**11. Sorafenib**

The combination of bevacizumab with some of the new agents has been studied as well. In the ATLAS study, after having received four cycles of cisplatin-based chemotherapy and bevacizumab, patients were randomized to receive treatment with bevacizumab (15 mg/kg) and erlotinib (150 mg daily) or only bevacizumab. The main objective of this study was reached (PFS), with 4.8 months vs 3.7 months (HR: 0.72, p=0.0012); neverthe‐ less no improvement was made in OS, a secondary goal of the study (14.4 months vs

The phase III BeTa trial compared the activity of the combination of bevacizumab and erloti‐ nib vs erlotinib in second line in 636 patients. An improvement in PFS was found (3.4 vs 1.7 months; HR: 0.62, p<0.0001), but again, no significant differences were found in OS (9.3 vs

Hypertension has been found to be a marker of clinical benefit from bevacizumab in var‐ ious malignancies [77], although no single biomarker have proven to be ready for clini‐ cal use. Cytokines and angiogenic factors profiling may help identify drug-specific

Aflibercept (VEGF-Trap) is a recombining fusion protein, which is added to VEGFR-1,

In a phase II trial in patients with lung adenocarcinoma treated after several treatment lines, aflibercept in a dose of 4 mg/kg was administered intravenously every 14 days, reaching a RR of 2%, with a PFS of 2.7 months and an OS of 6.2 months [78]. A phase III trial in second line after failure to cisplatin-based chemotherapy compared aflibercept vs docetaxel (VITAL trial). This trial showed an improved RR (23.3& vs 8.9%) and PFS (HR: 0.82), but the primary

Vadimezan, fosbretabulin and plinabulin are vascular disrupting agents (VDA); fosbretabu‐ lin selectively disrupts VE-cadherin and plinabulin acts on cytoskeleton. A phase II trial of carboplatin, paclitaxel, bevacizumab and fosbretabulin was well tolerated and with a trend to improve OS and PFS [79], also a phase II trial with docetaxel with or without plinabulin showed a higher response rate with the combination (55% vs 5%) [80]; however, a random‐ ized phase III study with vadimezan in first line failed to show an improvement in OS [81].

Several anti-angiogenic small-molecule tyrosine kinase inhibitors (TKIs) are in current clini‐ cal development. An advantage of TKIs includes the fact that they inhibit multiple receptors

13.3 months; p=0.56) [76].

9.2 months; p=0.75)

markers of activity.

VEGFR-2 and to the placental growth factor (PlGF).

16 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

**10. Multi-targeted tyrosine kinase inhibitors**

endpoint, OS, was not reached (HR: 1.01).

**9. Vascular disrupting agents**

**8.2. Aflibercept**

Sorafenib is an oral multi-kinase inhibitor of VEGFR-2 and -3, PDGFR-β, RAF-kinase, c-Kit, RET, and Ftl-3.

In the phase II ECOG 2501 trial, 342 patients with NSCLC who has failed at least two prior chemotherapy regimens received sorafenib for two cycles. Those patients who were noted to have stable disease after two cycles (n = 97) were randomized to receive sorafenib or place‐ bo. Sorafenib prolonged PFS compared with placebo (3.6 versus 1.9 months) [82]. In another phase II trial, of 52 patients with relapsed or refractory advanced NSCLC, 59% achieved SD, and in these patients, median PFS was 5.5 months [83].

The results of two phase III trials in the first-line treatment of NSCLC, ESCAPE (sorafenib plus paclitaxel/carboplatin) and NEXUS (sorafenib plus gemcitabine/cisplatin), were unsat‐ isfactory. Because of the safety findings from the ESCAPE trial, patients with squamous cell histology were withdrawn from the NEXUS trial in February 2008 and excluded from analy‐ sis. Median OS, the primary endpoint of both trials, was similar in the sorafenib and placebo groups [84,85].

The Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study randomized pretreated lung cancer patients to erlotinib, vandetanib, erloti‐ nib plus bexarotene or sorafenib based upon biomarker results obtained from individual pa‐ tients. K-ras-mutant patients treated with sorafenib had a non-statistically significant trend toward improved disease control rate (DCR) (61 versus 32%, p = 0.11), suggesting a prefer‐ ential benefit of sorafenib in k-ras-mutant patients [86].

Phase III MISSION trial of sorafenib in patients with advanced relapsed or refractory nonsquamous NSCLC whose disease progressed after two or three previous treatments, did not meet its primary endpoint of improving OS. An improvement in the secondary endpoint of PFS was observed [87].

These findings have led to suspend the development of sorafenib in NSCLC.
