Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in

Our plain-English summary of Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in, by A.K. Nowak, W.J. Lesterhuis, P.S. Kok, et al (The Lancet. Oncology, 2020).

The study

• Authors: A.K. Nowak, W.J. Lesterhuis, P.S. Kok, C. Brown, B.G. Hughes, D.J. Karikios, T. John, S.C. Kao, C. Leslie, A.M. Cook, N. Pavlakis, K. Briscoe, K.J. O'Byrne, C.S. Karapetis, W.S. Lam, A. Langford, S. Yip, M.R. Stockler
• Journal: The Lancet. Oncology
• Published: 2020;21(9):1213-1223
• Cited by: 143 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.

Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.

Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.

Interpretation: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.

Funding: AstraZeneca.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

This single-arm phase 2 trial in nine Australian hospitals added durvalumab, an immunotherapy drug, to first-line cisplatin and pemetrexed chemotherapy. The 54 eligible adults had malignant pleural mesothelioma considered unsuitable for cancer-directed surgery and not previously treated with systemic therapy. Asbestos exposure was not reported. At 6 months, 31 of 54 patients (57%; 95% CI 44 to 70) were alive without progression, meeting the preset activity target. Median progression-free survival was 6.9 months (95% CI 5.5 to 9.0) by mRECIST; median overall survival was 18.4 months (13.1 to 24.8). A confirmed partial response occurred in 26 patients (48%; 95% CI 35 to 61); none responded completely. The commonest grade 3 to 4 adverse events were low neutrophil counts (7 patients), nausea (6) and anaemia (4). Five patients died during treatment; the results section attributed none to durvalumab or chemotherapy. Exploratory, low-powered analyses found no apparent association between tumour PD-L1 levels and progression-free survival. The authors concluded that the combination was worthy of a randomised phase 3 trial. Their main stated limitation was the single-arm design; few tumours were non-epithelioid.

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: Multicentre, single-arm, open-label phase 2 clinical trial with a safety run-in (no comparison group)
• Who was studied: 55 adults were recruited between Dec 28, 2016 and Sept 27, 2017 at nine Australian hospitals. One was ineligible, leaving 54 eligible patients with malignant pleural mesothelioma considered unsuitable for cancer-directed surgery and not previously treated with systemic therapy. Five (9%) had previous non-radical surgery and four (7%) had previous radiotherapy outside measurable disease. Median age was 68, 45 (83%) were male, and 45 (83%) had epithelioid histology. Asbestos exposure was not reported.
• Exposure: This was a treatment study, not a study of asbestos exposure. Patients received cisplatin 75 mg/m², pemetrexed 500 mg/m² and durvalumab 1125 mg intravenously every 21 days for up to six cycles. Durvalumab was then continued alone, up to 12 months in total. Switching from cisplatin to carboplatin was permitted.
• Main results:
  • Primary endpoint: 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months, meeting the prespecified activity criterion
  • Median progression-free survival in all patients was 6.9 months (95% CI 5.5–9.0) by mRECIST
  • A confirmed objective tumour response by mRECIST occurred in 26 patients (48%; 95% CI 35–61); there were no complete responses
  • Median overall survival was 18.4 months (95% CI 13.1–24.8). Overall survival was 65% (54–79) at 12 months and 37% (26–52) at 24 months; the 24-month figure was a post-hoc analysis.
  • The most common grade 3–4 adverse events were neutropenia (7 patients, 13%), nausea (6, 11%) and anaemia (4, 7%)
  • 60 serious adverse events occurred in 29 patients. In 5 (9%) of 54 patients, serious adverse events were considered possibly related to durvalumab.
  • 12 (22%) patients had immune-related adverse events; none led to death
  • Five (9%) patients died during study treatment. The results section stated that none of these deaths were attributed to durvalumab or chemotherapy.
  • Of 51 patients with tumour tissue, 27 (53%) were PD-L1 positive. There was no apparent association between PD-L1 expression and progression-free survival: median 6.3 months (PD-L1 negative) vs 6.6 months (PD-L1 positive). The authors acknowledged the low power and exploratory nature of these analyses.
  • When durvalumab was stopped after 12 months, most patients treated to that point then had disease progression
• The authors' conclusion: The authors concluded that the trial met its criteria for activity and safety. In their view, durvalumab plus chemotherapy for mesothelioma is worthy of further research in a proposed randomised phase 3 trial.
• Limitations the authors state:
  • The single-arm, non-comparative design
  • Few patients had sarcomatoid, desmoplastic or biphasic tumours, so the trial could not show whether activity differs in these subtypes
  • The PD-L1 analyses had low power and were exploratory
  • Detailed TNM staging information was not collected
  • Treatment after the study was not recorded

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: Durvalumab (Imfinzi), Chemotherapy, Pleural Mesothelioma, Systemic Therapy, Mesothelioma, Cisplatin, Pemetrexed (Alimta), checkpoint inhibitors.

Related studies

• Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial — P.S. Kok, P.M. Forde, et al. (2022)
• 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)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma — A.K. Nowak, A.M. Cook, et al. (2015)
• Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study — L. Calabrò, A. Morra, et al. (2018)
• Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial — C.J. de Gooijer, V. van der Noort, et al. (2021)

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