Background: First-line CP was FDA-approved in 2004 for unresectable MPM. Given the role of inflammation in MPM and promising responses to PD-1 pathway blockade in pretreated MPM, we conducted a phase 2 single arm study of the anti-PD-L1 antibody, durvalumab (durva), combined with CP for patients (pts) with untreated MPM of any subtype. Methods: Eligible pts were treatment-naïve with surgically unresectable MPM. Primary endpoint was overall survival (OS); pts received up to 6 cycles of durva-CP, followed by maintenance durva up to 1 year. Carboplatin was permitted for pts with baseline hearing or renal impairment. The first 15 pts were monitored for dose-limiting toxicities (DLTs). Secondary endpoints included toxicity, objective response by modified RECIST, progression-free survival (PFS), and correlative analyses. With a sample size of 55 patients and 32 events, the study had 90% power to detect a 58% improvement in median OS from 12 months (m) (historical control) to 19 m with durva-CP. Results: PrE0505 enrolled 55 patients at 15 US-based sites between 06/2017 and 06/2018. Histologic subtypes were epithelioid (75%), biphasic (11%), sarcomatoid (13%), and desmoplastic (2%). There were no DLTs during the run-in period. As of January 2020 the median follow up is 20.6 m and 29 deaths have occurred. The median OS at the time of report is 21.1 m. The 12 m OS rate was 70% with a 2 sided 95% confidence interval (56%, 81%) and two-sided 80% CI (62%, 78%). Analyses for the secondary endpoints were ongoing at abstract submission. Exome sequencing, TCR sequencing and dual PD-L1/CD8 staining have been completed on baseline tumors from at least 45 of the 55 patients enrolled as well as RNA sequencing for those with adequate tissue. Initial results show that tumors harbored an average tumor mutation burden of 22 somatic sequence alterations and varying levels of aneuploidy were detected. Conclusions: The combination of chemotherapy with durvalumab delivered a promising median OS for previously untreated pts with unresectable MPM. Full results from the study along with the extensive correlative analyses performed will be reported. The phase 3 PrE0506/DREAM3R trial evaluating CP-durvalumab versus CP alone will commence enrollment in the United States and Australia in 2020. Clinical trial information: NCT02899195