Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences

Our plain-English summary of Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences, by L. Calabrò, G.L. Ceresoli, A. D'Incecco, et al (Cytokine & Growth Factor Reviews, 2017).

The study

• Authors: L. Calabrò, G.L. Ceresoli, A. D'Incecco, A. Scherpereel, J. Aerts, M. Maio
• Journal: Cytokine & Growth Factor Reviews
• Published: 2017;36:25-31
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Treatment with immune-checkpoint blocking monoclonal antibody (mAb) is demonstrating a significant efficacy in different tumor types. Here, we discuss the impact of this promising approach in malignant mesothelioma (MM), a still dreadful disease in which medical treatment has been set on platinum based chemotherapy for decades with unsatisfactory results.

Copyright © 2017 Elsevier Ltd. All rights reserved.

In plain English

This article was a review, not a new study. The authors first described standard treatment for malignant mesothelioma, a cancer whose cause they described as mostly related to previous asbestos exposure. They then discussed clinical trials of immune checkpoint drugs, which aim to reactivate silenced immune responses against cancer. They reported that tremelimumab, an anti-CTLA-4 drug, showed activity in two small phase 2 studies. In the larger DETERMINE trial, however, it did not improve overall survival compared with placebo in patients whose disease had come back. Early trials of drugs that block PD-1 or PD-L1 (pembrolizumab, nivolumab, avelumab) in previously treated patients reported partial responses in 9% to 21% of patients. These trials did not show a clear link between PD-L1 levels and benefit. The authors also described early results of drug combinations. They concluded that single-drug immunotherapy had shown a proven but limited benefit. They cautioned that the results were very preliminary, most trials were ongoing, and comparison with other studies was difficult.

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: Narrative review of pre-clinical background and clinical trials of immune checkpoint therapy in malignant mesothelioma
• Who was studied: No new patients were studied. The authors reviewed published, preliminary and ongoing clinical trials in patients with pleural or peritoneal malignant mesothelioma, mostly patients whose disease had progressed after chemotherapy.
• Exposure: The 'exposure' was treatment with immune checkpoint blocking antibodies: anti-CTLA-4 drugs (tremelimumab, ipilimumab), anti-PD-1 drugs (pembrolizumab, nivolumab) and anti-PD-L1 drugs (avelumab, durvalumab), alone or in combination. Asbestos was mentioned only as background on the cause of the disease.
• Main results:
  • In the MESOT-TREM-2008 phase 2 study of tremelimumab in second-line patients, the objective response rate was 7%. Long-lasting disease control was seen in 31% of patients and 2-year survival in 36%.
  • In the MESOT-TREM-2012 study (intensified tremelimumab schedule), 4 of 29 patients (14%) had an immune-related partial response. 15 of 29 (51.7%) had long-lasting immune-related disease control, and median overall survival was 11.3 months.
  • In the large randomised DETERMINE study, tremelimumab did not improve overall survival compared with placebo in relapsing patients.
  • In KEYNOTE-028, 25 pleural mesothelioma patients selected for PD-L1 positivity received pembrolizumab. 5 (20%) had a partial response and 13 (52%) had stable disease. Median progression-free survival was 5.4 months and median overall survival 18.0 months.
  • In the University of Chicago phase 2 pembrolizumab trial (initial cohort of 35 patients), 7 patients (21%) had a partial response and 20 (59%) had stable disease. Median progression-free survival was 6.2 months and median overall survival 11.9 months.
  • In the Netherlands phase 2 nivolumab trial in 34 pleural mesothelioma patients, disease control was 50% at 12 weeks and 33% at 24 weeks. The response rate was 15% and median progression-free survival was 3.6 months.
  • In a phase Ib trial of avelumab in 53 heavily pretreated pleural or peritoneal mesothelioma patients, 5 (9%) had a durable partial response and 25 (47%) had stable disease, for overall disease control of 56%.
  • The pembrolizumab, nivolumab and avelumab studies did not show a clear association between the level of PD-L1 expression and treatment efficacy.
  • In the NIBIT-MESO-1 study of tremelimumab plus durvalumab in 40 patients, 67.5% had mild-moderate (grade 1-2) and 17.5% had severe (grade 3-4) treatment-related side effects. The efficacy analysis was still ongoing.
  • In the MAPS-2 phase 2 study in second- or third-line pleural mesothelioma, disease control after 12 weeks was 44% with nivolumab alone and 50% with nivolumab plus ipilimumab.
• The authors' conclusion: The authors concluded that preliminary data on PD-1/PD-L1 targeting antibodies suggest single-drug immunotherapy has a proven but limited benefit in mesothelioma, and that these data should be considered with caution. They suggested combination strategies as an area to explore.
• Limitations the authors state:
  • The authors noted that the results were still very preliminary and most trials were still ongoing.
  • The authors noted that the reviewed studies generally did not report the outcome of patients' previous treatments.
  • The authors noted that modified response criteria for pleural mesothelioma were not used in the basket trials, making comparison with other studies difficult because of potential selection bias.
  • The authors noted that the link between PD-L1 expression and efficacy remains controversial, partly because studies used different tests and different cut-offs for positivity.

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: Mesothelioma, Monoclonal Antibody, Malignant Mesothelioma, Chemotherapy.

Related studies

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• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge — L. Calabrò, A. Morra, et al. (2018)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• Proton Beam Therapy and Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma — M.G. McCusker, K.A. Scilla, et al. (2019)
• PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review — M. Zhou, N. Joshi, et al. (2021)
• Immune checkpoint blockade in malignant mesothelioma — L. Calabrò, M. Maio (2015)

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