Background: Anti-angiogenic inhibitors combined with cisplatin-pemetrexed (CP) have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth factor receptor and platelet derived growth factor receptor inhibitor, showed preliminary efficacy in SWOG 0905 phase I. Methods: S0905 phase II randomized MPM patients to CP with cediranib/placebo followed by maintenance cediranib/placebo (CPC v CPP). Randomization was stratified by PS (0-1 vs 2) and histology [epithelioid (E) vs biphasic or sarcomatoid (B/S)].The primary endpoint was RECIST PFS. The trial was designed to detect a difference in PFS at the 1-sided 0.10 level, using a stratified log-rank test. Results: Ninety-two eligible patients were enrolled (2011-2016). Median age was 72, 85% men, 75% E and 25% B/S histology. The trial met its primary objective: PFS was significantly prolonged by CPC (HR 0.69, p = 0.096, median PFS 7.2 vs 5.6 months). CPC did not increase RECIST RR (26% vs 18%, p = 0.48), but did prolong the duration of response (median 6 vs 1.7 months). By modified RECIST, CPC increased RR (53% vs 20%, p = 0.01). CPC numerically improved OS (HR 0.84, p = 0.44; median OS 10 vs. 8.5 months). E patients had a markedly improved survival compared to B/S patients (median PFS 7.1 vs 3.4 months, HR 0.61, p = 0.047 and median OS 10.9 vs 6.4 months, HR 0.605, p = 0.045). B/S patients may derive less benefit from cediranib than E patients in terms of OS (HR 0.83 for E v HR 1.03 for B/S) despite a similar RECIST PFS (B/S HR 0.71 and E HR 0.72). Grade 3-4 toxicities were 64% versus 54% for CPC vs. CPP (p = 0.273). The most common toxicities (any grade) associated with CPC were diarrhea (46.7% vs. 17%) and hypertension (44% vs. 15%). Conclusions: The addition of cediranib to CP improves RECIST PFS in patients with MPM. E patients may benefit more with anti-angiogenic agents. Clinical trial information: NCT01064648