Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial

Our plain-English summary of Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial, by P.S. Kok, P.M. Forde, B. Hughes, et al (BMJ Open, 2022).

The study

• Authors: P.S. Kok, P.M. Forde, B. Hughes, Z. Sun, C. Brown, S. Ramalingam, A. Cook, W.J. Lesterhuis, S. Yip, K. O'Byrne, N. Pavlakis, J. Brahmer, V. Anagnostou, K. Ford, K. Fitzpatrick, A. Bricker, M.M. Cummins, M. Stockler, A.K. Nowak, Thoracic Oncology Group of Australasia (TOGA) and PrECOG, USA
• Journal: BMJ Open
• Published: 2022;12(1):e057663
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.

Methods And Analysis: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.

Ethics And Dissemination: The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.

Drug Supply: AstraZeneca.

Protocol Version: CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.

Trial Registration Number: ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This article was a protocol: it described a planned trial, DREAM3R, and reported no treatment results. DREAM3R was designed as an international, open-label, randomised phase 3 trial at sites in Australia, New Zealand and the USA. It aimed to enrol 480 previously untreated adults with advanced pleural mesothelioma. Participants were to be assigned in a 2:1 ratio to one of two groups. One group would receive the immunotherapy drug durvalumab with standard chemotherapy (cisplatin or carboplatin plus pemetrexed), then durvalumab alone. The other would receive chemotherapy alone, followed by observation. The main outcome was overall survival. The trial's size was based on an assumed median survival of 15 months with chemotherapy alone and 21.4 months with durvalumab. These were planning assumptions, not findings. As of 15 September 2021, 41 of 60 planned sites had opened and 45 participants had been randomised. The authors' stated hypothesis was that adding durvalumab would prolong overall survival. They noted that the trial had no ipilimumab plus nivolumab comparison arm and that the control arm did not include bevacizumab. The article did not study asbestos exposure.

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: Protocol for a planned international, open-label, randomised (2:1), multicentre phase 3 trial; no results reported
• Who was studied: Planned enrolment of 480 adults with advanced pleural mesothelioma not amenable to curative surgery and without prior systemic anticancer therapy. Recruitment was planned over 27 months at 29 sites in Australia, 1 in New Zealand and 30 in the USA.
• Exposure: Not asbestos exposure. The intervention studied was durvalumab 1500 mg every 3 weeks plus cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2 for 4 to 6 cycles, then durvalumab 1500 mg every 4 weeks. This was compared with the same chemotherapy alone followed by observation.
• Main results:
  • No treatment results were reported. As of 15 September 2021, 41 of the 60 planned sites had opened to recruitment and 45 participants had been randomised.
  • Planning assumption (not a finding): median survival of 15 months in the chemotherapy-only control group and 21.4 months in the durvalumab group.
• The authors' conclusion: No conclusions were drawn because no results were reported. The authors' primary hypothesis was that adding durvalumab would prolong overall survival compared with platinum and pemetrexed alone.
• Limitations the authors state:
  • The trial has no comparator arm of ipilimumab plus nivolumab, which the authors described as a first-line option, particularly for sarcomatoid disease.
  • The control arm does not include bevacizumab, which the authors described as a first-line option.

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, PD-L1, Cisplatin, Pemetrexed (Alimta), Unresectable, Carboplatin.

Related studies

• 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)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol — N. Fujimoto, K. Aoe, 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)
• 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 II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma — A.K. Nowak, C. Brown, et al. (2013)

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