Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma

ABSTRACT

Introduction: Malignant mesothelioma is a rare and lethal malignancy primarily affecting the pleura and peritoneum. Mesothelioma incidence is expected to increase worldwide and current treatments remain ineffective, leading to poor prognosis. Within this article potential targets to improve the quality of life of the patients and assessment of further avenues for research are discussed.

Areas covered: This review highlights emerging therapies currently under investigation for malignant mesothelioma with a specific focus on phase I and phase II clinical trials. Three main areas are discussed: immunotherapy (immune checkpoint blockade and cancer vaccines, among others), multitargeted therapy (such as targeting pro-angiogenic genes) and gene therapy (such as suicide gene therapy). For each, clinical trials are described to detail the current or past investigations at phase I and II.

Expert opinion: The approach of applying existing treatments from other cancers does not show significant benefit, with the most promising outcome being an increase in survival of 2.7 months following combination of chemotherapy with bevacizumab. It is our opinion that the hypoxic microenvironment, the role of the stroma, and the metabolic status of mesothelioma should all be assessed and characterised to aid in the development of new treatments to improve patient outcomes.

KEYWORDS:

• Malignant mesothelioma
• immunotherapy
• targeted therapy and gene therapy

Article highlights

• Since the success of immune checkpoint inhibitors and cancer vaccines approved by the FDA for the treatment of cancers such as melanoma, immunotherapy may be evaluated as a third-line therapy for cancer treatment after conventional treatments and targeted agents.

• Mesothelin is one of the main targets in immunotherapeutic approaches but the efficacy of this strategy is still poor.

• CTLA-4 and PD1/L1 blockage are widely investigated in numerous clinical trials as single or combined therapy in mesothelioma patients but the outcome is still unsatisfactory

• Main targeted therapies against EGFR and VEGFA/VEGFR showed no clinical activity in mesothelioma patients and only slightly promising results have been shown in patients treated with bevacizumab in combination with chemotherapy.

• It is our belief that to improve current therapies the role of the hypoxic microenvironment and influence of the stroma in chemoresistance should be further characterised, in addition to uncovering the extent of metabolic reprogramming that occurs in tumours cells.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded