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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Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.
Anne S. Tsao,O. Wolf Lindwasser,Alex A. Adjei,Prasad S. Adusumilli,Matthew L. Beyers,Gideon M. Blumenthal,Raphael Bueno,Bryan M. Burt,Michele Carbone,Suzanne E. Dahlberg,Marc de Perrot,Marc de Perrot,Dean A. Fennell,Dean A. Fennell,Joseph S. Friedberg,Ritu R. Gill,Daniel R. Gomez,David H. Harpole,Raffit Hassan,Mary Hesdorffer,Fred R. Hirsch,Julija Hmeljak,Hedy L. Kindler,Edward L. Korn,Geoffrey Liu,Aaron S. Mansfield,Anna K. Nowak,Harvey I. Pass,Tobias Peikert,Andreas Rimner,Bruce W. S. Robinson,Bruce W. S. Robinson,Kenneth E. Rosenzweig,Valerie W. Rusch,Ravi Salgia,Boris Sepesi,Charles B. Simone,Rajeshwari Sridhara,Peter W. Szlosarek,Emanuela Taioli,Ming-Sound Tsao,Ming-Sound Tsao,Haining Yang,Marjorie G. Zauderer,Shakun Malik +44 more
TL;DR: The objective of this meeting was to assemble a consensus on at least two or three practice‐changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.
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Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles.
TL;DR: A mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells and the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy.
Journal ArticleDOI
ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma
Isabelle Opitz,Arnaud Scherpereel,Thierry Berghmans,Ioannis Psallidas,Markus Glatzer,David Rigau,Philippe Astoul,Servet Bölükbas,Jeanette Boyd,Johan Coolen,Charlotte De Bondt,Dirk De Ruysscher,Valérie Durieux,Corinne Faivre-Finn,Dean A. Fennell,Françoise Galateau-Sallé,Laurent Greillier,Mir Ali Hoda,Walter Klepetko,Aude Lacourt,Phil McElnay,Nick A Maskell,Luciano Mutti,Jean-Claude Pairon,Paul Van Schil,Jan P. van Meerbeeck,David A. Waller,Walter Weder,Paul Martin Putora,Paul Martin Putora,Giuseppe Cardillo +30 more
TL;DR: It is emphasized that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.
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Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1)
Samuel G. Armato,Anna K. Nowak +1 more
TL;DR: Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
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Identifying and managing the adverse effects of immune checkpoint blockade.
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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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