Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology

Abstract

In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting “pleural mesothelioma” as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.

True Benefits of Immune Checkpoint Inhibitors in the Treatment of Malignant Pleural Mesothelioma in Japan

“…Therefore, while we can agree that the effort [27] to use the existing clinical trial data and FDA approval to propose that the appropriate balance between the economic impact of new cancer drugs and the actual benefit to patients is important, the findings [28] suggesting that the statistical robustness of the three randomized clinical trials (the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate 743 study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed) of front-line treatments recommended for MPM since 2004, using the Survival-Inferred Fragility Index, make it impossible to draw conclusions about the survival benefit of the three trials from virtual comparison, posing a significant obstacle to understanding in Japan.…”

Mesothelioma in the pleura, pericardium and peritoneum: Recommendations from the International Collaboration on Cancer Reporting (ICCR)

“…83,84 Even when experts agree on the general diagnosis of mesothelioma, the agreement on histological subtype (which now determines therapy) is moderate at best, but this can inform stratification of patients into clinical trials and ultimately affect the clinical trial outcomes. [85][86][87] Deep learning approaches for subtyping remain to be explored more fully, but the initial work has been promising. 28 The recognition of subtypes of mesothelioma that are characterised by molecular alterations, some of them actionable, places additional responsibility on the pathologist, as appropriate therapy may result in significant outcome benefit for the patient.…”

“…Because of the rarity of mesothelioma, difficulties in making the diagnosis remain, including distinguishing it from benign conditions, and significant changes on diagnostic category (benign/malignant) on expert review are reported as being in the order of 3% 83,84 . Even when experts agree on the general diagnosis of mesothelioma, the agreement on histological subtype (which now determines therapy) is moderate at best, but this can inform stratification of patients into clinical trials and ultimately affect the clinical trial outcomes 85–87 . Deep learning approaches for subtyping remain to be explored more fully, but the initial work has been promising 28 …”

Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling

“…Malignant Pleural Mesothelioma (MPM) is a lethal cancer with few therapeutic options, which makes the identification of novel actionable targets and molecules for improved care urgent [ 1 ]. A possible strategy for accelerating this process could consist in repositioning known and already approved drugs for novel uses.…”