Durvalumab with chemotherapy as first line treatment in advanced pleural mesothelioma: A phase 3, randomised trial (DREAM3R).

Abstract

TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesothelioma exceeded pre-specified efficacy criteria. The recent CM 743 trial showed overall survival (OS) was longer in those assigned ipilimumab and nivolumab (ipi nivo) than standard chemotherapy, however the benefits were primarily in the subgroup with non-epithelioid histology. DREAM3R will determine the effectiveness of durvalumab plus chemotherapy as first line treatment for advanced pleural mesothelioma. The DREAM3R protocol was recently amended to allow treatment with ipi nivo as per CM 743 in the control group, and to confine further accrual to epithelioid subtype. Methods: Treatment-naïve patients with advanced, epitheloid pleural mesothelioma will be randomized (1:1) to either experimental group treatment: durvalumab 1500 mg every 3 weeks plus chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, or control group treatment: physician’s choice of either chemotherapy or ipi nivo (up to 2 years). The target sample size of 480 recruited over 33 months, with follow up for another 18 months provides over 85% power if the true hazard ratio for OS is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 18 months in the control group. Key eligibility criteria: Epithelioid pleural mesothelioma; measurable disease per RECIST 1.1 modified for mesothelioma; ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for pleural mesothelioma, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Participants are stratified at randomization for: age (18-70 years vs. > 70), sex, planned control regimen (chemotherapy or ipi nivo), 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 use of healthcare resources in ANZ. Tertiary objectives are to identify potential prognostic and/or predictive biomarkers (including those identified in prior phase 2 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes), 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 ACTRN12620001199909 .