**14. Other multi-targeted TKIs**

Axitinib, with VEGFR, PDGFR-β and c-Kit as its main targets, is currently the most potent TKI in inhibiting VEGFR signal pathways. In a phase II study in advanced NSCLC, in which 28% of patients had received no prior chemotherapy, ORR was 9.4%, with PFS and OS of 4.9 and 14.8 months, respectively [95]. Currently, three ongoing phase II studies are exploring the effectiveness and safety of axitinib-based combination therapies in non-squamous (AGILE1030: with paclitaxel/carboplatin; AGILE1039: with pemetrexed/cisplatin) and squa‐ mous NSCLC (AGILE1038: with cisplatin/gemcitabine).

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

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

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 MET amplification [99].

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

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