Tremelimumab for the treatment of malignant mesothelioma

Our plain-English summary of Tremelimumab for the treatment of malignant mesothelioma, by A. Guazzelli, M. Hussain, M. Krstic-Demonacos, et al (Expert Opinion on Biological Therapy, 2015).

The study

• Authors: A. Guazzelli, M. Hussain, M. Krstic-Demonacos, L. Mutti
• Journal: Expert Opinion on Biological Therapy
• Published: 2015;15(12):1819-29
• Type of article: Review
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Tremelimumab demonstrated therapeutic activity in different malignancies, including malignant pleural mesothelioma (MPM); however, continued research could improve the therapeutic index of this agent.

Areas Covered: This review describes tremelimumab's clinical efficacy, administration and safety in patients affected with MPM and reports the state of the art clinical trials of tremelimumab. A literature search using the PubMed database was conducted using the search terms tremelimumab, MPM, current therapy, immune checkpoint blockage and cytotoxic T lymphocyte-associated antigen-4. Data was also obtained from meeting abstracts and clinical trial registries.

Expert Opinion: The use of immunotherapy has been extended from melanoma to thoracic malignancies or lung cancer and MPM. The first clinical trials for MPM with drugs modulating immune checkpoints have been tested or are currently being tested with the first results now under critical consideration. Among these drugs, tremelimumab has been attracting attention as a potential new treatment for MPM. Nevertheless, even though clinical efficacy has been preliminarily demonstrated, the cost/benefit ratio of this drug for this neoplasm is yet to be ascertained.

In plain English

This article reviewed tremelimumab, an antibody targeting the immune checkpoint CTLA-4, for malignant pleural mesothelioma. The authors drew on PubMed, meeting abstracts and trial registries. They described two single-arm phase II trials by Calabrò and colleagues in patients whose disease had progressed after chemotherapy. In the first trial (29 patients, 15 mg/kg every 90 days), 2 had a partial response, 31% had disease control, and the primary endpoint was not met. In the second trial (29 patients, 10 mg/kg every 4 weeks at first), 4 patients had an immune-related partial response and the primary endpoint was reached. Disease control was 15 of 29 (51.7%) by immune-related response criteria but 11 of 29 (37.9%) by modified RECIST; overall survival was not considered. In the first trial, 27 patients (93%) had at least one grade 1 to 2 treatment-related side effect, and four (14%) at least one grade 3 to 4. A placebo-controlled trial of about 564 patients was under way. The authors concluded there were no solid data that tremelimumab improves survival, citing small nonrandomised trials and patient selection bias.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review (drug evaluation) of published studies, meeting abstracts and clinical trial registries on tremelimumab in malignant pleural mesothelioma
• Who was studied: No patients were studied directly. The review described two single-arm phase II trials by Calabrò et al. Each had 29 patients with unresectable malignant mesothelioma that had progressed after first-line platinum-based chemotherapy. It also described an ongoing randomised, placebo-controlled phase 2b trial planned for about 564 patients.
• Exposure: The exposure was treatment with tremelimumab, a drug, not asbestos. In the first trial (MESOT-TREM-2008) the dose was 15 mg/kg once every 90 days. In the second trial (MESOT-TREM-2012) it was 10 mg/kg every 4 weeks for 6 doses (induction), then every 12 weeks (maintenance).
• Main results:
  • In the first reviewed trial (MESOT-TREM-2008), 2 of 29 patients had a partial response. Per the review's table, 7 (24.1%) had stable disease and 9 (31%) had disease control.
  • The first trial did not meet its primary endpoint.
  • In its discussion of the first trial, the review reported a median overall survival of 10.7 months. It reported survival rates of 48.3% at 1 year and 36.7% at 2 years.
  • In the second reviewed trial (MESOT-TREM-2012), 4 of 29 patients had an immune-related partial response, and the primary endpoint for immune-related response was reached.
  • In the second trial, disease control was 15 of 29 (51.7%) by immune-related response criteria and 11 of 29 (37.9%) by modified RECIST. The text rounds the first figure to 52%.
  • Overall survival was not considered in the second trial.
  • In the first trial, 27 patients (93%) had at least one grade 1 to 2 treatment-related adverse event, and four (14%) had at least one grade 3 to 4 treatment-related adverse event.
  • One patient in the first trial who had a long-lasting partial response developed a Guillain–Barré-like syndrome after eight doses.
  • A randomised, double-blind, placebo-controlled phase 2b trial in pleural and peritoneal mesothelioma was under way. It assigns patients to tremelimumab or placebo in a 2:1 ratio.
  • No data on the cost of tremelimumab treatment in malignant pleural mesothelioma had been reported.
• The authors' conclusion: In their conclusions section, the authors wrote that tremelimumab had been shown to be relatively safe and seemed to show clinical and immunological activity. In their expert opinion, they wrote that there were no solid data that it improves survival and that it is rather toxic, with severe gastrointestinal toxicity not rare. They noted that the phase 2b results were still awaited.
• Limitations the authors state:
  • The phase II results were limited by the small number of treated patients and the nonrandomised design.
  • Selecting patients with very good performance status and limited disease biases survival results.
  • The drug can take up to 6 months to act, which the authors considered too long for patients with advanced disease.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Tremelimumab, Mesothelioma, Pleural Mesothelioma, State-of-the-Art Defense, Clinical Trial, Immunotherapy, Lung Cancer, Neoplasm.

Related studies

• 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, A. Scherpereel, et al. (2017)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• 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, et al. (2015)
• Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study — L. Calabrò, A. Morra, et al. (2018)
• Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications — L. Calabrò, R. Danielli, et al. (2010)

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