Final Results of the Dream Trial: A Phase 2 Trial of Durvalumab with First-Line Chemotherapy in Mesothelioma with a Safety Run-In

Abstract

Background: Cisplatin and pemetrexed chemotherapy provides modest survival benefits for malignant pleural mesothelioma (MPM). This study evaluated cisplatin and pemetrexed with, and followed by, the anti-PD-L1 (programmed death ligand-1) antibody durvalumab in advanced MPM. Methods: DREAM was a single-arm, multicentre open label phase 2 study in patients with treatment-naive advanced MPM. Eligible patients had Eastern Cooperative Oncology Group performance status 0 or 1 and measurable disease. The first six patients were treated on a two-cycle safety lead-in. All patients received cisplatin 75mg/m2, pemetrexed 500mg/m2, and durvalumab 1125mg fixed dose on day 1 of a three-weekly schedule to maximum six cycles chemotherapy. Change from cisplatin to carboplatin AUC5 was permitted. Durvalumab was continued to complete up to 12 months total treatment. The primary endpoint was progression-free survival at six months (PFS6); secondary outcomes included objective tumour response rate (RR), overall survival (OS), and adverse event (AE) rates. Findings: Fifty-four patients were registered and treated. Most were male (83%), with epithelioid subtype (83%), and a median age of 68 years. The proportion alive and progression-free at six months was 54%; median PFS was 6.9 months (95% CI 5.5–9.0). Median OS was 18.4 months (95% CI 13.1–24.8). RR according to modified RECIST for MPM was 48% (95% CI 36–61%), with partial responses in 26 (48%) and stable disease in 21 (37%) patients, respectively. AEs reflected the expected toxicities of combining chemotherapy and durvalumab. None of the five deaths during study treatment were attributed to durvalumab. There was no association between tumour expression of PD-L1 and PFS. Interpretation: This single-arm phase 2 trial demonstrated that the combination of durvalumab, cisplatin, and pemetrexed has promising activity and safety to warrant the conduct of a randomised phase 3 trial. Funding: AstraZeneca provided study drug and funding. Declaration of Interest: The other authors declared no conflicts of interest. Ethical Approval: DREAM conformed to ethical principles of the Declaration of Helsinki and the International Council on Harmonization guidelines on Good Clinical Practice. The protocol was approved by a central Human Research Ethics Committee (HREC), and all site HRECs. All patients provided written informed consent before any screening procedures. Patients confirmed eligible after screening were registered to the study.