Journal ArticleDOI
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial
Luana Calabrò,Aldo Morra,Ester Fonsatti,Ornella Cutaia,Giovanni Amato,Diana Giannarelli,Anna Maria Di Giacomo,Riccardo Danielli,Maresa Altomonte,Luciano Mutti,Michele Maio +10 more
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TLDR
Although the effect size was small in the phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma.Abstract:
Summary Background Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma. Methods In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024. Findings Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3–11·1) and a median overall survival of 10·7 months (0·0–21·9). 27 patients (93%) had at least one grade 1–2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3–4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic). Interpretation Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma. Funding Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.read more
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CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor
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TL;DR: Significant new preclinical and early clinical developments in treatment of MPM include mesothelin specific antibody and toxin therapies, interleukin-4 (IL-4) receptor toxins, dendritic cell vaccines, immune checkpoint inhibitors, and gene-based therapies.
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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.
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Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
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TL;DR: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dACarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma.
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Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
Jedd D. Wolchok,Axel Hoos,Steven J. O'Day,Jeffrey S. Weber,Omid Hamid,Céleste Lebbé,Michele Maio,Michael Binder,Oliver Bohnsack,Geoffrey M. Nichol,R. Humphrey,F. Stephen Hodi +11 more
TL;DR: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria.
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Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma
Nicholas J. Vogelzang,James J. Rusthoven,James T. Symanowski,Claude Denham,E. Kaukel,Pierre Ruffié,Ulrich Gatzemeier,Michael Boyer,Salih Emri,Christian Manegold,Clet Niyikiza,Paolo Paoletti +11 more
TL;DR: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cis Platin alone in patients with malignant pleural mesothelioma.
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Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab
TL;DR: A detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy are provided.
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