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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Immune Checkpoint Blockade in Cancer Therapy
TL;DR: Concluding remarks are made that principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation, and whether they enhance the efficacy of either approach alone is investigated.
Journal ArticleDOI
Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination
Celine Boutros,Ahmad A. Tarhini,Emilie Routier,Olivier Lambotte,Francois Leroy Ladurie,Franck Carbonnel,Hassane Izzeddine,Aurélien Marabelle,Stéphane Champiat,Armandine Berdelou,Emilie Lanoy,M. Texier,C. Libenciuc,Alexander M.M. Eggermont,Alexander M.M. Eggermont,Jean-Charles Soria,Jean-Charles Soria,Jean-Charles Soria,Christine Mateus,Caroline Robert,Caroline Robert,Caroline Robert +21 more
TL;DR: The authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
Journal ArticleDOI
Coinhibitory Pathways in Immunotherapy for Cancer.
TL;DR: The immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer are discussed and blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients.
Journal ArticleDOI
Management of toxicities of immune checkpoint inhibitors.
TL;DR: This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer.
Journal ArticleDOI
The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition.
TL;DR: The concept of the tumor immunity continuum is proposed as a framework for developing rational combination strategies for anticancer immune therapies based on current understanding of tumor and circulating pharmacodynamic correlates of immune modulation.
References
More filters
Journal ArticleDOI
Five-Year Survival Rates for Patients (PTS) with Metastatic Melanoma (MM) Treated with Ipilimumab (IPI) in Phase II Trials
C. Lebbé,Jeffrey S. Weber,Michele Maio,Bart Neyns,Kaan Harmankaya,Kevin M. Chin,D. Opatt McDowell,L. Cykowski,M.B. McHenry,Jedd D. Wolchok +9 more
TL;DR: For example, Harmankaya et al. as discussed by the authors reported that IPI monotherapy may result in prolonged survival in some patients with multiple sclerosis (MDS) compared to treatment-naïve and previously treated patients.
Journal ArticleDOI
Four-Year Survival Update for Metastatic Melanoma (MM) Patients (PTS) Treated with Ipilimumab (IPI) + Dacarbazine (DTIC) on Phase 3 Study CA184-024
Michele Maio,Igor Bondarenko,C. Robert,Luc Thomas,Claus Garbe,Alessandro Testori,Stephen Francis,Kevin M. Chin,Jedd D. Wolchok +8 more
TL;DR: The continued survival of some patients at 4 yrs suggests that prolonged survival may indeed be obtained in some pts with treatment-naive MM, and this observation of long-term survival benefit in a phase III RCT is consistent with observations from phase I/II studies of IPI in patients with advanced melanoma.
Related Papers (5)
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
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,Dirk Schadendorf,Reinhard Dummer,Michael Smylie,Piotr Rutkowski,Pier Francesco Ferrucci,A. Hill,John Wagstaff,Matteo S. Carlino,John B A G Haanen,Michele Maio,Ivan Marquez-Rodas,Grant A. McArthur,Paolo A. Ascierto,Georgina V. Long,Margaret K. Callahan,Michael A. Postow,Michael A. Postow,Kenneth F. Grossmann,Mario Sznol,Brigitte Dréno,Lars Bastholt,Arvin Yang,Linda Rollin,Christine Horak,F. Stephen Hodi,Jedd D. Wolchok,Jedd D. Wolchok +32 more