Journal ArticleDOI
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
Michele Maio,Arnaud Scherpereel,Luana Calabrò,Joachim G.J.V. Aerts,Susana Cedres Perez,Alessandra Bearz,Kristiaan Nackaerts,Dean A. Fennell,Dariusz M. Kowalski,Anne S. Tsao,Paul D. Taylor,Federica Grosso,Scott J. Antonia,Anna K. Nowak,Anna K. Nowak,Maria Taboada,Martina Puglisi,Paul K. Stockman,Hedy L. Kindler +18 more
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TLDR
The DETERMINE study investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma and overall survival was overall survival in the intention-to-treat population.Abstract:
Summary 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 [ vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [ 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 [ vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [ vs one [ 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.read more
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Assessment of interferon-γ in pleural fluid as a prognostic factor of survival in malignant pleural mesothelioma.
Beatrice Dozin,Grazia Carbotti,Silvio Roncella,Paola Ferro,Paolo Dessanti,Pier Aldo Canessa,Silvano Ferrini,Marina Fabbi +7 more
TL;DR: In this paper, the authors analyzed the levels of pro-inflammatory (IL-1, IL-6, TNF), immune-regulatory (IL10) and Th1/CTL-related cytokines in the pleural exudate and their relationship with overall survival (OS) in Malignant Pleural Mesothelioma (MPM) patients.
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Overcoming the cardiac toxicities of cancer therapy immune checkpoint inhibitors
Omoruyi Credit Irabor,Nicolas Nelson,Y. Shah,Muneeb Khan Niazi,Spencer Poiset,Eugene Storozynsky,Dinender K. Singla,D. Craig Hooper,Bo Lu +8 more
TL;DR: An updated review of the literature on the pathologic mechanisms, diagnosis, and management of autoimmune cardiotoxicity resulting from ICIs and their combinations is provided and perspective on potential strategies and ongoing research developments to prevent and mitigate their occurrence is provided.
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Risk of colitis in immune checkpoint inhibitors and in chemotherapy/placebo for solid tumors: a systematic review and meta-analysis
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[The Current Therapy of Asbestos-Associated Malignant Pleural Mesothelioma - An Expert Consensus Paper].
C. Aigner,T. Brüning,W. Eberhardt,Martin Härter,H.-P. Kaelberlah,Martin Metzenmacher,R. Shah,Christian Taube,Michael Thomas +8 more
TL;DR: In this paper, a Ubersicht stellt den aktuellen Stand der Therapie des Mesothelioms, basierend auf den internationalen Leitlinien und neuen Studien, dar.
Journal ArticleDOI
Is pleural infection associated with longer survival in mesothelioma? A population-based cohort study using data from Hospital Episode Statistics.
TL;DR: Pleural infection occurred in 2.3% of people with mesothelioma and was associated with shorter survival, which refutes previous reports suggesting pleural infection may be associated with better outcomes in thoracic malignancy.
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TL;DR: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.
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