Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial

Our plain-English summary of Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial, by G.L. Ceresoli, J.G. Aerts, R. Dziadziuszko, et al (The Lancet. Oncology, 2019).

The study

• Authors: G.L. Ceresoli, J.G. Aerts, R. Dziadziuszko, R. Ramlau, S. Cedres, J.P. van Meerbeeck, M. Mencoboni, D. Planchard, A. Chella, L. Crinò, M. Krzakowski, J. Rüssel, A. Maconi, L. Gianoncelli, F. Grosso
• Journal: The Lancet. Oncology
• Published: 2019;20(12):1702-1709
• Cited by: 143 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Tumour Treating Fields (TTFields) are a regional, antimitotic treatment for solid tumours, which is based on the delivery of low-intensity alternating electric fields. The aim of the STELLAR study was to test the activity of TTFields delivered to the thorax in combination with systemic chemotherapy for the front-line treatment of patients with unresectable malignant pleural mesothelioma.

Methods: STELLAR was a prospective, single-arm, phase 2 trial done at 12 European academic and non-academic sites (five in Italy, three in Poland, one in France, one in Belgium, one in Spain, and one in the Netherlands) for treatment-naive patients with histologically confirmed unresectable malignant pleural mesothelioma. Patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, and at least one measurable or evaluable lesion according to modified Response Evaluation Criteria in Solid Tumors for mesothelioma. Patients received continuous TTFields at a frequency of 150 kHz to the thorax and concomitant chemotherapy with intravenous pemetrexed (500 mg/m2 on day 1) plus intravenous platinum (either cisplatin 75 mg/m2 on day 1 or carboplatin area under the curve 5 on day 1) every 21 days for up to six cycles. Patients not progressing after completion of chemotherapy received TTFields as maintenance treatment until progression, patient or physician decision, or unacceptable toxic effects. The primary endpoint of the trial was overall survival. Survival analyses were done in the intention-to-treat population, and safety analyses were done in all patients who received at least 1 day of TTFields treatment. This trial is registered with ClinicalTrials.gov, NCT02397928.

Findings: Between Feb 9, 2015 and March 21, 2017, 80 patients were enrolled in the study. Median follow-up was 12·5 months (IQR 7·4-16·6). Median overall survival was 18·2 months (95% CI 12·1-25·8). The most common grade 3 or worse adverse events were anaemia (nine [11%] patients), neutropenia (seven [9%]), and thrombocytopenia (four [5%]). Skin reaction was the only adverse event associated with TTFields and was reported as grade 1-2 in 53 (66%) patients, and as grade 3 in four (5%) patients. No treatment-related deaths were observed.

Interpretation: The trial showed encouraging overall survival results, with no increase in systemic toxicity. TTFields (150 kHz) delivered to the thorax concomitant with pemetrexed and platinum was an active and safe combination for front-line treatment of unresectable malignant pleural mesothelioma. Further investigation in a randomised trial is warranted.

Funding: Novocure.

Copyright © 2019 Elsevier Ltd. All rights reserved.

In plain English

STELLAR was a phase 2 trial without a comparison group. It tested Tumour Treating Fields (TTFields), low-intensity alternating electric fields delivered at 150 kHz to the chest by a portable device, combined with chemotherapy (pemetrexed plus cisplatin or carboplatin) as first treatment for malignant pleural mesothelioma that could not be removed surgically. The study did not examine asbestos exposure. Between February 2015 and March 2017, 80 previously untreated patients were enrolled at 12 European sites. Median overall survival was 18.2 months (95% CI 12.1 to 25.8), and median progression-free survival was 7.6 months (95% CI 6.7 to 8.6). Of 72 patients with a follow-up scan, 29 (40%) had a partial response. In an unplanned analysis, median survival was 21.2 months (95% CI 13.2 to 25.8) in 53 patients with epithelioid tumours and 12.1 months (7.9 to not reached) in 27 non-epithelioid patients (21 sarcomatoid or biphasic, six of unknown type). Skin reactions under the device occurred in 53 of 80 patients (66%) at grade 1 to 2 and in four (5%) at grade 3. No treatment-related deaths were observed. The authors concluded the combination was active and safe. They noted the limits of a single-arm design and called for a larger randomised trial.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective, multicentre, single-arm (no control group) phase 2 clinical trial of a treatment; overall survival was the primary endpoint
• Who was studied: 80 treatment-naive patients with histologically confirmed unresectable malignant pleural mesothelioma, enrolled at 12 European sites (Italy, Poland, France, Belgium, Spain, the Netherlands) between Feb 9, 2015 and March 21, 2017; median age 67, 67 (84%) male; tumour histology epithelioid 53 (66%), sarcomatoid or biphasic 21 (26%), unknown 6 (8%)
• Exposure: Not an asbestos exposure study. The intervention was continuous TTFields (150 kHz) to the thorax plus intravenous pemetrexed (500 mg/m² on day 1) with cisplatin (75 mg/m²) or carboplatin (AUC 5) every 21 days for up to six cycles, followed by TTFields maintenance in patients without progression. 50 (63%) received carboplatin and 30 (37%) cisplatin
• Main results:
  • Median overall survival in all 80 patients was 18.2 months (95% CI 12.1 to 25.8)
  • 1-year overall survival was 62.2% (95% CI 50.3 to 72.0) and 2-year overall survival was 41.9% (28.0 to 55.2)
  • Median progression-free survival in all patients was 7.6 months (95% CI 6.7 to 8.6)
  • Of 72 patients evaluable for response, 29 (40%) had a partial response, 41 (57%) had stable disease and two (3%) progressed at their first follow-up scan
  • In an unplanned post-hoc analysis, median overall survival was 21.2 months (95% CI 13.2 to 25.8) in 53 patients with epithelioid histology and 12.1 months (7.9 to not reached) in 27 patients with non-epithelioid histology. Per the baseline table, the 27 comprised 21 with sarcomatoid or biphasic and 6 with unknown histology
  • Grade 1 to 2 skin reaction under the device occurred in 53 (66%) of 80 patients
  • Grade 3 skin reactions under the device occurred in 4 (5%) patients
  • The most common grade 3 or worse adverse events were anaemia in nine (11%), neutropenia in seven (9%) and thrombocytopenia in four (5%) patients
  • No treatment-related deaths were observed. Three (4%) patients died of an adverse event (Candida sepsis, pneumonia, epilepsy), which the authors reported as intercurrent disease not related to treatment
• The authors' conclusion: The authors concluded that 150 kHz TTFields applied to the thorax with pemetrexed and platinum was an active and safe option for front-line treatment of unresectable malignant pleural mesothelioma, needing confirmation in a larger randomised trial
• Limitations the authors state:
  • Single-arm phase 2 design; results need confirmation in a larger randomised trial
  • No independent radiological review, which limits interpretation of response and progression-free survival data
  • The historical comparison group used for the sample size (EMPHACIS) included some patients not given folic acid and vitamin B12, possibly underestimating expected survival with standard treatment

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Carboplatin, Unresectable, Pleural Mesothelioma, Thorax, Chemotherapy, Performance Status.

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• Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study — N. Katirtzoglou, I. Gkiozos, et al. (2010)
• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)
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• A Randomized Phase II Study Adding Axitinib to Pemetrexed-Cisplatin in Patients with Malignant Pleural Mesothelioma: A Single-Center Trial Combining Clinical and Translational Outcomes — W.A. Buikhuisen, M. Scharpfenecker, et al. (2016)
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