The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation.

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Targeting angiogenesis for treatment of NSCLC brain metastases.

Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer diagnosis. The majority of people with NSCLC are unsuitable for surgery since most patients have metastatic disease at diagnosis. About 60% of brain metastases arise from lung cancer. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery, chemotherapy and new biologic agents. Angiogenesis is essential for the development and progression of cancer, and vascular endothelial growth factor (VEGF) is a critical mediator of tumour angiogenesis. One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced non-squamous NSCLC patients. Patients with central nervous system (CNS) metastases have initially been excluded from bevacizumab trials for the risk of cerebral haemorrhage as a result of the treatment. Nevertheless, the available data suggest an equal risk of intracranial bleeding in patients with CNS metastases treated with or without bevacizumab therapy. Several other anti-angiogenetic drugs are being investigated in the treatment of advanced NSCLC patients, but results of their activity specifically in CNS metastases are still lacking. This review will focus on the potential role of bevacizumab and other anti-angiogenetic agents in the treatment of brain metastases from NSCLC.

Angiogenesis inhibitors and vascular disrupting agents in non-small cell lung cancer.

Most patients diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. Chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may be safely and effectively administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumor proliferation. Approaches to limit VEGF activity include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment include the combination with other targeted therapies in advanced disease, and the integration into the combined modality approaches for the treatment of early and locally advanced disease stages. Vandetanib, a small molecule targeting VEGF tyrosine-kinase activity, due to first indications of antitumor activity and the excellent toxicity profile seems to be a promising agent for the treatment of advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, sunitinib, VEGF Trap and a new class named 'vascular disrupting agents', which includes ASA404, are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. This paper reviews the state of the art and the future developments of the main antiangiogenic agents in the treatment of NSCLC patients.