Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis

Our plain-English summary of Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis, by A. Zafar, A.A. Rashid, A. Moeed, et al (BMC Cancer, 2024).

The study

• Authors: A. Zafar, A.A. Rashid, A. Moeed, M.J. Tahir, A.J. Khan, O.N. Shrateh, A. Ahmed
• Journal: BMC Cancer
• Published: 2024;24(1):1353
• Type of article: Systematic review, Meta-analysis
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is an aggressive cancer with poor prognosis. Programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have recently presented as a viable option in some first line but primarily as a second-line treatment of advanced-stage malignant mesothelioma (asMM). Therefore, this systematic review and meta-analysis aims to assess the safety and efficacy of PD-1/L-1 ICIs in advanced-stage malignant mesothelioma.

Methods: PubMed, Scopus, and Cochrane databases were searched for all studies assessing the safety and efficacy of anti PD-1/PD-L1 agents. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were median progression free (mPFS) and overall survival (mOS). Safety outcomes were treatment- (TRAEs) and immune-related adverse events (IRAEs). A random-effects meta-analysis was performed to pool medians and to derive event rates.

Results: A total of 15 studies were included with total of 1064 asMM patients. ORR and DCR were 16% and 57%, respectively. A pooled mPFS was 4.53 (CI: 3.40-5.65) and mOS was 10.51 (CI: 9.03-12.00). Overall TRAEs had an event rate of 0.69 (0.50-0.83) whereas IRAEs had an event rate of 0.28 (0.15-0.46). There were no significant differences between pembrolizumab, nivolumab primarily, and avelumab subgroups for all the outcomes. Additionally, meta-regression found no covariate to be a significant factor in ORR and DCR.

Conclusion: In this meta-analysis we found that anti-PD1/PD-L1 treatment could be useful in pretreated asMM as they had at least comparable or greater mPFS, mOS, ORR, and DCR than other second-line agents currently being used.

Registration Number: This systematic review was registered at PROSPERO prior to the literature search, CRD42023442350.

© 2024. The Author(s).

In plain English

This systematic review and meta-analysis pooled earlier studies. The authors searched three databases up to July 2023 for studies of PD-1 or PD-L1 inhibitors given alone in pretreated advanced-stage malignant mesothelioma. They included 15 studies; the Results count 1,133 patients, the abstract 1,064. Seven were retrospective cohorts and eight were clinical trials, two of them randomized. Across 13 studies each, pooled objective response was 0.16 (95% CI 0.13 to 0.20) and disease control 0.57 (0.49 to 0.65). Pooled median progression-free survival was 4.53 months (3.40 to 5.65). Pooled median overall survival was 10.51 (9.03 to 12.00) in the Results but 10.80 months (9.26 to 12.35) in the Discussion. Treatment-related side effects had a pooled event rate of 0.69 (0.50 to 0.83) at any grade and 0.15 (0.10 to 0.23) at grades 3 to 5. Survival did not differ significantly between drugs. The authors concluded these drugs could be useful for such patients. Limitations they noted included no comparison group and missing asbestos-exposure data. They called most studies retrospective, though their own count was seven of 15.

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 review and meta-analysis (single-arm, no comparator) of published studies: randomized trials, phase 2 and phase 1b trials, and retrospective cohorts
• Who was studied: 15 studies of patients with advanced-stage malignant mesothelioma, nearly all previously treated and mostly with pleural mesothelioma, found in databases searched from inception to July 2023. The Results report 1,133 patients and the abstract reports 1,064. Mean patient age was 66.8 years and 74.5% were male.
• Exposure: Treatment with PD-1 or PD-L1 immune checkpoint inhibitor drugs given alone: pembrolizumab, nivolumab, avelumab and durvalumab. This is not a study of asbestos exposure.
• Main results:
  • Pooled objective response rate across 13 studies: 0.16 (95% CI 0.13 to 0.20)
  • Pooled disease control rate across 13 studies: 0.57 (0.49 to 0.65)
  • Pooled median progression-free survival across 13 studies: 4.53 (3.40 to 5.65), with high heterogeneity (I2 = 88%). No difference was found between the pembrolizumab, nivolumab and avelumab subgroups.
  • Pooled median overall survival across 14 studies: 10.51 (9.03 to 12.00) in the Results. The Discussion gives 10.80 (9.26 to 12.35). No significant difference was found between drug subgroups.
  • Overall survival event rate was 0.70 at 6 months (95% CI 0.60 to 0.79) and 0.44 at 12 months (0.37 to 0.51)
  • Treatment-related adverse events of grade 1 to 5 (nine studies): event rate 0.69 (0.50 to 0.83). Grade 3 to 5: 0.15 (0.10 to 0.23).
  • Immune-related adverse events: event rate 0.28 (0.15 to 0.46) for grade 1 to 5, and 0.05 (0.03 to 0.11) for grade 3 to 5
  • In meta-regression (mean age, male percentage, PD-1 positive percentage, ECOG 0 percentage), no covariate significantly predicted objective response rate or disease control rate
• The authors' conclusion: The authors concluded that anti-PD-1/PD-L1 agents could be useful in pretreated advanced-stage malignant mesothelioma, regardless of currently known predictive factors. They judged response and survival at least comparable to other second-line agents. That comparison was made against other published studies, not within this analysis.
• Limitations the authors state:
  • Single-arm meta-analysis with no comparator group
  • Moderate heterogeneity in several outcomes, which the authors attribute to the retrospective nature of the studies
  • Only three major databases were searched; EMBASE and PsycINFO were not accessible
  • The authors state that most included studies were retrospective cohorts, which could add bias. Their own breakdown, however, gives seven retrospective cohorts out of 15 studies.
  • Most studies did not report patients' asbestos exposure
  • Meta-regression by tumor histology was not possible for lack of data

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-1/PD-L1, checkpoint inhibitors, Mesothelioma, Systematic Review, Meta-Analysis, Prognosis, PD-L1, Overall Survival.

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