BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed 
good activity when used alone in patients with mesothelioma, but did not improve 
the overall survival of patients who failed on first-line or second-line 
chemotherapy compared with placebo in the DETERMINE study. We aimed to 
investigate the efficacy and safety of first-line or second-line tremelimumab 
combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with 
malignant mesothelioma.
METHODS: In this open-label, non-randomised, phase 2 trial, patients with 
unresectable pleural or peritoneal mesothelioma received intravenous 
tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 
weeks for four doses, followed by maintenance intravenous durvalumab at the same 
dose and schedule for nine doses. The primary endpoint was the proportion of 
patients with an immune-related objective response according to the 
immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; 
for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal 
mesothelioma). The primary analysis was done by intention to treat, whereas the 
safety analysis included patients who received at least one dose of study drug. 
This trial is registered with the European Clinical Trials Database, number 
2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but 
no longer recruiting patients.
FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were 
enrolled and received at least one dose each of tremelimumab and durvalumab. 
Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) 
of 40 patients had an immune-related objective response (all partial responses; 
confirmed in ten patients), with a median response duration of 16·1 months (IQR 
11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) 
had disease control. Median immune-related progression-free survival was 8·0 
months (95% CI 6·7-9·3), median progression-free survival was 5·7 months 
(1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline 
tumour PD-L1 expression did not correlate with the proportion of patients who 
had an immune-related objective response or immune-related disease control, with 
immune-related progression-free survival, or with overall survival. 30 (75%) 
patients experienced treatment-related adverse events of any grade, of whom 
seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related 
toxicity was generally manageable and reversible with protocol guidelines.
INTERPRETATION: The combination of tremelimumab and durvalumab appeared active, 
with a good safety profile in patients with mesothelioma, warranting further 
exploration.
FUNDING: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione 
Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.