Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

Our plain-English summary of Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress, by M. Perrino, F. De Vincenzo, N. Cordua, et al (Frontiers in Immunology, 2023).

The study

• Authors: M. Perrino, F. De Vincenzo, N. Cordua, F. Borea, M. Aliprandi, A. Santoro, P.A. Zucali
• Journal: Frontiers in Immunology
• Published: 2023;14:1121557
• Type of article: Review
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient's selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated. In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.

Copyright © 2023 Perrino, De Vincenzo, Cordua, Borea, Aliprandi, Santoro and Zucali.

In plain English

This article was a review of published clinical trials of immune checkpoint inhibitor drugs in malignant mesothelioma, and of research on markers that might predict which patients respond. It reported no new patient data and did not study asbestos exposure. Its introduction noted that asbestos exposure accounts for 80% of cases. Among the trials reviewed, CheckMate 743 (605 patients with unresectable disease) reported median overall survival of 18.1 months with nivolumab plus ipilimumab versus 14.1 months with chemotherapy, with a larger difference in non-epithelioid tumors. In the CONFIRM trial, nivolumab improved survival over placebo in previously treated patients. In PROMISE-meso, pembrolizumab did not significantly improve progression-free survival compared with chemotherapy. The authors described the evidence on tumor subtype, PD-L1 levels and tumor mutational burden as predictors as inconclusive, and noted that mesotheliomas usually had a low mutational burden. They described genetic and immune-cell features, such as an inflammatory gene signature, as possible markers that still need prospective validation. The authors concluded that knowledge of what drives response to these drugs is limited.

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 clinical trials and laboratory and genomic studies (not an original study)
• Who was studied: No study population of its own; the review covered published trials of immune checkpoint inhibitors in patients with malignant mesothelioma, ranging from 29 to 605 patients per trial, plus biomarker studies
• Exposure: Not an asbestos exposure study. The review covered treatment with immune checkpoint inhibitor drugs (tremelimumab, pembrolizumab, nivolumab, avelumab, durvalumab, ipilimumab), alone, in combination, or with chemotherapy. The introduction states that asbestos exposure accounts for 80% of mesothelioma cases.
• Main results:
  • Reviewed trial CheckMate 743 (first-line, 605 patients): nivolumab plus ipilimumab gave median overall survival of 18.1 months versus 14.1 months with platinum-pemetrexed chemotherapy (HR 0.74; p=0.0020)
  • In CheckMate 743, non-epithelioid tumors had median overall survival of 18.1 months with immunotherapy versus 8.8 months with chemotherapy (HR 0.46, 95% CI 0.31 to 0.68). Epithelioid tumors had 18.7 versus 16.5 months (HR 0.86, 95% CI 0.69 to 1.08).
  • Reviewed trial CONFIRM (332 previously treated patients): nivolumab improved progression-free survival (HR 0.67; p=0.0012) and overall survival (HR 0.69; p=0.0090) compared with placebo
  • Reviewed trial PROMISE-meso (144 previously treated patients): median progression-free survival was 2.5 months with pembrolizumab versus 3.4 months with chemotherapy (HR 1.06; p=0.76), not a statistically significant improvement
  • In the CONFIRM and PROMISE-meso trials, PD-L1 expression of at least 1% was not related to progression-free or overall survival. The authors described the predictive role of PD-L1 as unclear.
  • In the mesothelioma group of the KEYNOTE-158 trial, only 1 of 85 evaluable cases had high tumor mutational burden. Mesotheliomas usually have a low average mutational burden of around 2 mutations per megabase.
  • In an exploratory analysis of CheckMate 743, a high four-gene inflammatory signature score was associated with median overall survival of 21.8 months versus 16.8 months with a low score, in the nivolumab plus ipilimumab arm
• The authors' conclusion: The authors concluded that, despite recent progress in treatment, knowledge of the factors behind response to immune checkpoint inhibitors in mesothelioma is limited, and that biomarkers are needed to guide patient selection
• Limitations the authors state:
  • The authors noted that the inflammatory gene signature data from CheckMate 743 require prospective validation
  • The authors noted that PD-L1 status was not a stratification factor in CheckMate 743, so the PD-L1 findings there are purely descriptive

Topics

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

Medical terms in this study, explained in our Lexicon: Immunotherapy, checkpoint inhibitors, Biomarker, Mesothelioma, Neoplasm, Prognosis, Unresectable, Pemetrexed (Alimta).

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