The Predictive and Prognostic Nature of Programmed Death-Ligand 1 in Malignant Pleural Mesothelioma: A Systematic Literature Review

Our plain-English summary of The Predictive and Prognostic Nature of Programmed Death-Ligand 1 in Malignant Pleural Mesothelioma: A Systematic Literature Review, by A.S. Mansfield, R.J. Brown, C. Sammon, et al (JTO Clinical and Research Reports, 2022).

The study

• Authors: A.S. Mansfield, R.J. Brown, C. Sammon, M.J. Daumont, M. McKenna, J.K. Sanzari, P.M. Forde
• Journal: JTO Clinical and Research Reports
• Published: 2022;3(5):100315
• Type of article: Review
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti-programmed death (ligand) 1 (PD-[L]1) therapies.

Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies.

Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti-PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti-PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti-PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups.

Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM.

© 2022 The Authors.

In plain English

This article was a systematic review of published research. The authors searched two medical databases for studies of adults with malignant pleural mesothelioma reporting outcomes by tumor levels of PD-L1, a protein measured by tissue staining. They included 29 studies published from 2014 to 2020, covering 3162 patients in total. Asbestos exposure was not studied. Among studies in which patients were not specified to have received immunotherapy targeting PD-1 or PD-L1, 10 of 16 with a statistical test reported a significantly higher risk of death with PD-L1-positive tumors (hazard ratios 1.10 to 3.91). The other six did not report significant differences. Among six studies of patients given these drugs, one found a lower risk of death with PD-L1-positive tumors (hazard ratio 0.16, 95% confidence interval 0.04 to 0.73), and five found no statistically significant difference. The one randomized trial comparing pembrolizumab with chemotherapy within PD-L1 subgroups did not find statistically significant differences in overall or progression-free survival between treatments. The authors concluded the evidence was not sufficient to influence clinical decisions and called for higher-quality studies. They noted the studies were small, mostly observational, and varied in how PD-L1 was measured.

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: Systematic literature review of published randomized trials and observational studies (no meta-analysis was performed); the 29 included studies were 24 observational and 5 interventional (3 nonrandomized, 2 randomized)
• Who was studied: 29 published studies, from 2014 to 2020, of adult patients with malignant pleural mesothelioma (MPM); 3162 patients in total, with individual study sizes from 10 to 329; MEDLINE and EMBASE searched until November 4, 2020
• Exposure: Not an asbestos exposure study. The factor examined was tumor PD-L1 expression measured by immunohistochemistry, in patients treated with or without anti-PD-1/PD-L1 immunotherapy (nivolumab, pembrolizumab, ipilimumab, durvalumab plus tremelimumab) or chemotherapy.
• Main results:
  • Studies in patients not treated with immunotherapy: of 16 studies giving a statistical assessment of overall survival, six did not report significant differences.
  • Studies in patients not treated with immunotherapy: 10 studies reported a statistically significantly higher risk of death in patients with PD-L1-positive tumors than in those with PD-L1-negative tumors (hazard ratios ranging from 1.10 to 3.91).
  • Studies in patients treated with immunotherapy (six studies): one study reported a statistically significant lower risk of death in patients with PD-L1-positive tumors compared with PD-L1-negative tumors (HR 0.16, 95% CI 0.04 to 0.73, p = 0.007).
  • Studies in patients treated with immunotherapy: in the other five studies, differences in survival were not statistically significant, though the estimates pointed toward longer survival with PD-L1-positive tumors (HR range 0.54 to 0.84).
  • PROMISE-meso randomized trial (144 patients, pembrolizumab versus gemcitabine or vinorelbine): no statistically significant difference in overall survival or progression-free survival between treatment arms within PD-L1 subgroups (less than 1%, 1% or more, less than 20%, 20% or more). For example, overall survival HR was 0.96 (95% CI 0.53 to 1.75) for PD-L1 less than 1%, and 1.09 (95% CI 0.57 to 2.09) for PD-L1 1% or more.
• The authors' conclusion: The authors concluded that, although further investigation of PD-L1 in MPM may be warranted, the current evidence is not sufficient to influence clinical decision-making. They called for further high-quality studies, especially randomized trials.
• Limitations the authors state:
  • The included studies were small and, in the authors' words, observational in nature (24 of the 29 included studies were observational).
  • The findings may reflect differences between studies in patient characteristics and in how PD-L1 was measured (assays, antibody clones, cutpoints, cell types, timing).
  • The review assumed that the 15 studies not specifying treatment did not include patients given PD-1 or PD-L1-targeted therapies.
  • Comparisons across studies may be biased, and only one study directly compared treated and untreated patients with similar PD-L1 status.
  • Because of the limitations of the evidence base, no meta-analysis was done.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Systematic Review, PD-L1, Biomarker.

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• Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation — A.J. Currie, A. Prosser, et al. (2009)
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