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Tremelimumab Combined With Durvalumab In Patients With Mesothelioma (NIBIT-MESO-1): An Open-label, Non-randomised, Phase 2 Study.

L. Calabrò, A. Morra, D. Giannarelli, G. Amato, A. D’Incecco, A. Covre, A. Lewis, M. Rebelatto, R. Danielli, M. Altomonte, A. M. Di Giacomo, M. Maio
Published 2018 · Medicine

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BACKGROUND Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. METHODS In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients. FINDINGS From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines. INTERPRETATION The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. FUNDING Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.
This paper references
10.1016/S1470-2045(15)00544-6
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
S. Antonia (2016)
10.1093/ANNONC/MDH059
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
M. Byrne (2004)
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/j.cytogfr.2017.07.003
Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences.
L. Calabrò (2017)
10.1016/j.lungcan.2015.06.018
Second line therapy in malignant pleural mesothelioma: A systematic review.
W. Buikhuisen (2015)
10.1093/annonc/mdt161
Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials.
J. Wolchok (2013)
10.2471/BLT.11.086678
Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008.
V. Delgermaa (2011)
10.1200/JCO.2017.35.18_SUPPL.LBA8507
Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial
A. Scherpereel (2017)
10.1158/1078-0432.CCR-14-3128
CCR 20th Anniversary Commentary: Immune-Related Response Criteria—Capturing Clinical Activity in Immuno-Oncology
A. Hoos (2015)
10.1007/s11102-009-0193-z
Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes
T. Dillard (2009)
10.4049/jimmunol.1401686
Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Rituparna Das (2015)
10.1016/S1470-2045(17)30169-9
Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
E. Alley (2017)
10.1056/NEJMoa1504030
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
J. Larkin (2015)
10.1097/COC.0000000000000239
CTLA-4 and PD-1 Pathways
Elizabeth I Buchbinder (2016)
10.1111/cei.13081
Immune checkpoint inhibitors: new strategies to checkmate cancer
R. Wilson (2018)
10.1007/s00262-017-1954-6
PD-1 and PD-L1 antibodies in cancer: current status and future directions
A. Balar (2017)
10.1016/S2213-2600(15)00092-2
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
L. Calabrò (2015)
10.1002/SIM.721
Sample size tables for exact single-stage phase II designs.
R. A'hern (2001)
10.1200/JCO.2017.72.9012
Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial.
F. Grosso (2017)
10.1183/09031936.06.00135305
Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses
J. Hegmans (2006)
10.1186/s13045-017-0479-y
Clinical applications of PD-L1 bioassays for cancer immunotherapy
D. Liu (2017)
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)
10.1056/NEJMoa1003466
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
10.1016/S0140-6736(15)01238-6
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial
G. Zalcman (2016)
10.1183/16000617.0063-2016
Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment
A. Bibby (2016)
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)
10.1200/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)
10.1038/bjc.2016.308
Patterns of response to anti-PD-1 treatment: an exploratory comparison of four radiological response criteria and associations with overall survival in metastatic melanoma patients
L. Khoja (2016)
10.1007/s00262-011-1103-6
Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma
A. Bograd (2011)
10.1016/j.ejca.2008.10.026
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
E. Eisenhauer (2009)



This paper is referenced by
10.1101/243477
Integrated Multi-omics Molecular Subtyping Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma
Raunak Shrestha (2018)
10.14288/1.0370936
Computational prioritization of cancer driver genes for precision oncology
Raunak Shrestha (2018)
Multimodality treatment of malignant pleural mesothelioma
Schil (2019)
10.1016/j.jtho.2019.06.020
Pathologic considerations and standardization in mesothelioma clinical trials.
M. Tsao (2019)
10.1016/j.critrevonc.2019.102815
Emerging therapies in malignant pleural mesothelioma.
M. Cinausero (2019)
10.1007/978-3-030-33832-9_20
The Formidable Metamorphosis of the Salamander’s Wool: Asbestos from Eternal Material to Awful Pathologies
L. Santarelli (2020)
10.3390/cancers12040915
Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting
Fabio Nicolini (2020)
10.1016/j.jtho.2019.08.2506
EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach.
A. Nicholson (2019)
10.1101/243477
BAP1 Haploinsufficiency Predicts a Distinct Immunogenic Class of Malignant Peritoneal Mesothelioma
Raunak Shrestha (2018)
10.1016/s1470-2045(20)30462-9
Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in.
A. Nowak (2020)
10.1007/978-3-030-16884-1_23
Unmet Needs and Future Outlook of Mesothelioma Management
D. Fennell (2019)
10.3389/fonc.2020.00258
Treatment-Related Adverse Events of Combination Immune Checkpoint Inhibitors: Systematic Review and Meta-Analysis
R. Park (2020)
10.1186/s12885-019-5785-z
The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis
Lihu Gu (2019)
10.1097/MD.0000000000021273
Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors
B. Wang (2020)
10.1186/s13073-019-0620-3
BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma
Raunak Shrestha (2019)
10.3389/fimmu.2020.00676
Inducers, Attractors and Modulators of CD4+ Treg Cells in Non-Small-Cell Lung Cancer
Mengxiao Xie (2020)
10.2147/OTT.S231052
Cancer Immunotherapies Targeting Tumor-Associated Regulatory T Cells
Xiaoxu Ge (2019)
10.21037/tlcr.2019.11.23
Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives.
S. Gray (2020)
10.1016/j.ctarc.2020.100232
Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes.
Paul Markowitz (2020)
10.1080/14712598.2019.1606209
Immune checkpoint inhibition for the treatment of mesothelioma
A. Nowak (2019)
10.1016/J.ANNONC.2020.09.009
A multicentre randomised phase III trial comparing pembrolizumab vs single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial.
S. Popat (2020)
10.3390/ijms21124427
Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials
Omid Kooshkaki (2020)
10.21037/TLCR.2020.03.38
Clinical significance of histologic subtyping of malignant pleural mesothelioma.
L. Brčić (2020)
10.1177/1758835920971421
Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma
H. Yang (2020)
10.3389/fonc.2020.00777
Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma
Robert A. Belderbos (2020)
10.3390/cancers12020361
Circulating Levels of PD-L1 in Mesothelioma Patients from the NIBIT-MESO-1 Study: Correlation with Survival
C. Chiarucci (2020)
10.1111/jcpt.12750
Monoclonal antibody therapy in cancer: When two is better (and considerably more expensive) than one
G. Peterson (2018)
10.1007/s00262-018-2286-x
The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology
A. M. Di Giacomo (2018)
10.1016/j.jtocrr.2020.100075
Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population
Tamkin Ahmadzada (2020)
10.3389/fonc.2019.01519
Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future
Fabio Nicolini (2019)
10.1093/ejcts/ezaa158
ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.
I. Opitz (2020)
10.1007/s00262-020-02502-1
Cancer bio-immunotherapy XVI annual NIBIT-(Italian Network for Tumor Biotherapy) meeting, October 11–13 2018, Milan, Italy
M. Bellone (2020)
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