**12. Vandetanib**

Vandetanib is an oral TKI that inhibits VEGFR-2 and -3, RET and EGFR.

Vandetanib in combination with carboplatin/paclitaxel resulted in prolonged PFS (56 weeks; HR= 0.76, p= 0.098) compared with carboplatin/paclitaxel alone (52 weeks) in previously un‐ treated patients with advanced NSCLC. The secondary endpoint of OS was not significantly different between the two arms [88]. Another phase II trial showed that vandetanib in com‐ bination with docetaxel was superior to docetaxel alone in pretreated NSCLC patients with regard to PFS (18.7 weeks versus 12 weeks; HR = 0.64, p = 0.037) [89].

Motesanib mainly inhibits targets including VEGFR, PDGFR, c-Kit and RET. In a phase II study of motesanib or bevacizumab in combination with carboplatin/paclitaxel as frontline treatment for advanced non-squamous NSCLC, the efficacy was similar, with a median PFS of 7.7 months (versus 8.3 months with bevacizumab) and a median OS of 14.0 months in both arms [96]. However, the phase III study of motesanib plus carboplatin/paclitaxel in pa‐ tients with non-squamous advanced NSCLC (MONET1) did not meet its primary endpoint

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 19

BIBF 1120 inhibits VEGFR-1, -2 and -3, in addition to PDGFR-α/β and FGFR-1-3. In a phase II trial of 73 patients with relapsed or advanced NSCLC, the median PFS and OS were 11.6 and 37.7 weeks, respectively, with a disease control rate (DCR) of 46% [98]. BIBF 1120 is be‐ ing studied, in the second-line NSCLC setting, in two phase III trials, in combination with

A phase Ib/II study of cabozantinib, a TKI with potent activity against MET, VEGFR-2, RET, c-Kit and Ftl-3, with or without erlotinib in pretreated advanced NSCLC patients showed that the combination was well tolerated with evidence of clinical activity in a largely erlotinib pretreated cohort, including patients with EGFR T790M mutation and

Although multitargeted TKIs have made certain advances in treating NSCLC, the outcomes remain unsatisfactory if they were applied non-selectively among NSCLC patients. Among the non-selective populations, TKI monotherapies showed no significant differences when compared with mono-targeted agent therapies (erlotinib, gefitinib) in treating NSCLC in terms of ORR, PFS and OS. Therefore, it is extremely important to identify populations that are suitable for TKIs. The future of multi-targeted drugs is highly depended on the capabili‐

In recent years, we have acquired a lot of information regarding the role of angiogenesis and its pathophysiological relationship with some types of neoplasias, engaging in proc‐ esses such as tumour growth and dissemination capacity as loco-regional as distant. In lung cancer, we know that neoangiogenesis is the result of the action of several growth factors (mainly VEGF, TGF-alpha, EGF, VEG/PF and PDGF) whose output is controlled by transcription factors hypoxia-induced such as HIF-1, whose expression has been asso‐ ciated as an independent factor of poor prognosis. Acquired knowledge has allowed de‐ signing therapeutic strategies aimed at blocking the action of various pro-angiogenic factors and thereby altering the disease natural course. Some drugs acting against VEGF, as bevacizumab, have demonstrated clinical efficacy improving OS and PFS although with treatment-related toxicities expected with blocking this pathway, as showed some trials, particularly in patients subsets with a known clinical profile that when is present

Another multikinase inhibitors like pazopanib are in an earlier stage of development.

ty of delivering these molecule-targeted therapies to patients most likely to benefit.

of improved OS (HR: 0.89, p = 0.137) [97].

MET amplification [99].

**15. Conclusions**

docetaxel (LUME-Lung 1) and with pemetrexed (LUME-Lung 2).

The phase III ZODIAC trial randomized patients with advanced NSCLC to receive either docetaxel/vandetanib or docetaxel/placebo as second-line treatment. Although vandetanib improved ORR (17 versus 10%, p= 0.0001) and PFS (HR: 0.79, p< 0.0001), OS was not signifi‐ cantly improved (HR: 0.91, p= 0.196) [90]. In the ZEAL trial, vandetanib was investigated in combination with pemetrexed also in the second-line setting. Despite an improvement in ORR (19 versus 8%, p < 0.001), this study did not meet its primary endpoint of PFS (HR: 0.86, p = 0.108) [91]. In another phase III trial (ZEPHYR), patients who had progressed after chemotherapy and erlotinib were randomized to vandetanib versus placebo. PFS was im‐ proved (HR: 0.63, p < 0.0001), but not OS (HR: 0.95, p = 0.527) [92]. The above phase III trials did not carry out stratified analysis on the EGFR gene status and therefore were not able to further identify the potential populations that may benefit from vandetanib.

These results led to withdrawal of the application for approval of vandetanib in NSCLC.
