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E V O LV I N G S TA N D A R D S O F C A R E
TTFields in Mesothelioma (The STELLAR Trial): More Stars Needed in the Constellation By Paul Baas, MD, PhD, and Cornedine J. de Gooijer, MD
Recently, a manuscript by Ceresoli et al. was published in The Lancet Oncology.1 The study states that the use of tumortreating fields (TTFields) is a major improvement in the treatment of patients with mesothelioma compared to previous standards.2 Herein, we take a closer look at the study.
Background of TTFields Application
control group receiving chemotherapy alone, statistical significance was not determined. It is a well-known scientific observation that single-armed studies nearly always tend to overestimate outcomes observed in randomized trials or in the real world. The results of STELLAR suggest similarity with the data obtained from the nintedanib study where the (randomized) phase II single-armed study suggested benefit, but which failed in the phase III setting in mesothelioma.4,5
Previous exp erimental studies have indicated that the use of low- Not Written in the Stars (Yet) The STELLAR trial reported a frequency electric fields may median OS (primary enddisrupt tumor progression 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 2 reaction. However, of 5.5 months in cells were only tested median OS compared in vitro, and no clear to the results obtained Dr. Paul Baas explanation is given as to for combination cisplatin why 150 kHz is the optimal and pemetrexed in the regfrequency. istration study in 2003.2 The device has been However, these results should be placed in approved based on the lack of significant the context of recent toxicity and electronic trials in mesothesafety of the apparalioma. 6 The Table shows the objective tus.3 The U.S. Food and Drug Administration, response rate, PFS, and however, did report that OS in previous randomDr. Cornedine J. de Gooijer ized trials in patients with although the results of the 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 The confidence intervals observed for
STELLAR Results in Practice from page 10
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 Author: Dr. Ceresoli is with the Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy.
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 first 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. Modified 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. Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients
Table. Overview of Previous Study Results Study
Number of patients
ORR
mPFS (months; [95% CI])
mOS (months; [95% CI])
Vogelzang2
226
41%
6.1 [5.4-6.7]
12.1 [10.9-14.8]
STELLAR1
80
37%
7.6 [6.7-8.6]
18.2 [12.1-25.8]
MAPS
225
Not reported
7·3 [6·7-8·0]
16·1 [14·0-17·9]
LUME-Meso phase II4
41
44%
5.7 [5.5-7.0]
14.2 [12.3-20.9]
229
43%
7·0 [6·7-7·2]
16·1 [13·7-19·3]
8
5
LUME-Meso phase III
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. This underscores the need for randomized studies to reveal the true added benefit of TTFields in mesothelioma. The monthly costs of TTFields ($21,000 in 2016) and the effect on quality of life need to be justified 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. The effect on quality of life for patients and relatives should not be underestimated.7 The 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 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. Differences 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. ✦
with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2019;7(7):569-580. 6. Tsao AS, Lindwasser OV, Adjei AA, et al. Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. J Thorac Oncol. 2018;13:1655-1667. 7. NovoTTFTM - 100L System - H180002. U.S. Food and Drug Administration. https://www.fda.gov/ medical-devices/recently-approved-devices/ novottftm-100l-system-h180002. Published May 28, 2019. Accessed January 12, 2020. 8. Voloshin T, Kaynan N, Davidi S, et al. TumorTreating Fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy 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 field 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. Influence of treatment with tumor-treating fields 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 fields 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.
About the Authors: Dr. Baas is chief of Department of Thoracic 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.
