Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis

Our plain-English summary of Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis, by M. Gemelli, D.L. Cortinovis, A. Baggi, et al (Cancers, 2022).

The study

• Authors: M. Gemelli, D.L. Cortinovis, A. Baggi, P. di Mauro, S. Calza, A. Berruti, S. Grisanti, M. Rota
• Journal: Cancers
• Published: 2022;14(24)
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p < 0.001 and p = 0.006, respectively) or anti CTLA-4 (p < 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13−27%) and 56% (95% CI 45−67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted.

In plain English

This systematic review and meta-analysis pooled results from 17 clinical trials (2328 patients with pleural mesothelioma) testing immune checkpoint inhibitor drugs: anti-PD-1/PD-L1, anti-CTLA-4, or both, some with chemotherapy. Asbestos exposure was not studied. For treated patients, pooled 12-month survival was 53% (95% CI 44–61%): 66% (61–70%) with combined treatments, 51% (45–57%) with single-agent anti-PD-1/PD-L1 and 40% (27–54%) with anti-CTLA-4. Pooled response and disease control rates were 20% (95% CI 13–27%) and 56% (45–67%), neither differing significantly between combined and single-agent anti-PD-1/PD-L1 treatment. Combined treatment gave significantly higher response and disease control as a first treatment, but 12-month survival and 6-month progression-free rates did not differ significantly between first and later lines. Side effects of any grade occurred in 87% (95% CI 77–97%) of patients on combined treatment versus 82% (74–90%) on single agents (p = 0.01). With anti-PD-1/PD-L1 or combination treatment, PD-L1-positive patients had higher odds of response than PD-L1-negative patients (odds ratio 2.24, 95% CI 1.27–4.12). The authors concluded that efficacy was independent of treatment line, and noted that most included trials had no comparison arm.

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 of published clinical trials (phase I, II and III) and congress abstracts
• Who was studied: 17 clinical trials including 2328 patients with pleural mesothelioma. The trials were found in Medline/PubMed and EMBASE among English-language studies published between 2005 and 30 April 2021, plus three conference abstracts.
• Exposure: Immune checkpoint inhibitor drugs: anti-PD-1/PD-L1 and anti-CTLA-4, given alone, combined, or with chemotherapy. Asbestos exposure was not studied.
• Main results:
  • The pooled 12-month overall survival estimate for patients on checkpoint inhibitor treatments was 53% (95% CI 44–61%). By treatment type, it was 66% (95% CI 61–70%) with combination treatments, 51% (95% CI 45–57%; p < 0.0001) with single-agent anti-PD-1/PD-L1, and 40% (95% CI 27–54%; p < 0.0001) with anti-CTLA-4.
  • The pooled 6-month progression-free survival estimate was 19% (95% CI 13–25%) overall. It was 29% (95% CI 24–33%) with combination treatment, 16% (95% CI 12–20%; p = 0.006) with single-agent anti-PD-1/PD-L1, and 5% (95% CI 1–12; p < 0.0001) with anti-CTLA-4.
  • The pooled overall response rate for all checkpoint inhibitor treatments was 20% (95% CI 13–27%). The pooled disease control rate was 56% (95% CI 45–67%).
  • Response and disease control rates were not statistically significantly different between combined and single-agent anti-PD-1/PD-L1 treatments (p = 0.088 and p = 0.058).
  • With combination treatment, response and disease control rates were significantly higher in first-line than in later-line treatment (p < 0.0001 and p = 0.0112). The 12-month overall survival and 6-month progression-free survival rates did not differ significantly by line (p = 0.0545 and p = 0.1464).
  • Among patients on anti-PD-1/PD-L1 or combination treatments, PD-L1-positive patients had an odds ratio of response of 2.24 (95% CI 1.27, 4.12) compared with PD-L1-negative patients.
  • Compared with PD-L1-negative patients, PD-L1-positive patients had a hazard ratio for death of 0.71 (95% CI 0.52–0.96) and for disease progression of 0.72 (95% CI 0.55–0.95).
  • The pooled rate of adverse events of any grade was 84% overall. It was 87% (95% CI 77–97%) with combined treatment versus 82% (95% CI 74–90%, p = 0.01) with single agents. Grade 3–4 adverse events occurred in 24% overall: 28% with combinations and 22% with monotherapies.
• The authors' conclusion: The authors concluded that both combined and single-agent checkpoint inhibitors showed activity in any line of treatment, and that efficacy was independent of the line of treatment. They added that superiority over standard treatment remains questionable because no direct comparison could be made.
• Limitations the authors state:
  • Most included studies lacked a comparison arm. As a result, checkpoint inhibitors could not be compared with single-agent chemotherapy, and no network meta-analysis could be done.
  • Duration of response could not be pooled in the meta-analysis.
  • Trials used different criteria for judging response, and some cases had no independent assessment.
  • Activity in previously treated patients could not be evaluated by histologic subtype, because few studies reported those data.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Pleural Mesothelioma, Systematic Review, Meta-Analysis, Clinical Trial, PD-L1, CTLA-4, PD-1/PD-L1.

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