nosed with mesothe

EVOLVING STANDARDS OF CARE

TTFields in Mesothelioma (The STELLAR Trial): More Stars Needed in the Constellation

By Paul Baas, MD, PhD, and Cornedine J. de control group receiving chemotherapy Gooijer, MD alone, statistical signifi cance was not determined. Recently, a manuscript by Ceresoli et al. It is a well-known scientifi c observawas published in Th e Lancet Oncology. 1 tion that single-armed studies nearly Th e study states that the use of tumoralways tend to overestimate outcomes treating fields (TTFields) is a major observed in randomized trials or in the improvement in the treatment of patients real world. Th e results of STELLAR sugwith mesothelioma compared to previous gest similarity with the data obtained standards. 2 Herein, we take a closer look from the nintedanib study where the at the study. (randomized) phase II single-armed study suggested benefit, but which Background of TTFields failed in the phase III setting in mesoApplication thelioma. 4,5 Previous experimental studies have indicated that the use of lowNot Written in the Stars (Yet) frequency electric fi elds may Th e STELLAR trial reported a disrupt tumor progresmedian OS (primary endsion through the mitotic point) of 18.2 months spindle during mito(95% CI [12.1, 25.8]). sis. In addition, heat The study looked is produced that may for an OS of 17.6 augment a cytotoxic months, an increase reaction. 2 However, of 5.5 months in cells were only tested median OS compared in vitro, and no clear to the results obtained explanation is given as to Dr. Paul Baas for combination cisplatin why 150 kHz is the optimal and pemetrexed in the regfrequency. istration study in 2003. 2

Th e device has been However, these results approved based on should be placed in the lack of signifi cant the context of recent toxicity and electronic trials in mesothesafety of the apparalioma. 6 The Table tus. 3 Th e U.S. Food and shows the objective Drug Administration, response rate, PFS, and however, did report that Dr. Cornedine J. de Gooijer OS in previous randomalthough the results of the ized trials in patients with STELLAR study are within malignant mesothelioma the range (of reported PFS and OS) and treated with platinum-pemetrexed. show improvement, in the absence of a Th e confi dence intervals observed for

Table. Overview of Previous Study Results

Study Number of patients ORR mPFS (months; [95% CI]) mOS (months; [95% CI])

Vogelzang 2

226 41% 6.1 [5.4-6.7] 12.1 [10.9-14.8]

STELLAR 1

80 37% 7.6 [6.7-8.6] 18.2 [12.1-25.8]

MAPS 8

225 Not reported 7·3 [6·7-8·0] 16·1 [14·0-17·9]

LUME-Meso phase II 4

41 44% 5.7 [5.5-7.0] 14.2 [12.3-20.9]

LUME-Meso phase III 5

229 43% 7·0 [6·7-7·2] 16·1 [13·7-19·3]

Results are reported from the control arms in the MAPS and both LUME-Meso trials, in which patients received platinum-pemetrexed, and for the cisplatin-pemetrexed arm from the Vogelzang trial. Abbreviations: mPFS, median progression-free survival; mOS, median overall survival; ORR, objective response rate.

TTFields in combination with standard chemotherapy in the STELLAR trial overlap with historical data. Although the authors attributed the lack of benefit for angioinhibitory strategies in the MAPS and LUME-Meso trials to a patient population with a worse prognosis (more patients with sarcomatoid mesothelioma), other prognostic factors (like platelet count and lactate dehydrogenase) were not reported. Th is underscores the need for randomized studies to reveal the true added benefi t of TTFields in mesothelioma.

Th e monthly costs of TTFields ($21,000 in 2016) and the eff ect on quality of life need to be justifi ed based on phase III data. TTFields were used continuously during the four cycles of platinum-pemetrexed therapy and as maintenance therapy until progression. Patients received a median of eight cycles of TTFields, hence a median 5.5 months of continual use of this device. Th e eff ect on quality of life for patients and relatives should not be underestimated. 7 Th e TTFields device, applied to the thorax, is recommended to be used for 18 hours per day (also at night). In 66% of patients, a local reaction to the skin at the site of the medical device was observed. 1

STELLAR Results in Practice

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to QoL deterioration in patients with MPM. At the same time, increased compliance with TTFields therapy was an independent prognostic for survival in the glioblastoma trial. 12 Proactive skin care and the availability of a smaller and lighter device may be valuable strategies to improve QoL and compliance to treatment (and ultimately outcomes) in patients with MPM. ✦

About the Authors: Dr. Baas is chief of Department of Th oracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Dr. de Gooijer is with the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Please note that the full reference list for this article appears online at lungcancernews.org.

Based on the results of this study, we conclude that the TTFields approach may hold some promise, but there is a clear lack of prospective phase III evidence. A randomized study is of paramount importance, and more insight into its working mechanisms is needed. Diff erences in pathology and performance status of the patients enrolled on this study compared to populations on other trials and historic controls can account for potential spread in outcome. Finally, we need to focus on translational research factors to support a role for this device. ✦

References: 1. Mun EJ, Babiker HM, Weinberg U, et al. Tumor

Treating Fields: A fourth modality in cancer treatment. Clin Cancer Res. 2018;24:266-275. 2. Ceresoli GL, Aerts JG, Dziadziuszko R, et al.

Tumor Treating Fields in combination with pemetrexed and cisplatin/carboplatin as fi rst line treatment for unresectable malignant pleural mesothelioma: results of the STELLAR multicenter, single arm, prospective phase 2 trial.

Lancet Oncol. 2019;20:1702-1709. 3. Byrne MJ, Nowak AK. Modifi ed RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004;15:257-260. 4. Zalcman G, Mazieres J, Margery J, et al.

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405-1414. 5. Scagliotti GV, Gaafar R, Nowak AK, et al.

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Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Th oracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. J Th orac Oncol. 2018;13:1655-1667. 7. NovoTTF TM - 100L System - H180002. U.S. Food and Drug Administration. https://www.fda.gov/ medical-devices/recently-approved-devices/ novottft m-100l-system-h180002. Published May 28, 2019. Accessed January 12, 2020. 8. Voloshin T, Kaynan N, Davidi S, et al. Tumor

Treating Fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor effi - cacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020 Mar 6. [Epub ahead of print]. 9. Lacouture ME, Davis ME, Elzinga G, et al.

Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric fi eld device for the treatment of recurrent glioblastoma.

Semin Oncol. 2014;41(Suppl 4):S1-S14. 10. Ceresoli GL, Vergote I, Rivera F, Pless M. Safety of Tumor Treating Fields delivery to the torso: pooled analysis from TTFields clinical trials (Abstract 8215). Proceedings of the 2019 Annual Meeting of the American Association for Cancer

Research. 2019;79(13 Suppl.). 11. Taphoorn MJB, Dirven L, Kanner AA, et al.

Infl uence of treatment with tumor-treating fi elds on health-related quality of life of patients with newly diagnosed glioblastoma: A secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4(4):495-504. 12. Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fi elds therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neuro Oncol. 2019;141(2):467-473.