**8. Current state of antiangiogenic therapy for NSCLC: VEGF as target treatment**

In this section, we analyze the activity of a monoclonal antibody (bevacizumab) and other new antiangiogenic therapies.

#### **8.1. Bevacizumab**

Bevacizumab is a monoclonal antibody directed against VEGF and was the first antiangio‐ genic drug approved for the treatment of advanced NSCLC. Currently it's the only ap‐ proved in this setting in Europe and the USA.

After proving the improvement in the response rate (RR) and progression free survival (PFS) of bevacizumab together with chemotherapy in first line in a randomized phase II study in which 99 patients with advanced or metastatic NSCLC were included [68], the ECOG group undertook a phase III trial (ECOG 4599) in first line, in which patients with brain metastasis, hemoptysis, and squamous histology were excluded, due to the risk of hemoptysis observed in the previous study with this histology [69]. The studied random‐ ized 878 patients with recurrent or advanced NSCLC to receive carboplatin/paclitaxel with or without bevacizumab on a dose of 15 mg/kg every 21 days and crossover was not allowed. The main objective, overall survival (OS), was improved in the trial arm: 12.3 months vs 10.3 months, with a hazard ratio (HR): 0.79 (95% CI: 0.67-0.92; p=0.003). In addition, the RR was also improved (35 vs 15% (p<0.001)) and the PFS went from 4.5 to 6.2 months (HR: 0.66; 95% CI: 0.57-0-77, p<0.001). However, adding bevacizumab to the chemotherapy also increased toxicity; there were 15 toxic deaths (2 in the arm of che‐ motherapy alone) due to pulmonary hemorrhage, digestive bleeding, febrile neutropenia, ictus and lung embolism. A subgroup analysis found that patients over 70 had a higher incidence of grade 3-5 toxicities (87 vs 61%).

Radiation exposure, the requirement of long breath holding during chest imaging acquisi‐ tion and lack of standardized protocols, remain potential drawbacks of this technique. How‐ ever, implementation of low-dose scanning strategies may allow a more widespread use in

Quantification of tumor vascularity by dynamic MR (DCE MR) is technically more challeng‐ ing than perfusion CT because there is a lack of a direct relationship between MR signal in‐ tensity and contrast agent concentration. This is due to the fact that tissue signal intensity on MR is related to the effect of CM on water in the microenvironment, which changes tissue

While perfusion CT yield information is based predominantly on the first pass of CM (BV, BF), the MR imaging technique may sample a volume of interest over a longer time and yields parameters that reflect microvessel perfusion, permeability and extracellular leakage of space. In addition, by applying pharmacokinetic models to the MR imaging acquisitions, it is possible to calculate quantitative parameters, such as the transfer constant (Ktrans) that

A central flaw of dynamic MR is that acquisition and pharmacokinetic models vary widely. Thus, comparing studies from different institutions is difficult. This technique, on the other

Few studies have applied dynamic MR in the assessment of lung cancer. Ohno et al [67] evaluated the role of DCE MR as a prognostic indicator in NSCLC patients treated with che‐ motherapy using cisplatin and vincristine. In their study, the mean survival period of pa‐ tients with lower slope of enhancement was significantly longer than that seen in the group with higher slope of enhancement. This study provides promising data for the application of

hand, is of limited value in organs with physiological movement such as the lungs.

dynamic MR in response assessment to chemotherapy and targeted therapy.

**8. Current state of antiangiogenic therapy for NSCLC: VEGF as target**

In this section, we analyze the activity of a monoclonal antibody (bevacizumab) and other

Bevacizumab is a monoclonal antibody directed against VEGF and was the first antiangio‐ genic drug approved for the treatment of advanced NSCLC. Currently it's the only ap‐

the future.

**treatment**

**8.1. Bevacizumab**

new antiangiogenic therapies.

proved in this setting in Europe and the USA.

**7. Dynamic MR**

relaxivity in complex and unpredictable ways [66].

14 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

describes the transendothelial transport of the CM.

The AVAiL study [70] randomized 1043 patients to receive cisplatin and gemcitabine with or without bevacizumab in a dose of 7.5 or 15 mg/kg each 21 days. In this study the main goal was PFS, which was higher in patients which received the drug than those who took placebo, both in small dose arm (6.7 months vs 6.1 months; HR: 0.75, p=0.003) as well as in higher one (6.5 months vs 6.1 months, HR: 0.82, p=0.03). Nevertheless, OS didn't improve, which could be explained by the high percentage of patients who received treatment after‐ wards (more than 60%). Regarding toxicity, 7 patients died due to lung hemorrhage in the trial arm (2 in the control trial), although it was observed that in patients who were under anticoagulant treatment there was no lung hemorrhage.

The SAiL safety study, which included more than 2000 patients, showed the effectiveness of combining other doublets of chemotherapy; in terms of safety it displayed a grade 3 or high‐ er lung hemorrhage incidence only in 1% of the patients [71].

An efficiency meta-analysis published in 2011 confirms effectiveness in terms of PFS, pre‐ senting uncertainty in terms of improvement of OS [72].

A meta-analysis published recently with 2210 patients evaluated the bevacizumab toxicity profile with high dose of bevacizumab (15 mg/kg), and stated that bevacizumab is related to a higher risk of toxicity deaths (HR: 2.04; 95% CI: 1.18-3.52), but it was not the case in lower doses of 7.5 mg/kg (HR: 1.20; 95% CI: 0.60-2.41). In addition, bevacizumab was associated to a greater incidence of grade 3-4 toxicities, especially in the group of high doses [73].

More studies have been conducted in sub-populations, for example, the PASSPORT study in 109 patients with brain metastasis, subgroup that had not been included in previous studies, and which proved that bevacizumab can be administrated in patients with controlled brain metastasis [74]. Another review on the incidence of bleeding in patients with brain metasta‐ sis treated with antiangiogenic drugs proved to be safe when it is administered to treated patients as well as patients with metastasis that appears during treatment [75].

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 13.3 months; p=0.56) [76].

simultaneously, with anti-angiogenic and anti-proliferative activity against NSCLC, thereby potentially providing a higher likelihood of single-agent activity. Another benefit is that these agents are often available orally, offering patients greater convenience. However, tox‐ icity remains a concern given the multi-targeted kinase inhibition and the additive adverse effects that may be of particular concern when the agents are combined with chemotherapy.

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 17

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

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,

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

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‐

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

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‐

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

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

and in these patients, median PFS was 5.5 months [83].

ential benefit of sorafenib in k-ras-mutant patients [86].

**11. Sorafenib**

RET, and Ftl-3.

groups [84,85].

PFS was observed [87].

**12. Vandetanib**

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 9.2 months; p=0.75)

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 markers of activity.
