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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1
Yu-Fei Hao,Matthew C. Cook +1 more
TL;DR: This work considers IEIs arising from rare genetic variants in CTLA4 and PDCD1 and compares clinical and laboratory manifestations arising as drug-induced phenocopies in cancer patients treated with immune checkpoint inhibitors (ICI) and identifies outstanding questions regarding mechanism of disease.
Journal ArticleDOI
Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status
Paul Baverel,Lorin Roskos,Manasa Tatipalli,Nancy Lee,Paul K. Stockman,Maria Taboada,Paolo Vicini,Kevin Horgan,Rajesh Narwal +8 more
TL;DR: Results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.
Journal ArticleDOI
Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma.
TL;DR: Malignant pleural mesothelioma is characterized as an immunological cold tumor with low T-cell infiltration, which could explain the disappointing results of clinical trials investigating CI treatment in MPM.
Journal ArticleDOI
The effect of patient sex on the efficacy and safety of anticancer immunotherapy.
Laura Pala,Fabio Conforti +1 more
TL;DR: In this paper, the authors present an overview of existing biological differences between males and females, including the immune system dimorphism, which represent the rationale for a sexual-based difference in activity and toxicity of anticancer immunotherapies.
Journal ArticleDOI
The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future
TL;DR: The authors explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy.
References
More filters
Journal ArticleDOI
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
Elizabeth Eisenhauer,P. Therasse,Jan Bogaerts,Lawrence H. Schwartz,Daniel J. Sargent,Robert Ford,Janet Dancey,S. Arbuck,S. Gwyther,Margaret M. Mooney,Larry Rubinstein,Lalitha K. Shankar,Lori E. Dodd,Robert M. Kaplan,Denis Lacombe,Jaap Verweij +15 more
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
Journal ArticleDOI
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Naiyer A. Rizvi,Naiyer A. Rizvi,Matthew D. Hellmann,Matthew D. Hellmann,Alexandra Snyder,Alexandra Snyder,Pia Kvistborg,Vladimir Makarov,Jonathan J. Havel,William Lee,Jianda Yuan,Phillip Wong,Teresa S. Ho,Martin L. Miller,Natasha Rekhtman,Andre L. Moreira,Fawzia Ibrahim,Cameron Bruggeman,Billel Gasmi,Roberta Zappasodi,Yuka Maeda,Chris Sander,Edward B. Garon,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Ton N. Schumacher,Timothy A. Chan,Timothy A. Chan +28 more
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Journal Article
[New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)].
Hirokazu Watanabe,Morihito Okada,Yasushi Kaji,Miyako Satouchi,Yozo Sato,Yuichiro Yamabe,Hiroaki Onaya,Masahiro Endo,Miyuki Sone,Yasuaki Arai +9 more
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.
Related Papers (5)
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial
Gérard Zalcman,Gérard Zalcman,Julien Mazieres,Jacques Margery,Laurent Greillier,Clarisse Audigier-Valette,Denis Moro-Sibilot,Olivier Molinier,Romain Corre,Isabelle Monnet,Valérie Gounant,Frédéric Rivière,H. Janicot,Radj Gervais,Chrystele Locher,Bernard Milleron,Quan Tran,Marie-Paule Lebitasy,Franck Morin,Christian Creveuil,Jean-Jacques Parienti,Arnaud Scherpereel +21 more
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
Raphael Bueno,Eric Stawiski,Leonard D. Goldstein,Steffen Durinck,Assunta De Rienzo,Zora Modrusan,Florian Gnad,Thong T. Nguyen,Bijay S. Jaiswal,Lucian R. Chirieac,Daniele Sciaranghella,Nhien Dao,Corinne E. Gustafson,Kiara J. Munir,Jason A. Hackney,Amitabha Chaudhuri,Ravi Gupta,Joseph Guillory,Karen Toy,Connie Ha,Ying-Jiun Chen,Jeremy Stinson,Subhra Chaudhuri,Na Zhang,Thomas D. Wu,David J. Sugarbaker,Frederic J. de Sauvage,William G. Richards,Somasekar Seshagiri +28 more
Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer
Hossein Borghaei,Luis Paz-Ares,Leora Horn,D. R. Spigel,M. Steins,Neal Ready,L.Q. Chow,Everett E. Vokes,Enriqueta Felip,Esther Holgado,F. Barlesi,M. Kohlhufl,Oscar Arrieta,Marco Angelo Burgio,J. Fayette,H. Lena,Elena Poddubskaya,David E. Gerber,Scott N. Gettinger,Charles M. Rudin,Naiyer A. Rizvi,L. Crina,G. R. Blumenschein,Scott J. Antonia,C. Dorange,C. T. Harbison,F. Graf Finckenstein,Julie R. Brahmer +27 more