Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study

Our plain-English summary of Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study, by D. Cortinovis, F. Grosso, L. Carlucci, et al (Clinical Lung Cancer, 2021).

The study

• Authors: D. Cortinovis, F. Grosso, L. Carlucci, P.A. Zucali, G. Pasello, M. Tiseo, F. Sperandi, L. Hollander, F. Galli, V. Torri, E. Rulli, S. Canova, A. Maconi, P. Bidoli, G.L. Ceresoli, M. D'Incalci, ATREUS investigators
• Journal: Clinical Lung Cancer
• Published: 2021;22(4):361-370.e3
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM.

Methods: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks).

Results: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2.

Conclusions: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.

Copyright © 2020 Elsevier Inc. All rights reserved.

In plain English

This phase II study, with no comparison group, tested trabectedin in people with malignant pleural mesothelioma that could not be surgically removed. From July 2013 to February 2018, 145 patients were enrolled at 7 Italian sites: 78 with epithelioid and 67 with nonepithelioid (biphasic or sarcomatoid) tumors. Epithelioid patients received it second-line; nonepithelioid, first- or second-line. Of 62 epithelioid patients evaluable at 12 weeks, 27 (43.5%, 80% confidence interval 34.9% to 52.5%) were alive without progression. Epithelioid medians were 2.4 months for progression-free survival and 9.0 for overall survival. Of 52 evaluable nonepithelioid patients, 16 (30.8%, 90% confidence interval 20.3% to 42.9%) were alive without progression; that cohort's medians were 1.7 and 5.4 months. Liver damage led to lowering the starting dose from 1.3 to 1.1 mg/m2. Grade 3-4 liver toxicity affected 59 of 84 patients (70.2%) at the higher starting dose and 19 of 48 (39.6%) at the lower. One death, from multiorgan failure, was counted as toxic. The authors concluded that this toxicity and the small survival benefit preclude further developing trabectedin as a single drug on this schedule.

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: Phase II, single-arm (no comparison group), multicenter clinical trial with two separate cohorts by tumor type
• Who was studied: 145 patients with unresectable malignant pleural mesothelioma enrolled at 7 Italian sites from July 2013 to February 2018: 78 epithelioid and 67 nonepithelioid (biphasic or sarcomatoid). Epithelioid patients were treated second-line. Of 59 treated nonepithelioid patients, 22 were treated first-line and 37 second-line.
• Exposure: The study tested a treatment, not asbestos exposure. Patients received intravenous trabectedin, initially 1.3 mg/m2 over 3 hours every 21 days. The starting dose was later amended to 1.1 mg/m2 because of liver toxicity. Patients were premedicated with dexamethasone. Patients' asbestos exposure history was recorded as a background characteristic.
• Main results:
  • Epithelioid cohort: of 62 patients evaluable for the 12-week endpoint (out of 66 in the per-protocol population), 27 (43.5%) were alive and without progression at 12 weeks (80% CI 34.9% to 52.5%; 95% CI 31.0% to 56.7%).
  • Epithelioid cohort: there were no complete responses. Among 70 patients with at least one disease evaluation, 5 had a partial response (response rate 7.1%, 95% CI 2.4% to 15.9%).
  • Epithelioid cohort as a whole (not only the 62 evaluable at 12 weeks): median progression-free survival was 2.4 months (IQR 1.2 to 5.4). Median overall survival was 9.0 months (IQR 3.6 to 15.1).
  • Epithelioid cohort: on independent central radiology review, the 12-week progression-free rate was 36.5% (23 of 63 evaluable patients).
  • Nonepithelioid (biphasic/sarcomatoid) cohort: of 52 patients evaluable for the 12-week endpoint (out of 54 in the per-protocol population), 16 (30.8%) were alive and without progression at 12 weeks (90% CI 20.3% to 42.9%; 95% CI 18.7% to 45.1%). On central review the figure was 25.0% (13 of 52).
  • Nonepithelioid cohort as a whole: 1 partial response among 47 patients with at least one disease evaluation (2.1%). Median progression-free survival was 1.7 months (IQR 1.2 to 4.0). Median overall survival was 5.4 months (IQR 2.3 to 10.7).
  • Safety population (132 patients): grade 3-4 hepatotoxicity occurred in 78 (59.1%) overall. This was 59 (70.2%) of 84 patients at a starting dose of 1.3 mg/m2 and 19 (39.6%) of 48 at 1.1 mg/m2.
  • Grade 3-4 neutropenia occurred in 27 (20.5%) patients overall, falling from 23.8% to 14.6% by dose level. Overall grade 3-4 fatigue was 8.3%.
  • Fifty-one serious adverse events occurred in 44 (30.3%) patients, and 18 of these events were judged at least possibly treatment-related. One toxic death was due to multiorgan failure. Two other deaths (1 sepsis, 1 pneumonitis) were considered possibly related to trabectedin.
  • Recorded asbestos exposure among eligible patients with known status: 49 (66.2%) in the epithelioid cohort and 32 (54.2%) in the nonepithelioid cohort. Most of the exposure was professional.
• The authors' conclusion: The authors concluded that trabectedin showed some signals of activity, at the expense of relevant liver toxicity. In their view, this toxicity and the small survival benefit preclude further development of trabectedin as a single agent on the schedule tested.
• Limitations the authors state:
  • Central review of CT scans found a moderate discrepancy with the local site assessments. The authors said this calls for cautious interpretation of an endpoint based on radiological progression, such as 12-week progression-free survival.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Unresectable, Tumor Microenvironment, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Second-Line Therapy, Progression-Free Survival.

Related studies

• HPLC-MS/MS method to measure trabectedin in tumors: preliminary PK study in a mesothelioma xenograft model — L. Ceriani, M. Ferrari, et al. (2015)
• Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro — M.A. Hoda, C. Pirker, et al. (2016)
• 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 — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in — A.K. Nowak, W.J. Lesterhuis, et al. (2020)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Ifosfamide in malignant mesothelioma: a phase II study — M.K. Andersen, A. Krarup-Hansen, et al. (1999)

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