During the last decade, several targeted agents have been investigated in MPM and, for some of them, the preclinical rationale for exploring clinical activity was weak. MPM is characterized by a complex genomic alteration, with the loss of chromosomal loci encoding for tumor suppressor genes such as p16, p14, NF2 and TP53. These genomic changes are very common but, unfortunately, they are not suitable to be targeted by available drugs. Deregulations in growth factor receptor pathways, apoptosis and angiogenesis have also been demonstrated, and these alterations may be amenable to intervention.[55–57] As a result, a number of clinical trials have tested targeted agents directed against these receptors or pathways in order to inhibit mesothelial cell growth. Unfortunately, none of these new drugs have consistently shown activity in MPM. Selected studies with targeted agents in MPM are summarized in Table 3.
EGF Receptor Inhibitors
The EGF receptor (EGFR) was considered a promising target for systemic therapy of MPM, since biological studies showed that this receptor is highly expressed in MPM tissue samples.[58,59] In a Phase II study with the EGFR tyrosine kinase inhibitor (TKI) gefitinib, 43 chemotherapy-naive patients were included. EGFR overexpression, defined as immunohistochemistry score 2+ and 3+, was detected in 97% of patients. One complete response and one PR were observed in patients with epithelioid histology. Approximately 50% of patients had stable disease up to 24 weeks. Median PFS was 2.7 months and no differences were observed between patients with low and high EGFR expression. Median OS was 6.8 months; 3.6 months in patients with low EGFR-expressing tumors and 8.1 months in patients with high EGFR-expressing tumors.
In another Phase II study, erlotinib was evaluated in 63 pretreated patients. No objective responses were observed and disease stabilization was achieved in 42% lasting at least 6 weeks, and this finding was not correlated with EGFR expression. The median OS was 10 months. The combination of erlotinib and bevacizumab was investigated in 24 pretreated patients without showing any antitumor activity, with a median PFS of 2.2 months and a median OS of 5.8 months. Despite the high level of EGFR expression, the lack of activity of EGFR inhibitors in MPM is probably due to the almost total absence of EGFR sensitizing mutations in this disease.
VEGF levels are increased in serum and pleural fluid of patients with mesothelioma and overall, serum VEGF levels in MPM patients are higher than in healthy subjects or in patients with other malignancies. Elevated serum VEGF levels are more frequently associated with advanced disease stage and correlate with microvascular density and, ultimately, with poor prognosis. In vitro studies indicated that VEGF stimulates MPM cells in a dose-related manner and anti-VEGF antibodies are able to inhibit MPM cell growth.
Bevacizumab, a monoclonal antibody targeting VEGF, is currently under investigation and ongoing trials are testing the possibility to combine this agent with other approved and/or investigational drugs. To date, none of the studies already performed have shown hints of superior efficacy in terms of higher objective RR or improvement in other efficacy outcomes when compared with historical data. A randomized Phase II trial combining cisplatin and gemcitabine with or without bevacizumab included 115 chemotherapy-naive patients and showed no improved clinical benefit in the bevacizumab arm. The RR was 25 and 22%, and median OS was 15.6 and 14.7 months, respectively. A subset analysis suggested a survival advantage in patients with low VEGF baseline serum levels.
A multicenter randomized Phase II/III study is currently investigating the combination of pemetrexed plus cisplatin with or without bevacizumab. A preliminary report of the study showed a RR of 15% in the triplet combination arm with a percentage of nonprogressive patients at 6 months (the primary end point of the study) significantly higher compared with the chemotherapy-alone arm (73.5 vs 43%). Currently, there is no evidence to support the use of bevacizumab in association with chemotherapy in patients with advanced MPM.
Many Phase II studies explored the activity of multiple VEGF receptor (VEGFR) TKIs. In a Phase II study, vatalanib, a VEGF and PDGF receptor (PDGFR) TKI, was tested in 47 untreated patients and the study did not meet the specified end point of a 3-month PFS of 75%, achieving a RR of 11% with a PFS of 4.1 months and OS of 10 months. Cediranib, a pan-VEGFR TKI, was evaluated in a Phase II study including 54 pretreated patients. In 9% of 47 evaluable patients, an objective response was reported with a median PFS of 2.6 months and median OS of 9.5 months. A Phase I and randomized Phase II trial comparing cisplatin and pemetrexed with or without cediranib as first-line therapy is currently enrolling patients.
Thalidomide displays antiangiogenic properties through the inhibition of VEGF, basic FGF and TGF-α. A Phase I trial in 40 patients established the recommended dose for Phase II/III studies of 200 mg/day and showed a clinically relevant proportion of patients without progression at 6 months. Two Phase II studies evaluated thalidomide alone or in combination with cisplatin and gemcitabine, reporting a RR of 6% with an OS of 11 months in 27 patients receiving thalidomide alone and the same OS with PR occurring in 14% of 31 patients receiving thalidomide in combination with chemotherapy. The final results of a randomized Phase III study testing maintenance therapy with thalidomide (arm A) versus observation (arm B), after induction chemotherapy, were recently reported. The study included 222 patients with at least disease stabilization following induction chemotherapy with platinum-derivatives and pemetrexed, and showed no benefit for maintenance thalidomide with a median PFS of 16 and 15 weeks, and OS of 11 and 13 months for arm A and arm B, respectively.
Sorafenib inhibits both PDGFR and VEGFR-2, and in a Phase II study of 50 evaluable patients, including both chemotherapy-naive and previously treated, a RR of 6% was reported, with a median PFS and median OS of 3.6 and 9.7 months, respectively. Patients who had received prior chemotherapy had a superior OS compared with those who were chemotherapy-naive (13.2 and 5 months, respectively) but this is probably expression of a patient selection bias. A Phase I study evaluating sorafenib at two dose levels in combination with cisplatin plus pemetrexed in 12 untreated patients showed that sorafenib amplifies chemotherapy toxicity without any evidence of improved tumor control.
Sunitinib is a multitargeted TKI that blocks PDGFR-β, VEGFR-2 and c-kit. In a Phase II study, 51 evaluable patients received sunitinib after failure of first-line chemotherapy with cisplatin plus pemetrexed or gemcitabine. The RR was 10% with a median TTP of 3.4 months and median OS of 6.7 months.
In mesothelioma cells, PDGFR-α is overexpressed and high PDGF serum level has been suggested as an independent predictor for adverse outcome. MPM cell lines overexpress PDGFR-α and its inhibition induces cell growth in vitro. Imatinib is a selective TKI of bcr–abl-mutated tyrosine kinase, c-kit and PDGFR. Expression of c-kit has indeed been reported in 26% of MPM patients. Phase II studies of single-agent imatinib failed to show any hint of activity of this drug and further studies are not needed.[79,80]In vitro and in vivo experiments with imatinib in MPM cell lines have pointed at a possible enhancement of sensitivity to gemcitabine and pemetrexed. A Phase I trial investigating imatinib in combination with cisplatin and pemetrexed is actually ongoing, but not recruiting patients. In Italy, a Phase II study evaluating imatinib in combination with gemcitabine has been conducted but results have not been reported so far.
Dasatinib is a PDGFR and Src inhibitor that was shown to exert a cytotoxic effect in mesothelioma cell lines. To evaluate Src as a putative predictive biomarker, 15 patients candidate to surgery received 4 weeks of preoperative dasatinib. Only one patient had a minor response. A Phase II trial explored its activity in 46 pretreated patients with no response and a discouraging PFS and OS of 2 and 4.8 months, respectively. A CALGB Phase II study of dasatinib in pretreated patients is currently ongoing but not recruiting.
PI3K–AKT–mTOR Pathway Inhibitors
The PI3K–AKT–mTOR pathway is often dysregulated in MPM and in vitro studies have shown that its inhibition may induce apoptosis in MPM cell lines. A large fraction of malignant mesothelioma carries NF2 mutations resulting in the inactivation of the tumor suppressor merlin and displaying an unregulated mTORC1 signaling pathway that is sensitive to rapamycin.
A synergistic antitumor effect of sirolimus and cisplatin has been shown in MPM cell lines. Everolimus, an oral mTOR inhibitor, is currently being evaluated in a Phase II study planned to enroll 55 patients with the primary end point being to determine the 4-month PFS. In a Phase I study testing the oral inhibitor of PI3K and mTOR, GDC-0980, antitumor activity was demonstrated in three patients with MPM.
Histone Deacetylase Inhibitors
Histone deacetylases are regulatory enzymes that modulate chromatin function and structure. Although the exact mechanism is still unclear, preclinical data suggest that they play a key role in the malignant transformation and cellular differentiation in mesothelioma through different mechanisms that, among others, include the downregulation of TS (one of the cellular targets of pemetrexed), the inhibition of proteasome function, the reduction of expression of HIF-1α and VEGF leading to reduced angiogenesis, and the downregulation of antiapoptotic proteins. Based on the promising results of a Phase I trial in which two of 13 mesothelioma patients had a PR, a Phase III trial was planned to investigate whether vorinostat was able to prolong OS compared with placebo in patients having failed up to two prior systemic regimens with pemetrexed and a platinum. The study, including 661 patients, is the largest randomized trial to complete enrollment in advanced pretreated MPM and showed that vorinostat, as second-line therapy, did not significantly extend either PFS or OS (6.3 vs 6.1 weeks and 30.7 vs 27.1 weeks, respectively).[90,91]
In vitro data showed that valproic acid, which acts as an histone deacetylase inhibitor, has a synergistic antitumor effect with doxorubicin and this preclinical finding led to a Phase II study that included 45 pretreated MPM patients who received doxorubicin in combination with valproic acid. The RR was 16% with a median PFS and OS of 2.5 and 6.7 months, respectively, and two toxic deaths were observed in patients with poor performance status.
NGR–hTNF consists of human TNF-α coupled to the tumor-homing peptide NGR that binds a particular form of CD13, a receptor selectively expressed by tumour blood vessels. In a Phase II study including 57 patients who failed prior chemotherapy, the RR was 2% with a median PFS of 2.8 months and OS of 12.1 months. A randomized double-blind Phase III study planned to enroll 400 patients is currently ongoing to evaluate NGR–hTNF versus placebo plus best investigator choice after failure of pemetrexed-based chemotherapy. A Phase II randomized trial of maintenance NGR–hTNF versus placebo in patients with nonprogressive disease after six cycles of first-line pemetrexed-based chemotherapy is also currently recruiting patients.
Most cancer cells are dependent on the G2 checkpoint to survive, and this has led to the development of the G2 checkpoint inhibitor CBP501. In a Phase I study in combination with cisplatin, of the three patients with MPM included, one had a PR lasting 9.7 months and two had stable disease, lasting 11 and 3 months, respectively. An ongoing Phase I/II study is evaluating the combination of CBP501 in combination with full dose cisplatin and pemetrexed, and, upon the determination of the maximum tolerated dose, the Phase II part will evaluate the combination in previously untreated MPM patients.
One of the most intriguing targets for systemic treatment of MPM is mesothelin, a tumor differentiation antigen overexpressed by most epithelioid mesothelioma but not in normal cells. Three mesothelin-targeted agents are currently in different stages of clinical development: SS1P, a recombinant immunotoxin; MORAb 009, a chimeric antimesothelin monoclonal antibody; and CRS-207, a live attenuated Listeria monocytogenes vector encoding human mesothelin. The rationale for testing mesothelin as a tumor vaccine is based on studies showing that mesothelin can elicit a strong T-cell response in patients. Some hints of activity for these agents have been shown in Phase I studies. Preclinical models suggested a synergism with systemic chemotherapy and trials of combined therapy are underway.
Future Oncol. 2012;8(3):293-305. © 2012 Future Medicine Ltd.