Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy

Our plain-English summary of Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy, by S. Cedres, A. Valdivia, P. Iranzo, et al (Cancers, 2023).

The study

• Authors: S. Cedres, A. Valdivia, P. Iranzo, A. Callejo, N. Pardo, A. Navarro, A. Martinez-Marti, J.D. Assaf-Pastrana, E. Felip, P. Garrido
• Journal: Cancers
• Published: 2023;15(24)
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4-8 months. The combination of chemotherapy based on platinum and antifolate is the standard treatment, and the addition of bevacizumab adds two months to median survival. Recently, in first-line treatment, immunotherapy combining nivolumab with ipilimumab has been shown to be superior to chemotherapy in the CheckMate-743 study in terms of overall survival (18.1 months), leading to its approval by the FDA and EMA. The positive results of this study represent a new standard of treatment for patients with MPM; however, not all patients will benefit from immunotherapy treatment. In an effort to improve the selection of patient candidates for immunotherapy for different tumors, biomarkers that have been associated with a greater possibility of response to treatment have been described. MPM is a type of tumor with low mutational load and neo-antigens, making it a relatively non-immunogenic tumor for T cells and possibly less susceptible to responding to immunotherapy. Different retrospective studies have shown that PD-L1 expression occurs in 20-40% of patients and is associated with a poor prognosis; however, the predictive value of PD-L1 in response to immunotherapy has not been confirmed. The purpose of this work is to review the state of the art of MPM treatment in the year 2023, focusing on the efficacy results of first-line or subsequent immunotherapy studies on patients with MPM and possible chemo-immunotherapy combination strategies. Additionally, potential biomarkers of response to immunotherapy will be reviewed, such as histology, PD-L1, lymphocyte populations, and TMB.

In plain English

This article was a narrative review, not a new study. Oncologists in Barcelona and Madrid described the state of treatment for malignant pleural mesothelioma (MPM) in 2023. They focused on published immunotherapy trials and on possible markers of which patients respond. They reported that platinum plus pemetrexed chemotherapy had been the standard treatment for almost two decades. In the CheckMate-743 trial of 605 previously untreated patients, nivolumab plus ipilimumab gave a median overall survival of 18.1 months, compared with 14.1 months for chemotherapy. In the IND.227 trial, adding pembrolizumab to chemotherapy gave a median survival of 17.3 months, compared with 16.1 months for chemotherapy alone. The authors described the predictive role of PD-L1 as unclear. They noted that tumor mutation burden is low in MPM and that higher levels were not linked to better survival in CheckMate-743. They found the role of tumor histology uncertain across trials. They also described experimental approaches, including mesothelin-targeted drugs, vaccines, viruses and CAR-T cells. The authors concluded that new therapies had improved survival but that much work remained. The article did not study asbestos exposure.

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 published and presented clinical trials and biomarker studies on MPM treatment, with emphasis on immunotherapy
• Who was studied: No new patients were studied. The review covered patients with malignant pleural mesothelioma enrolled in the trials it discussed, for example the 605 previously untreated patients with unresectable MPM in CheckMate-743.
• Exposure: Not an asbestos exposure study. Asbestos is mentioned only as the exposure related to MPM. The 'exposures' reviewed were treatments: platinum-pemetrexed chemotherapy, bevacizumab, tumor treating fields, immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab, durvalumab, tremelimumab, avelumab), chemo-immunotherapy combinations, mesothelin-targeted therapies, vaccines, oncolytic viruses and CAR-T cells.
• Main results:
  • As reported for the CheckMate-743 trial, first-line nivolumab plus ipilimumab gave a median overall survival of 18.1 months, compared with 14.1 months for chemotherapy.
  • In CheckMate-743, the 3-year survival rate was 23.2% with immunotherapy and 15.4% with chemotherapy.
  • In CheckMate-743, grade 3 to 4 adverse events occurred in 31% of patients given immunotherapy and 32% of patients given chemotherapy.
  • In CheckMate-743, among patients with non-epithelioid histology, median overall survival was 18.1 months with immunotherapy and 8.8 months with chemotherapy (HR 0.46, 95% CI 0.31 to 0.68).
  • As reported for the IND.227 phase III trial, adding pembrolizumab to chemotherapy gave a median overall survival of 17.3 months, compared with 16.1 months for chemotherapy.
  • The authors described the predictive role of PD-L1 for response to immunotherapy in MPM as unclear, with conflicting results across trials.
  • In an exploratory CheckMate-743 analysis, higher tumor mutation burden did not correlate with better survival in either treatment arm.
  • In CheckMate-743, patients in the nivolumab plus ipilimumab arm with a high four-gene inflammatory signature score had a median overall survival of 21.8 months, compared with 16.8 months for those with low scores.
• The authors' conclusion: The authors concluded that research had led to approval of new therapies that improve survival. They added that there is still a long way to go to optimize first-line treatment and to approve therapies for use after immunotherapy stops working.
• Limitations the authors state:
  • The authors noted that the MARS-2 surgery trial results had not yet been published and should be interpreted with caution.
  • The authors noted that CheckMate-743 was not designed to identify differences by histological subtype.
  • The authors noted that PD-L1 expression was not a stratification factor in CheckMate-743.
  • The authors noted that the PrE0505 genomic analysis came from a small cohort.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Asbestos Exposure, Median Survival, Chemotherapy, Antifolate, Bevacizumab, Nivolumab (Opdivo).

Related studies

• Current and future options for the diagnosis of malignant pleural effusion — F. Rodriguez-Panadero, B. Romero-Romero (2013)
• Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives — S.G. Gray, L. Mutti (2020)
• Immunotherapy for malignant pleural mesothelioma. Current status and future prospects — R.M. Wong, I. Ianculescu, et al. (2014)
• Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future — F. Nicolini, M. Bocchini, et al. (2019)
• Tumour treating fields therapy for glioblastoma: current advances and future directions — O. Rominiyi, A. Vanderlinden, et al. (2021)
• Is immunotherapy a viable option in treating mesothelioma? — D.W. Dumoulin, J.G. Aerts, et al. (2017)

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