lerability of EGFR antibodies and EGFR TKIs may still differ in sensitive patients, and/or in earlier lines of treatment. Similarly, the activity of VEGF/VEGFR-targeting agents on vasculature (and on tumour cells bearing VEGFR), may be affected by prior treatment with VEGF antibodies, although true resistance to angiogenesis inhibition does not occur, and BIBF 1120 covers broad-spectrum angiokinases. Since the conception of this trial, phase III data from other trials has matured, suggesting that treatment SB939 with EGFR and VEGF antibodies in combination with cytotoxic chemotherapy might not be effective in early lines of treatment (62, 63), and may even adversely affect prognosis in a subpopulation of patients. This trial demonstrated that a weekly alternating administration of BIBF 1120 and afatinib is feasible, with well-manageable side-effects.
The tolerability of the regimen suggests that more intense dosing approaches (e.g. combining continuous antiangiogenic treatment with intermittent afatinib therapy) are feasible. Further phase I and II studies combining afatinib and/or BIBF1120 with chemotherapy in earlier lines of therapy are ongoing. This study was supported by Boehringer Ingelheim. The Authors would like to acknowledge the editorial assistance of Ogilvy buy KU-55933 Healthworld Medical Education. Boehringer Ingelheim provided financial support for this assistance. Dr Stopfer and Dr Merger are employees of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. Dr Amellal is an employee of Boehringer Ingelheim, Reims, France. No other author has any conflict of interest. This study was supported by Boehringer Ingelheim. The authors would like to acknowledge the editorial assistance of Ogilvy purchase KU-55933 Healthworld Medical Education. Boehringer Ingelheim provided financial support for this assistance.
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (e.g., T790M), mesenchymal–epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (e.g., Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (e.g., afatinib [BIBW 2992] and PF-00299804) and/or vascular endothelial growth factor receptor order KU-55933 pathways (e.g., BMS-690514 and XL647).
In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance. The epidermal growth factor receptor (EGFR) family comprises 4 members—EGFR/(human epidermal growth factor receptor 1 [HER1]/ErbB1), HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4—receptor tyrosine kinases (RTKs) that regulate downstream signaling pathways important to tumor cell proliferation, survival, migration, and metastasis.1 The first-generation reversible EGFR tyrosine kinase (TK) inhibitors (TKIs) erlotinib (Genentech; South San Francisco, CA, US) and gefitinib (AstraZeneca; Wil
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