DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial.

Abstract

TPS8599 Background: Combination PD1/CTLA4 immune checkpoint blockade and platinum-pemetrexed (CP) chemotherapy are standard first-line options for the treatment of unresectable malignant pleural mesothelioma (MPM). Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining the PD-L1 inhibitor durvalumab and standard first line CP both exceeded pre-specified efficacy criteria. The Phase 3 DREAM3R trial aims to determine the effectiveness of including durvalumab with first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomized (2:1) to either durvalumab 1500 mg every 3 weeks plus chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles (Arm A), followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, versus doublet chemotherapy alone for 4-6 cycles with all patients monitored for progression. The target sample size is 480 patients recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival (OS) is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Key eligibility criteria include: MPM of any histological subtype; measurable disease per RECIST 1.1 modified for mesothelioma (mRECIST 1.1); ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for MPM, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Patients will be further stratified at randomization by: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), planned platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and healthcare resource use in ANZ. Tertiary correlative objectives aim to further explore and validate potential prognostic and/or predictive biomarkers (including those identified in the DREAM and PrE0505 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes) via 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. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN 12620001199909.