Targeted Therapy in Mesotheliomas: Uphill All the Way

Our plain-English summary of Targeted Therapy in Mesotheliomas: Uphill All the Way, by E. Bertoli, E. De Carlo, M. Bortolot, et al (Cancers, 2024).

The study

• Authors: E. Bertoli, E. De Carlo, M. Bortolot, B. Stanzione, A. Del Conte, M. Spina, A. Bearz
• Journal: Cancers
• Published: 2024;16(11)
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

In plain English

This article is a narrative review of research on targeted drug treatments for mesothelioma. It did not study patients or asbestos exposure, and it did not describe how the literature was searched. The authors summarized laboratory and clinical trial evidence for treatments aimed at tumor features such as CDKN2A and MTAP loss, NF2, the enzyme ASS1, the surface protein mesothelin, and BAP1, and they listed ongoing trials. Among the trials described, a phase II/III trial in 249 patients with non-epithelioid pleural mesothelioma reported median overall survival of 9.3 versus 7.7 months when ADI-PEG20 rather than placebo was added to chemotherapy. A trial comparing anetumab ravtansine with vinorelbine in 248 patients found no statistically significant difference. The review described PARP inhibitors used alone as seeming to have limited activity. The authors concluded that there had been relatively few changes in standard practice so far, and that molecular testing should be broadly adopted and clinical trials encouraged.

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 preclinical studies and clinical trials of targeted therapies in mesothelioma, with a table of ongoing trials. No literature search method is described.
• Who was studied: No patients were studied directly. The review covers published studies and trials in mesothelioma (pleural, pericardial or peritoneal), with most data on pleural mesothelioma (MPM).
• Exposure: Asbestos exposure was not studied. The review concerns drug treatments aimed at molecular and cellular features of mesothelioma. Its introduction notes, citing other sources, that about 80% of cases are linked to asbestos fibers.
• Main results:
  • The review described BAP1 as the most commonly altered gene in pleural mesothelioma (about 60% of cases), citing other work.
  • In the cited ATOMIC-meso trial (249 patients with non-epithelioid pleural mesothelioma), adding ADI-PEG20 to platinum and pemetrexed was reported to give median overall survival of 9.3 months versus 7.7 months with placebo (HR 0.71; 95% CI 0.55 to 0.93).
  • In a cited randomized phase II trial of 248 patients with mesothelin-positive mesothelioma, second-line anetumab ravtansine did not show a statistically significant difference from vinorelbine. Overall survival was 9.5 versus 11.6 months (HR 1.07, p = 0.66).
  • In the cited MiST2 trial of abemaciclib in 26 patients with p16ink4A-negative mesothelioma, disease control rates were 54% at 12 weeks and 23% at 24 weeks.
  • In part 2 of the cited tazemetostat trial (61 patients with BAP1-inactivated relapsed or refractory pleural mesothelioma), the disease control rate was 54% at week 12.
  • The authors judged that PARP inhibitors used alone appear to have limited antitumor activity in mesothelioma patients.
  • The authors stated that PI3K inhibition had not yet shown enough signs of clinical activity, and that EGFR-targeted drugs had failed to show significant clinical efficacy in pleural mesothelioma.
• The authors' conclusion: The authors concluded that, despite advances in understanding the biology of mesothelioma, standard clinical practice has changed relatively little so far, and that molecular analysis should be broadly adopted and clinical trials encouraged.

Topics

Medical terms in this study, explained in our Lexicon: Targeted Therapy, Mesothelioma, Platinum-Pemetrexed, Chemotherapy, Immunotherapy, Epithelioid, Histology, Prognosis.

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