Immunotherapy for pleural mesothelioma: from innovation to the frontlines of core clinical questions

Our plain-English summary of Immunotherapy for pleural mesothelioma: from innovation to the frontlines of core clinical questions, by T. Yoshida, K. Kuribayashi (Discover Oncology, 2025).

The study

• Authors: T. Yoshida, K. Kuribayashi
• Journal: Discover Oncology
• Published: 2025;17(1):43
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

In August 2018, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) became the first in the world to approve immune checkpoint inhibitor (ICI) monotherapy with nivolumab for previously treated, unresectable, advanced, or recurrent pleural mesothelioma (PM), setting a global precedent. Subsequently, in October 2020, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab and ipilimumab (CheckMate 743 trial) as the first-line treatment for unresectable PM. This marked the first update to standard first-line therapy in approximately 15 years since the approval of cisplatin (CDDP) plus pemetrexed (PEM) based on the EMPHACIS trial in 2004. Most recently, in September 2024, the FDA approved pembrolizumab plus platinum and PEM (KEYNOTE-483 trial) as another first-line option for advanced or metastatic PM. These developments underscore the rapid evolution of systemic therapy for PM. However, several urgent clinical questions have emerged in real-world practice. This article aims to address these issues based on the latest evidence and expert insights.

© 2025. The Author(s).

In plain English

This article was a narrative review, not a new study. It looked at published trials and real-world reports on immune-based drug treatment for pleural mesothelioma that could not be removed by surgery, organized around five clinical questions. It did not address asbestos exposure. For the CheckMate 743 trial, the authors reported median overall survival of 18.1 versus 14.1 months for nivolumab plus ipilimumab versus chemotherapy (hazard ratio 0.74, 95% CI 0.60 to 0.91). For the KEYNOTE-483 trial, they reported 17.3 versus 16.1 months for pembrolizumab plus platinum and pemetrexed versus chemotherapy (hazard ratio 0.79, 95% CI 0.63 to 0.99). In non-epithelioid disease, CheckMate 743 showed 18.1 versus 8.8 months. In epithelioid disease, survival gains were not statistically significant in either trial. A Dutch real-world study suggested platinum-pemetrexed still worked after nivolumab plus ipilimumab. PD-L1 testing did not reliably predict benefit. The authors concluded that nivolumab plus ipilimumab suits non-epithelioid disease and fit patients, and that pembrolizumab plus chemotherapy suits epithelioid or frail patients needing rapid control. They called the real-world findings, post-progression strategies and higher Japanese response rates hypothesis-generating.

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, real-world studies and guidelines
• Who was studied: No patients were studied directly. The review covered published trials and real-world cohorts of patients with unresectable pleural mesothelioma, including CheckMate 743 (N 605), KEYNOTE-483 (N 440), KEYNOTE-A17 (N 18, Japanese), JME-001 (N 20, Japanese), and real-world cohorts from Japan, France, Latin America, Australia and the Netherlands.
• Exposure: The 'exposures' were treatments, not asbestos. These were immune checkpoint inhibitors (nivolumab plus ipilimumab; pembrolizumab plus platinum and pemetrexed; nivolumab alone) and platinum-pemetrexed chemotherapy. Asbestos exposure was not discussed.
• Main results:
  • CheckMate 743, whole trial population (as summarized by the authors): median overall survival was 18.1 vs 14.1 months, nivolumab plus ipilimumab vs chemotherapy, with hazard ratio 0.74 (95% CI 0.60 to 0.91).
  • KEYNOTE-483, whole trial population (as summarized by the authors): median overall survival was 17.3 vs 16.1 months, pembrolizumab plus platinum and pemetrexed vs chemotherapy, with hazard ratio 0.79 (95% CI 0.63 to 0.99).
  • Non-epithelioid pleural mesothelioma in CheckMate 743: median overall survival was 18.1 vs 8.8 months, hazard ratio 0.46 (95% CI 0.31 to 0.68).
  • Epithelioid pleural mesothelioma: the overall survival benefit was not statistically significant in either trial. CheckMate 743 showed 18.7 vs 16.5 months (HR 0.86). KEYNOTE-483 showed 19.8 vs 18.2 months (HR 0.89).
  • FLORA real-world Dutch study (n = 277 in the table): platinum-pemetrexed given after nivolumab plus ipilimumab produced an overall response rate of 37%, median progression-free survival of 5.6 months and median overall survival of 8.2 months. The authors noted this progression-free survival was similar to historical first-line chemotherapy.
  • PD-L1 in CheckMate 743: no statistically significant interaction was found between PD-L1 status and treatment effect. The authors described PD-L1 as not a robust predictive biomarker.
  • Japanese trials reported higher response rates than the multinational trials: 74% in KEYNOTE-A17 and 78% in JME-001. The authors regarded these differences as hypothesis-generating.
• The authors' conclusion: The authors concluded that nivolumab plus ipilimumab is most appropriate for non-epithelioid pleural mesothelioma and fit patients. They saw pembrolizumab plus chemotherapy as a complementary option for epithelioid or frail patients needing rapid disease control. They also concluded that treatment choice should integrate histology, tumor burden, immune features and patient frailty.
• Limitations the authors state:
  • The authors cautioned that the two main trials should not be compared directly with each other.
  • The real-world studies differed in design and population, so the authors treated their findings as hypothesis-generating.
  • The FLORA findings on chemotherapy after immunotherapy were observational and need prospective confirmation.
  • The proposed strategies after progression on KEYNOTE-483 were described as hypothesis-generating, not standard practice recommendations.
  • The KEYNOTE-483 PD-L1 analyses were conference data that had not been peer-reviewed.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Pleural Mesothelioma, checkpoint inhibitors, Nivolumab (Opdivo), Unresectable, Ipilimumab (Yervoy), CheckMate 743, First-line Therapy.

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