Angiogenesis is a crucial mechanism for growth, proliferation and metastasis in many tumor types including lung cancer [1]. The VEGF ligand plays a key role in regulation, both in normal and cancer cells, promoting endothelial cell migration and proliferation necessary for angiogenesis. VEGF is overexpressed in a majority of malignant tumors, including non-small-cell lung cancer (NSCLC), and elevated blood levels of VEGF are associated with tumor aggressiveness and a poor prognosis [2]. Thus, it was logical that inhibiting abnormal blood vessel formation we can induce an antitumor effect [3]. There are many agents that demonstrate anti angiogenic properties but unfortunately, for many years, only bevacizumab (a monoclonal antibody against VEGF ligand) has shown consistent efficacy in several cancer types; however, cancer cells inhibited by bevacizumab escape from its effect by upregulating other proangiogenic molecules such as PDGF and FGF. Hence, ongoing research has focused on developing novel agents that inhibit multiple signaling pathways for angiogenesis [4–7]. The concept of developing multi targeted tyrosine kinase inhibitors (TKIs) is significantly important because it allows us to block several key receptors in the tumor cells, decrease their chance of resistance and, at the same time, keep a selected and tolerable toxicity profile. Unfortunately, in lung cancer, all these multitargeted TKIs have shown controversial results. As an example, sorafenib which was approved for the treatment of renal cell carcinoma and hepatocellular carcinoma [8,9] was studied in lung cancer. Two Phase III trials of first-line chemotherapy for NSCLC (paclitaxel/carboplatin in ESCAPE and gemcitabine/cisplatin in NExUS) alone or in combination with sorafenib failed to demonstrate overall survival (OS) benefit in the sorafenib arms [10,11]. Sunitinib, another oral small molecule inhibitor of VEGF receptor (VEGFR), PDGF receptor (PDGFR), c-Kit and Flt-3, has approval indications for renal cell carcinoma and gastrointestinal stromal tumor [12,13]. Phase II data suggested that sunitinib has single-agent activity in previously treated advanced NSCLC patients with response