BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently 
needed. In the DETERMINE study, we investigated the effects of the 
cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody 
tremelimumab in patients with previously treated advanced malignant 
mesothelioma.
METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done 
at 105 study centres across 19 countries in patients with unresectable pleural 
or peritoneal malignant mesothelioma who had progressed after one or two 
previous systemic treatments for advanced disease. Eligible patients were aged 
18 years or older with Eastern Cooperative Oncology Group performance status of 
0 or 1 and measurable disease as defined in the modified Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST 
version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) 
in blocks of three, stratified by European Organisation for Research and 
Treatment of Cancer status (low risk vs high risk), line of therapy (second line 
vs third line), and anatomic site (pleural vs peritoneal), by use of an 
interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) 
or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a 
treatment discontinuation criterion was met. The primary endpoint was overall 
survival in the intention-to-treat population. Safety was assessed in all 
patients who received at least one dose of study drug. The trial is ongoing but 
no longer recruiting participants, and is registered with ClinicalTrials.gov, 
number NCT01843374.
FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly 
assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 
patients received treatment (two patients in the tremelimumab group were 
excluded from the safety population because they did not receive treatment). At 
the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the 
tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. 
Median overall survival in the intention-to-treat population did not differ 
between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab 
group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 
0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse 
occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 
189 patients in the placebo group; the most common were dyspnoea (34 [9%] 
patients in the tremelimumab group vs 27 [14%] patients in the placebo group), 
diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most 
common serious adverse events were diarrhoea (69 [18%] patients in the 
tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] 
vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading 
to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 
(6%) of 189 in the placebo group; those leading to the death of more than one 
patient were mesothelioma (three [1%] patients in the tremelimumab group vs two 
[1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory 
failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), 
lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one 
[<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events 
leading to death occurred in five (1%) patients in the tremelimumab group and 
none in the placebo group. The causes of death were lung infection in one 
patient, intestinal perforation and small intestinal obstruction in one patient; 
colitis in two patients, and neuritis and skin ulcer in one patient.
INTERPRETATION: Tremelimumab did not significantly prolong overall survival 
compared with placebo in patients with previously treated malignant 
mesothelioma. The safety profile of tremelimumab was consistent with the known 
safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy 
combination regimens can provide greater efficacy than monotherapies in 
malignant mesothelioma are ongoing.
FUNDING: AstraZeneca.