Review on clinical trials of targeted treatments in malignant mesothelioma

Abstract

Purpose

Malignant mesothelioma (MM) is an aggressive tumor of the serosal surfaces with a poor prognosis. Advances in the understanding of tumor biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. This article is a comprehensive review of all clinical trials evaluating the effect of targeted treatments in MM.

Methods

An extensive literature search was performed in January 2011 using pubmed and medline. No constraints on publication date were applied.

Results

Thirty-two trials exploring 17 different targeted agents in MM were found. Treatment in first- and second-line targeted agents induced response rates ranging from 0–14% and 0–16%, respectively. The tyrosine kinase inhibitor sunitinib induced partial response in 10% and stable disease in 66% of MPM patients as second-line treatment. A preliminary analysis of a phase II/III trial suggests that addition of bevacizumab to pemetrexed and cisplatin first-line treatment significantly improves disease control (CR + PR + SD) in the bevacizumab arm (73.5%) compared with treatment with pemetrexed and cisplatin without bevacizumab (43.2%) (P = 0.010). Another phase II trial did not observe any significant clinical benefit of adding of bevacizumab to gemcitabine and cisplatin.

Conclusions

Disease stabilization is reported in some patients with several targeted treatments and might be beneficial in subgroups of patients or in combination with classic chemotherapy. None of the hitherto explored targeted treatments can currently be recommended as standard treatment in MM.

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Abbreviations

ABL:

Abelson murine leukemia viral oncogene homolog

AKT:

A member of the non-specific serine/threonine-protein kinase family

ALK:

Anaplastic lymphoma kinase

BCR:

Breakpoint cluster region

CALGB:

Cancer and leukemia group B

c-KIT:

V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

CML:

Chronic myeloid leukemia

CR:

Complete response

EGF:

Endothelial growth factor

EGFR:

Endothelial growth factor receptor

EML4:

Echinoderm microtubule-associated protein-like 4

EPP:

Extrapleural pneumectomy

FDG-PET:

Fludeoxyglucose(18F) positron emission tomography

GIST:

Gastrointestinal stromal tumor

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

IFP:

Interstitial fluid pressure

IGF-1:

Insulin-like growth factor 1

KDR:

Kinase insert domain receptor

MM:

Malignant mesothelioma

MPM:

Malignant pleural mesothelioma

mTOR:

Mammalian target of rapamycin

NGR:

Asparagine–glycine–arginine

hTNF:

Human tumor necrosis factor-alpha

OS:

Overall survival

PD:

Progression disease

PDGF:

Platelet derived growth factor

PDGFR:

Platelet derived growth factor receptor

P/D:

Pleurectomy/decortication

PFS:

Progression free survival

PI3K:

Phosphatidylinositol 3-kinase

PR:

Partial response

RNA:

Ribonucleic acid

SRC:

Sarcoma

SD:

Stable disease

TGF-alpha:

Tumor growth factor-alpha

TKI:

Tyrosine kinase inhibitor

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Correspondence to Jan Nyrop Jakobsen.

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Jakobsen, J.N., Sørensen, J.B. Review on clinical trials of targeted treatments in malignant mesothelioma. Cancer Chemother Pharmacol 68, 1–15 (2011). https://doi.org/10.1007/s00280-011-1655-3

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Keywords

  • Malignant mesothelioma
  • Malignant pleural mesothelioma
  • Targeted treatments
  • Tyrosine kinase inhibitors