Emerging biological therapies for the treatment of malignant pleural mesothelioma

Our plain-English summary of Emerging biological therapies for the treatment of malignant pleural mesothelioma, by A.P. Davis, S.C. Kao, S.J. Clarke, et al (Expert Opinion on Emerging Drugs, 2021).

The study

• Authors: A.P. Davis, S.C. Kao, S.J. Clarke, M. Boyer, N. Pavlakis
• Journal: Expert Opinion on Emerging Drugs
• Published: 2021;26(2):179-192
• Type of article: Review
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options with minimal new therapy approvals for unresectable disease in the past 15 years. However, considerable work has occurred to develop immunotherapies and biomarker driven therapy to improve patient outcomes over this period.Areas covered: This review examines current standard of care systemic therapy in the first- and second line setting. The last 12 months has seen 2 significant trials (Checkmate 743 and CONFIRM) which provide evidence supporting the role of immunotherapy in the management of MPM. Further trials are underway to assess the role of combination chemoimmunotherapy and personalized therapy. Additionally, a large number of clinical trials are ongoing to assess the efficacy of oncoviral, dendritic cell, anti-mesothelin and chimeric antigen receptor T cell therapy in the treatment of MPM.Expert opinion: Recent Phase III trial results have established a role for immunotherapy in the management of MPM. The optimal sequencing and combination of chemotherapy and immunotherapy remains to be determined. Novel therapies for MPM are promising however efficacy remains to be determined and issues remain regarding access to and delivery of these therapies.

In plain English

This article is a review, not a new study. The authors summarized previously reported clinical trials of drug and other treatments for malignant pleural mesothelioma (MPM), a tumor of the pleural lining of the lung. Cisplatin plus pemetrexed chemotherapy, reported in 2003, gave a median survival of 12.1 months, versus 9.3 months on cisplatin alone. In the Checkmate 743 trial, people with unresectable MPM given ipilimumab and nivolumab as first treatment had a median survival of 18.1 months, versus 14.1 months on chemotherapy. In the epithelioid subtype, however, there was no significant difference in survival. In the CONFIRM trial, which included people with pleural or peritoneal mesothelioma after two or more earlier lines of treatment, nivolumab gave a median survival of 9.2 months, versus 6.6 months on placebo. The PROMISE-meso trial, comparing pembrolizumab with chemotherapy, found no survival benefit. The authors concluded that immune checkpoint inhibitors are likely to set a new standard of care. They said the best order and combination of treatments is not yet known, mesothelin-targeted therapy has not succeeded so far, and newer therapies are promising but unproven.

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 and ongoing clinical trials of systemic and novel treatments for malignant pleural mesothelioma
• Who was studied: Previously reported and ongoing clinical trials in patients with malignant pleural mesothelioma (some trials also included peritoneal mesothelioma), mostly with unresectable disease. No search method or number of studies reviewed is stated. At least one cited trial (reference 83) lists review authors Pavlakis and Kao among its authors.
• Exposure: Treatments, not asbestos exposure: chemotherapy (cisplatin or carboplatin with pemetrexed, raltitrexed, vinorelbine, gemcitabine), anti-VEGF drugs (bevacizumab, nintedanib), immune checkpoint inhibitors (tremelimumab, ipilimumab, nivolumab, pembrolizumab, durvalumab, atezolizumab), Tumor Treating Fields, an oncovirus, miRNA, mesothelin-targeted drugs, dendritic cell therapy and CAR-T cells
• Main results:
  • In the 2003 phase III trial reviewed (Vogelzang et al.), cisplatin plus pemetrexed gave a median overall survival of 12.1 months, compared with 9.3 months for cisplatin alone.
  • In the MAPS trial reviewed, adding bevacizumab to platinum and pemetrexed chemotherapy gave a median overall survival of 18.8 months, compared with 16.1 months with standard therapy.
  • In the DETERMINE trial reviewed, tremelimumab compared with placebo in previously treated patients did not show a benefit in median overall survival: 7.7 versus 7.3 months (HR 0.92, 95% CI 0.76 to 1.12, p = 0.41).
  • In the Checkmate 743 trial reviewed, first-line ipilimumab and nivolumab, compared with platinum and pemetrexed chemotherapy in unresectable MPM, gave a median overall survival of 18.1 versus 14.1 months (HR 0.74, 95% CI 0.60 to 0.91, p = 0.002).
  • In Checkmate 743, the authors stated that the survival benefit was largely driven by the non-epithelioid subtype. There was no significant difference in overall survival in the epithelioid subtype. The epithelioid subtype is described as 76% of patients in one place and 75% of cases in another.
  • The CONFIRM trial reviewed enrolled 332 patients with MPM and peritoneal mesothelioma who had 2 or more prior lines of treatment. Those randomized to nivolumab had a median overall survival of 9.2 months, compared with 6.6 months for placebo (HR 0.72, 95% CI 0.55 to 0.94, p = 0.02 in Table 3). The benefit for nivolumab was seen in epithelioid but not in non-epithelioid histology.
  • In the PROMISE-meso trial reviewed (144 patients), pembrolizumab compared with vinorelbine or gemcitabine chemotherapy showed no benefit in overall or progression-free survival. Response rate was 22% with pembrolizumab versus 6% with chemotherapy.
  • In the phase II trial reviewed comparing the mesothelin-targeted drug anetumab ravtansine with vinorelbine, there was no significant difference in median progression-free survival (4.3 versus 4.5 months).
  • In the single-arm phase 2 STELLAR trial reviewed (80 untreated patients), Tumor Treating Fields with platinum and pemetrexed chemotherapy gave a median overall survival of 18.2 months.
• The authors' conclusion: The authors concluded that the Checkmate 743 and CONFIRM results with immune checkpoint inhibitors are likely to establish a new standard of care in first- and second-line treatment, with uptake depending on reimbursement and cost. They said the best sequencing and combination with chemotherapy is yet to be determined, that mesothelin-targeted therapy has not been successful to date, and that novel therapies are promising but their efficacy remains to be determined.
• Limitations the authors state:
  • The authors noted that the CONFIRM trial used a placebo comparison, which may not be standard of care in the second-line setting.
  • The authors noted that the Tumor Treating Fields device has not been validated in phase III trials.
  • The authors described novel approaches targeting mesothelin or the immune response as immature to date.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Unresectable, Biomarker, Systemic Therapy, CheckMate 743, Immunotherapy, Clinical Trial, Mesothelin.

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• Approved and emerging treatments of malignant pleural mesothelioma in elderly patients — G.L. Ceresoli, A. Rossi (2019)
• Emerging therapies in malignant pleural mesothelioma — M. Cinausero, K. Rihawi, et al. (2019)
• Immune therapies for malignant mesothelioma — S.A. Antoniu, G. Dimofte, et al. (2014)
• Chemotherapy and targeted therapies for unresectable malignant mesothelioma — R.J. Kelly, E. Sharon, et al. (2011)
• Therapies currently in Phase II trials for malignant pleural mesothelioma — G. Pinton, A.G. Manente, et al. (2013)

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