Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment

Our plain-English summary of Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment, by Y. Yoshikawa, K. Kuribayashi, T. Minami, et al (Frontiers in Oncology, 2020).

The study

• Authors: Y. Yoshikawa, K. Kuribayashi, T. Minami, M. Ohmuraya, T. Kijima
• Journal: Frontiers in Oncology
• Published: 2020;10:554570
• Type of article: Review
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.

Copyright © 2020 Yoshikawa, Kuribayashi, Minami, Ohmuraya and Kijima.

In plain English

This was a review article. It reported no new data of its own. Instead, it summarized published research on malignant pleural mesothelioma, a cancer the authors describe as strongly associated with occupational or environmental asbestos exposure. No specific asbestos fiber types were discussed. The review covered two topics. The first was gene mutations and epigenetic changes, which are chemical changes that switch genes on or off without altering the DNA sequence. The second was treatment with immune checkpoint inhibitor drugs. One cited study of 158 mesothelioma cases reported that DNA methylation status was significantly related to asbestos body burden and to patient survival. In the cited MERIT trial in Japan, nivolumab given after earlier chemotherapy produced a 29% objective response rate and a median survival of 17.3 months. A cited Dutch trial of the same drug reported 24% and 11.8 months. A cited placebo-controlled trial of vorinostat in 661 patients did not improve overall survival. The authors concluded that immunotherapy is expected to improve outcomes but does not work in every patient. They said reliable biomarkers are needed to select the patients who may benefit.

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 laboratory studies and clinical trials; no new data collected by the authors
• Who was studied: No study population of its own; the review drew on published studies of malignant pleural mesothelioma patients, tumor samples, cell lines and mice
• Exposure: Asbestos exposure in general (occupational or environmental), mentioned as background; no fiber types named. The review's focus was genetic and epigenetic changes in the tumors and drug treatments (chemotherapy, epigenetic drugs, immune checkpoint inhibitors)
• Main results:
  • Cited research: inactivating mutation of the CDKN2A gene occurs in approximately 70% or more of malignant pleural mesothelioma cases
  • Cited research: the overall frequency of BAP1 gene alterations in malignant pleural mesothelioma is reported to be approximately 57%
  • Cited study (Christensen et al., 158 mesothelioma cases and 18 normal pleura samples): methylation status was significantly related with asbestos body burden and patient survival
  • Cited study (Yogelzang et al.): a 17% overall response rate in 41 mesothelioma patients given dihydro-5-azacytidine, a DNA methyltransferase inhibitor
  • Cited trial (Krug et al., 661 patients: vorinostat n=329, placebo n=332): vorinostat as second- or third-line therapy did not improve overall survival, 30.7 weeks (95% CI: 26.7–36.1) on vorinostat versus 27.1 weeks (95% CI: 23.1–31.9) on placebo
  • Cited research: median overall survival was 5.0 months in PD-L1-positive patients versus 14.5 months in PD-L1-negative patients; PD-L1 positivity was reported as an independent risk factor for survival (risk ratio 1.71, 95% CI: 1.03–2.78, p = 0.04)
  • Cited KEYNOTE-028 trial (pembrolizumab alone, patients with PD-L1 TPS of 1% or more): objective response rate 20%, disease control rate 76%, median progression-free survival 5.8 months, median survival 18.0 months
  • Cited NivoMes trial (nivolumab, single institution in the Netherlands): objective response rate 24%, disease control rate 47%, median progression-free survival 2.6 months, 6-month survival 74%, median survival 11.8 months
  • Cited MERIT trial (nivolumab, multicenter, Japan): objective response rate 29%, disease control rate 68%, median progression-free survival 6.1 months, 6-month survival 85%, median survival 17.3 months; nivolumab was then approved in Japan for recurrent mesothelioma after chemotherapy
  • Cited trials (NIBIT-MESO, MAPS-2, INITIATE) of anti-CTLA-4 combined with anti-PD-1/PD-L1 antibodies in recurrent mesothelioma: objective response rate 26 to 29% and disease control rate 50 to 68%
• The authors' conclusion: The authors concluded that immunotherapy with immune checkpoint inhibitors is generally well tolerated and is expected to improve outcomes. They added that it does not help in all cases, citing the negative PROMISE-meso trial. In their view, reliable predictive biomarkers are needed to select patients, and further study of mesothelioma cells and epigenetic alterations may help identify such biomarkers.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, checkpoint inhibitors, Pleural Mesothelioma, Asbestos Exposure, Mesothelial Cells, Pleural Cavity, Unresectable, Chemotherapy.

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