A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma
Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA. Lung cancer (Amsterdam, Netherlands)
(Impact Factor: 3.96).
07/2012; 77(3):567-71. DOI: 10.1016/j.lungcan.2012.05.111
Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM.
Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months.
53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients.
This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.
Available from: Adolfo Favaretto
- "In that study, the addition of bevacizumab did not significantly improve response rate, progression-free survival (PFS) or overall survival (OS). Another multicentre single-arm phase II study of the combination of cisplatin and pemetrexed plus bevacizumab in MPM patients failed to meet the primary end point of a 33% improvement in PFS rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone (Dowell et al, 2012). We report here the final results of a multicentre, open label phase II study designed to explore the efficacy of the combination of pemetrexed and carboplatin with bevacizumab as front-line therapy in patients with unresectable MPM. "
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The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).
Eligible patients received pemetrexed 500 mg m−2, carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml−1 per minute and bevacizumab 15 mg kg−1, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.
Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.
The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.
Available from: PubMed Central
- "The most effective treatment regimen (cisplatin and pemetrexed) induces partial response in half of patients and improves survival from 9 to 12 months . Novel targeted therapies have been investigated in MPM with limited success, including vascular endothelial growth factor (VEGF) inhibitors [5,6]. Discovery of additional targets and rational combinations of targeted therapies may lead to effective novel therapies. "
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Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis.
We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied.
EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression.
EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted.
Available from: Hideaki Shimada
- "Inhibition of angiogenesis produced antitumor responses and decreased pleural effusion , and therefore targeting angiogenesis was clinically examined for the therapeutic efficacy . A phase II study, however, demonstrated that antibody for VEGF, bevacizumab, with chemotherapy failed to prolong the progression free survival compared with the chemotherapy alone . Taking these results together, molecular target medicine, as a single agent, could produce only a limited success, and no survival bene�ts have been observed even in a combination with other anticancer agents. "
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ABSTRACT: Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world. The current treatment modalities are not effective in terms of the overall survival and the quality of life. Mesothelioma mainly develops in the thoracic cavity and infrequently metastasizes to extrapleural organs. A local treatment can thereby be beneficial to the patients, and gene therapy with an intrapleural administration of vectors is one of the potential therapeutics. Preclinical studies demonstrated the efficacy of gene medicine for mesothelioma, and clinical trials with adenovirus vectors showed the safety of an intrapleural injection and a possible involvement of antitumor immune responses. Nevertheless, low transduction efficiency remains the main hurdle that hinders further clinical applications. Moreover, rapid generation of antivector antibody also inhibits transgene expressions. In this paper, we review the current status of preclinical and clinical gene therapy for malignant mesothelioma and discuss potential clinical directions of gene medicine in terms of a combinatory use with anticancer agents and with immunotherapy.
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