Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma

Abstract

BACKGROUND. We conducted a phase 2, multicenter, open‐label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non–small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity. METHODS. Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21‐day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS. Twenty‐four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months‐5.9 months). The median survival was 5.8 months (95% CI, 2.8 months‐10.1 months). The most common toxicities were rash and diarrhea. There were no treatment‐related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS. The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first‐line therapy. More therapeutic studies with effective agents are needed for these patients. Cancer 2008. © 2008 American Cancer Society.

Asbestos, Lung Cancers, and Mesotheliomas

“…In a phase II clinical study in 63 patients with MM, erlotinib alone was ineffective in terms of median overall survival time, despite overexpression of EGFR in 75% of tumors, and immunohistochemical studies revealed activation of ERK and PI3K/AKT pathways in tumors, suggesting the importance of combination therapy to eradicate these survival pathways (76). Based on observations that vascular endothelial growth factor (VEGF) is produced by MM and other tumor cells, playing a critical role in establishment and maintenance of tumors, chemotherapeutic approaches using erlotinib and Bevacizumab, a humanized anti-VEGF monoclonal antibody, have been evaluated in phase II clinical studies in patients with recurrent or refractory non-small cell lung cancer (NSCLC) (77) and in previously treated patients with MM (78). Although the combination of drugs was tolerated reasonably in patients in both studies, and both progression-free and overall survival were increased in patients with NSCLC in comparison to use of either agent alone, no evidence of a favorable radiographic response was observed in patients with MM.…”

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

“…Most MM tumors (68%) expressed epidermal growth factor receptor (EGFR), but contrary to lung cancer, the activating mutations of EGFR are rare in MM [27] [28]. This may explain the failure of erlotinib in phase II trials in MM used as a single agent or in combination with BVZ [29] [30]. Platelet derived growth factor (PDGF) plays an important part in MM pathogenesis, but the PDGF inhibitor imatinib failed to produce objective responses in phase II trials [31] [32].…”

Second line therapy in malignant pleural mesothelioma: A systematic review

“…The EGFR TKI erlotinib and the combination of erlotinib and the chimeric mouse-human antibody targeting the extracellular domain of EGFR, cetuximab were studied in 2 phase 2 studies. Results were disappointing with no patients achieving a partial response [52,53].…”