The potential role of antiangiogenic agents in mesothelioma has provoked significant interest. Preclinical work has detected vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 in a majority of mesothelioma tumor specimens.31–33 Moreover, VEGF has been found to stimulate the proliferation of mesothelioma cells in vitro, and this growth can be inhibited by the use of purified rabbit polyclonal antibodies targeting VEGF.33
Bevacizumab, a humanized monoclonal antibody directed against VEGF, has been shown to increase survival when used in combination therapy in patients with metastatic colon cancer34 and non–small-cell lung cancer,35 and it has been shown to prolong TTP in patients with metastatic breast cancer.36 To study its use in mesothelioma, a phase II trial randomized previously untreated patients to receive cisplatin plus gemcitabine, with or without bevacizumab.22 The addition of bevacizumab did not result in significant improvements in either response (25% vs. 22%), median progression free survival (PFS) (6.9 vs. 6.0 months), or median OS (15.6 vs. 14.7 months) compared with chemotherapy alone. Subset analysis did show a correlation between higher baseline plasma VEGF levels and shorter PFS and OS, suggesting a basis for further inquiry of bevacizumab in a more selected population.
Cediranib, an oral small molecule inhibitor of VEGF, has also been studied in mesothelioma. In a phase II trial of cediranib in 47 evaluable patients with mesothelioma that had progressed after first-line chemotherapy, four patients had partial responses and 16 patients had stable disease, (disease control rate 42%), with median PFS of 2.6 months and median OS of 9.5 months. 37 A phase I/II trial of cediranib in combination with cisplatin plus pemetrexed as first-line systemic therapy in patients with mesothelioma is currently underway (NCT01064648).
Multitargeted small molecule tyrosine kinase inhibitors (TKIs) with anti-VEGF activity also have been investigated in mesothelioma. Vatalanib, an oral anilinophthalazine that targets VEGFR1 and 2, c-KIT, platelet-derived growth factor receptor (PDGFR), and c-Fms, has been studied in a small phase II trial in previously untreated patients with mesothelioma (n = 47).38 Although there were five objective responses (RR 11%) and median PFS was 4.1 months, the 3-month PFS (55%) did not meet a prespecified primary endpoint of 75%.
Sorafenib, an oral inhibitor of VEGFR2 and 3, ref, PDGFR, and c-KIT, has been studied in a phase II trial for both chemotherapy-naive and previously treated patients with mesothelioma.39 Although the response rate in this trial was only 4%, the 3-month PFS was 78% and median PFS was 3.7 months, with a median OS of 10.7 months.
In a phase II trial of sunitinib, patients who had progressed after 1 prior therapy received second-line treatment with this oral inhibitor of VEGFR1–3, PDGFR, and c-Kit.40 Among 22 assessable patients, there were three responses (RR 15%), with a median TTP of 3.5 months and a median OS of 5.9 months. In the face of limited activity for these agents, there are no current plans to develop these agents further in mesothelioma.
Histone Deacetylase Inhibition
Histones serve as a protein spool around which DNA is wound; the wrapping and unwrapping of DNA about these central histones are regulated by histone acetyltransferases and histone deacetylases (HDACs). Inhibitors of HDAC can alter access of transcription factors to DNA, thereby causing increased expression of some genes but repression of others.41–43 In a phase I trial of vorinostat, an oral HDAC inhibitor, there were 13 patients with mesothelioma. Of these, two patients had objective response to vorinostat monotherapy (RR 15%), and six patients remained on therapy for more than 4 months.44 From signals of activity for this agent in mesothelioma, an international phase III trial is underway in which patients who have progressed after prior pemetrexed-containing therapy are randomized to receive vorinostat or placebo (NCT00128102).
Mesothelin is a glycosyl-phosphatidyl inositol-linked (GPI-anchor) cytoplasmic membrane glycoprotein thought to be involved in cell adhesion and is tightly associated with a range of cancers, including mesothelioma.45 Three anti-mesothelin agents are in clinical development: Morab-009 is a monoclonal anti-mesothelin antibody,46 SS1P is an anti-mesothelin antibody with a conjugated toxin (Pseudomonas exotoxin A),47 whereas CRS-207 is a mesothelin vaccine derived from attenuated Listeria monocytogenes and intended to elicit an antibody response against surface mesothelin.48 By targeting surface mesothelin, investigators hope to block cell adhesion as well as elicit an antibody-dependent cytotoxicity response against mesothelin-positive tumor cells.46,49 Separate phase II trials of MORAb-009 (NCT00738582) and SS1P (NCT01445392) in combination with cisplatin plus pemetrexed have completed accrual, but no results have yet been released. A phase I trial of CRS-207 monotherapy has completed accrual, though it appears that its sponsor will be focusing its development in pancreatic cancer at this time.
Other Targets of Interest
In addition to the work mentioned previously, there are ongoing efforts in mesothelioma exploring the efficacy of mammalian target of rapamycin (mTOR) inhibition (NCT00770120), G2 checkpoint abrogation (NCT00700336), human tumor necrosis factor-α (hTNF-α) (NCT01098266), and vaccines targeting the Wilms tumor suppressor gene (WT1) (NCT01265433). Although it is too early to determine the role that these agents will have in the standard treatment of patients with mesothelioma, it is encouraging to see the investment in clinical drug development and infrastructure in this disease.