23 trial; NCT02397928) that reported improved OS with TTFields in combination with pemetrexed plus platinum-based chemotherapeutic (cisplatin or carboplatin) as compared to historical control for front-line treatment of unresectable MPM, with no increases in systemic toxicity.
Citation Format: Mijal Munster, Helena Mumblat, Shiri Davidi, Rosa Schneiderman, Yaara Porat, Anna Shteingauz, Tali Voloshin, Noa Kaynan, Einav Zeevi, Moshe Giladi, Uri Weinberg, Adrian Kinzel, Yoram Palti. Efficacy of Tumor Treating Fields (TTFields) in combination with cisplatin or pemetrexed for the treatment of mesothelioma in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 573.