Anti-CTLA-4 therapy for malignant mesothelioma

Our plain-English summary of Anti-CTLA-4 therapy for malignant mesothelioma, by A. Guazzelli, E. Bakker, M. Krstic-Demonacos, et al (Immunotherapy, 2017).

The study

• Authors: A. Guazzelli, E. Bakker, M. Krstic-Demonacos, M.P. Lisanti, F. Sotgia, L. Mutti
• Journal: Immunotherapy
• Published: 2017;9(3):273-280
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences.

In plain English

This special report was a review. It discussed trials of tremelimumab, an antibody blocking the immune checkpoint CTLA-4, in patients with unresectable malignant mesothelioma that had progressed after platinum-based chemotherapy. It did not study asbestos exposure. In MESOT-TREM-2008, 2 of 29 patients (7%) had a durable partial response, so the main goal was not reached. Four (14%) had serious side effects, including one death from gastrointestinal toxicity. In MESOT-TREM-2012, which used more intensive dosing, four patients (14%) had an immune-related partial response and median overall survival was 11.3 months. In the larger placebo-controlled DETERMINE trial, the developers announced that tremelimumab alone did not improve survival. Data presented in 2016 showed no statistically significant difference between treated and placebo patients, with diarrhoea, loss of appetite and rashes more frequent among treated patients. The authors noted that trials enrolled only very fit patients with limited disease and that response criteria were hard to apply to this tumor. The authors concluded that these considerations may rule out tremelimumab as a single agent for mesothelioma. They also concluded that checkpoint inhibitors for mesothelioma remain largely questionable and unsupported by current evidence.

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: Special report (narrative review) of preclinical and clinical studies of anti-CTLA-4 therapy (tremelimumab), alone or combined with PD-1/PD-L1 inhibitors, in malignant mesothelioma
• Who was studied: Reviewed clinical trials in patients with unresectable malignant mesothelioma (pleural or peritoneal) after failure of platinum-based first-line treatment: MESOT-TREM-2008 (29 patients), MESOT-TREM-2012 (29 patients) and the placebo-controlled DETERMINE trial (564 patients in Table 1; 571 patients according to the text)
• Exposure: The exposure examined was a treatment, not asbestos: the anti-CTLA-4 antibody tremelimumab. MESOT-TREM-2008 gave 15 mg/kg intravenously once every 90 days. MESOT-TREM-2012 gave 10 mg/kg every 4 weeks for six doses, then maintenance every 12 weeks.
• Main results:
  • MESOT-TREM-2008 (29 patients): two patients (7%) achieved a durable partial response (one lasting 6 months, one lasting 18 months), so the primary end point was not reached
  • MESOT-TREM-2008: nine patients (31%) showed disease control; median progression-free survival was 6.2 months and overall survival was 10.7 months
  • MESOT-TREM-2008: serious (grade 3 to 4) side effects occurred in four patients (14%), including one death due to gastrointestinal toxicity
  • MESOT-TREM-2012: the primary end point was reached. Four patients (14%) achieved an immune-related partial response, fifteen (52%) had disease control, median immune-related progression-free survival was 6.2 months and median overall survival was 11.3 months.
  • MESOT-TREM-2012: two patients had grade 3 hepatic or gastrointestinal toxic effects
  • DETERMINE (NCT01843374): AstraZeneca and MedImmune announced that tremelimumab as monotherapy did not improve survival and the primary end point was not reached. Data presented at ASCO 2016 reported 571 patients enrolled, 81% of whom had died during the study, with no statistically significant difference between treated and placebo patients.
  • DETERMINE: side effects such as diarrhoea, loss of appetite and rashes were seen at higher rates in tremelimumab-treated patients than in placebo patients
• The authors' conclusion: The authors concluded that biological and clinical considerations may rule out tremelimumab as a single agent for malignant mesothelioma, and that the use of immune checkpoint inhibitors for mesothelioma is still largely questionable and not supported by current evidence
• Limitations the authors state:
  • The authors noted that checkpoint inhibitor trials have recruited only very fit mesothelioma patients with limited disease
  • The authors stated that immune-related response criteria are very arguable and unlikely to be reliable for mesothelioma, because its spread in the chest and shrinkage after treatment are very hard to measure
  • The authors stated that, apart from some anecdotal very good responses, no positive impact on survival has been achieved with these treatments so far

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: CTLA-4, Malignant Mesothelioma, Immunotherapy, checkpoint inhibitors, PD-1/PD-L1, Clinical Trial, Tremelimumab, Unresectable.

Related studies

• CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy? — L. Calabrò, G.L. Ceresoli, et al. (2015)
• Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications — L. Calabrò, R. Danielli, et al. (2010)
• Tremelimumab for the treatment of malignant mesothelioma — A. Guazzelli, M. Hussain, et al. (2015)
• Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences — L. Calabrò, G.L. Ceresoli, et al. (2017)
• Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy — R. Hassan, C. Schweizer, et al. (2010)
• Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab — S. Khanna, A. Thomas, et al. (2016)

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