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Efficacy And Safety Of An Intensified Schedule Of Tremelimumab For Chemotherapy-resistant Malignant Mesothelioma: An Open-label, Single-arm, Phase 2 Study.

L. Calabrò, A. Morra, E. Fonsatti, Ornella Cutaia, C. Fazio, D. Annesi, Marica Lenoci, G. Amato, R. Danielli, M. Altomonte, D. Giannarelli, A. M. Di Giacomo, M. Maio
Published 2015 · Medicine

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BACKGROUND CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma. METHODS In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888. FINDINGS Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever. INTERPRETATION Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study. FUNDING Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.
This paper references
10.1200/JCO.1998.16.1.145
Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience.
D. Curran (1998)
10.1053/j.seminoncol.2010.09.006
Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications.
L. Calabrò (2010)
10.1634/THEONCOLOGIST.12-7-850
Multidisciplinary treatment of malignant pleural mesothelioma.
G. Ceresoli (2007)
10.1053/j.seminoncol.2010.09.001
Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy.
M. Callahan (2010)
10.1158/1078-0432.CCR-09-1624
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
10.1093/ANNONC/MDH059
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
M. Byrne (2004)
10.1016/j.lungcan.2011.08.011
Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.
P. Zucali (2012)
10.1200/JCO.2006.09.9887
Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.
J. Jassem (2008)
10.1111/j.1749-6632.2010.05554.x
Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model
Jedd M. Hillegass (2010)
10.1038/bjc.2013.504
Existing models, but not neutrophil-to-lymphocyte ratio, are prognostic in malignant mesothelioma
T. Meniawy (2013)
10.1016/j.ctrv.2009.09.003
Second-line treatment for malignant pleural mesothelioma.
G. Ceresoli (2010)
10.1158/1078-0432.CCR-10-2245
High Blood Neutrophil-to-Lymphocyte Ratio Is an Indicator of Poor Prognosis in Malignant Mesothelioma Patients Undergoing Systemic Therapy
S. Kao (2010)
10.1007/s00262-013-1418-6
Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme
A. M. Di Giacomo (2013)
10.1200/JCO.2011.38.4032
Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.
T. Lynch (2012)
10.1200/JCO.2003.11.136
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
N. Vogelzang (2003)
10.1200/JCO.2012.44.6112
Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
A. Ribas (2013)
10.1155/2012/927240
New Roads Open Up for Implementing Immunotherapy in Mesothelioma
R. Cornelissen (2012)
10.1177/0300060513504163
The value of inflammatory parameters in the prognosis of malignant mesothelioma
O. Abakay (2014)
10.2217/imt.13.9
Tremelimumab: a review of development to date in solid tumors.
A. Tarhini (2013)
10.1007/s00262-014-1609-9
CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy?
L. Calabrò (2014)
10.4161/cam.4.1.11361
What's the place of immunotherapy in malignant mesothelioma treatments?
M. Grégoire (2010)
10.1016/S1470-2045(13)70381-4
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
L. Calabrò (2013)
10.1016/s0923-7534(20)33712-1
Five-Year Survival Rates for Patients (PTS) with Metastatic Melanoma (MM) Treated with Ipilimumab (IPI) in Phase II Trials
C. Lebbé (2012)
10.1056/NEJMRA050152
Advances in malignant mesothelioma.
B. Robinson (2005)



This paper is referenced by
10.1016/S2213-2600(18)30151-6
Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.
L. Calabrò (2018)
10.1080/13543784.2017.1351545
Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma
A. Guazzelli (2017)
10.1016/S1470-2045(17)30511-9
CTLA-4 blockade in mesothelioma: ineffective or reason for optimism?
A. Thomas (2017)
10.1080/14737140.2017.1358091
Immunotherapy advances for mesothelioma treatment
Emyr Bakker (2017)
10.1038/s41392-020-0205-z
Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies
R. D. Cervantes-Villagrana (2020)
10.1080/2162402X.2018.1554969
Making cold malignant pleural effusions hot: driving novel immunotherapies
Pranav Murthy (2019)
10.1016/S1470-2045(17)30446-1
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
M. Maio (2017)
10.1080/14737140.2016.1191951
Immune checkpoint inhibitors in malignant pleural mesothelioma: promises and challenges
G. Ceresoli (2016)
10.1016/j.jtho.2018.08.2024
Treat it or Leave it: Immuno-Oncology in Mesothelioma Observed by the Eyes of Argus.
C. J. de Gooijer (2018)
10.2217/LMT.15.23
Novel insights into the pathophysiology and treatment of malignant pleural mesothelioma
Alistair M. Cook (2015)
10.1007/978-3-319-96244-3_6
Caring for Patients During and After Immunotherapy Treatment
B. Rose (2019)
10.1016/S1470-2045(18)30868-4
Checkpoint inhibitors in mesothelioma: hope for the future?
A. Bibby (2019)
10.1007/978-3-319-99510-6_6
Immunotherapy of Malignant Peritoneal Mesothelioma and Pseudomyxoma Peritonei
Irina Zh. Zhubina (2019)
10.2217/imt.15.89
Tremelimumab-associated tumor regression following after initial progression: two case reports.
A. Shimomura (2016)
10.1007/s00508-016-1036-3
Management of malignant pleural mesothelioma—part 2: therapeutic approaches
M. A. Hoda (2016)
10.1101/243477
Integrated Multi-omics Molecular Subtyping Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma
Raunak Shrestha (2018)
10.21037/tlcr.2019.11.23
Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives.
S. Gray (2020)
10.1007/s11654-016-0580-7
Immunonkologische Therapiestrategien
Knut Dietrich (2016)
10.21037/tlcr.2017.05.02
Immunotherapy for malignant pleural mesothelioma: current status and future directions.
J. Dozier (2017)
10.1016/j.critrevonc.2016.08.011
The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?
G. Bronte (2016)
10.1016/b978-0-12-409547-2.12426-6
6.02 – Cancer Immunotherapy
Reham Ajina (2017)
10.29245/2572-9411/2017/2.1098
Current status and future prospects of PET/CT in NSCLC treated with checkpoint-based immunotherapy
M. Higuchi (2017)
10.3389/fonc.2020.00187
Immunotherapy in Malignant Pleural Mesothelioma
C. J. de Gooijer (2020)
10.5603/ARM.a2020.0103
New horizons from novel therapies in malignant pleural mesothelioma.
M. Sayan (2020)
10.3348/kjr.2017.18.1.42
Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know
Marta Braschi-Amirfarzan (2017)
10.1016/j.bcp.2016.07.012
New therapeutic strategies for malignant pleural mesothelioma
M. Bonelli (2017)
10.1016/j.ctrv.2016.02.001
Management of toxicities of immune checkpoint inhibitors.
L. Spain (2016)
10.2147/LCTT.S83338
Modern management of malignant pleural mesothelioma
S. Patel (2016)
10.1016/j.ejim.2017.08.019
Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach.
P. Iglesias (2018)
10.21037/jtd.2017.12.88
New horizons from immunotherapy in malignant pleural mesothelioma.
L. Calabrò (2018)
10.2147/CMAR.S265828
Regulatory T Cells in Cancer Immunotherapy: Basic Research Outcomes and Clinical Directions
Guoming Zeng (2020)
10.1016/j.jtho.2016.05.027
Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC
F. Facchinetti (2016)
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