Targeting tumor neovasculature in non-small-cell lung cancer

Critical Reviews in Oncology/Hematology 86 (2013) 130–142

Targeting tumor neovasculature in non-small-cell lung cancer Athanasios G. Pallis a,∗ , Konstantinos N. Syrigos b a

Department of Medical Oncology, University General Hospital of Heraklion, P.O. Box 1352, Heraklion 71110, Crete, Greece b Oncology Unit GPP, Athens School of Medicine, Sotiria General Hospital, Athens, Greece Accepted 24 October 2012

Contents 1. 2. 3.

4.

5.

6. 7.

8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. AVE0005 (VEGF-trap) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VEGF-receptors tyrosine kinase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Sorafenib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Pazopanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Cediranib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. BIBF 1120 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Axitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Motesanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vascular disrupting agents (VDAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Vadimezan (ASA404) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. ABT-751 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of multiple pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomarkers of response to antiangiogenic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. VEGF as a biomarker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Other biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Resistance to antiangiogenic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future challenges. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

131 131 132 132 133 134 134 134 134 134 135 135 136 136 136 136 136 136 137 137 138 138 138 139 139 139 142

Abstract Recent insight into the molecular biology of cancer and mechanisms of tumorigenesis, has allowed for the identification of several potential molecular targets and the development of novel “targeted therapies”. One of the most active research fields in NSCLC is the discovery of therapies that target angiogenesis. The vascular endothelial growth factor (VEGF) pathway represents a crucial component of the tumor angiogenesis process. Two different strategies have been developed in clinical practice in order to restrict tumor vasculature development; either the use of monoclonal antibodies against VEGF or small molecule tyrosine kinase inhibitors to target the tyrosine kinase domain of VEGF receptor. Among these agents that have been tested bevacizumab, a monoclonal antibody against VEGF, has been approved for the treatment of metastatic NSCLC in combination with chemotherapy, while several other agents are under phase III investigation. Moreover, ∗

Corresponding author. E-mail address: [email protected] (A.G. Pallis).

1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.10.003

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

131

several issues such as predictive biomarkers of response to antiangiogenic therapy and mechanisms of resistance to these agents remain to be elucidated. The purpose of this paper is to present the current status of antiangiogenic therapies in the treatment of NSCLC and to discuss these issues. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiogenesis; NSCLC; VEGF; VEGFR; Bevacizumab

1. Introduction

Table 1 Pro-angiogenic factors involved in the regulation of angiogenesis.

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in the Western world with approximately 160,000 deaths annually [1]. Despite the progress that have been achieved the last decade and the introduction of new chemotherapeutic agents, prognosis remains poor and patients with advanced disease have a median overall survival of approximately 10–12 months when treated with platinum-based doublets [2]. Therefore, it is clear that chemotherapy has reached a plateau of activity [3] and newer more active approaches are needed in order to improve prognosis of this devastating disease. Our improved understanding of molecular biology of cancer and mechanisms of tumorigenesis, has allowed for the identification of several potential molecular targets and development of novel “targeted therapies”. These therapies inhibit signaling pathways (“targets”) involved in the development and progression of cancer. One of the most active research fields in NSCLC is the development of therapies that target angiogenesis. The purpose of this paper is to review the status of therapies targeting tumor neovasculature in the treatment of NSCLC.

Pro-angiogenic factors

2. Tumor angiogenesis The formation of a new vasculature (i.e. angiogenesis) is controlled by the equilibrium between anti-angiogenesis and pro-angiogenesis factors [4]. Under normal conditions angiogenesis is restricted only to distinct time periods such as development, reproduction, and wound healing [5]. Formation of new blood vessels is a fundamental process for the development of solid tumors and to the growth of secondary metastatic lesions. Tumors greater than 2 mm3 require a new blood supply in order to remain metabolically active and expand in size [6]. In the setting of tumor growth the balance of pro- and anti-angiogenic is shifted to persistent production of pro-angiogenic factors, an imbalance that results in the development of new blood vessels that are required for the tumor growth. Several pro-angiogenic factors have been identified (Table 1). Among these, vascular endothelial growth factor (VEGF) is considered as the most potent [7]. The VEGF gene family comprises/includes four homologues: VEGF-A (usually referred as VEGF), VEGF-B, VEGF-C and VEGF-D. VEGF-A is considered as the most important in both physiological and pathological angiogenesis [7]. Its importance is

Growth factors VEGF, EGF, TGF-␣, PDGF, G-CSF, TNF-␣, and PIGF Proteases Cathepsin, gelatinase A, B, stromelysin, and urokinase-type plasminogen activator (uPA) Cytokines IL-1, IL-6, IL-8, MCP-1, ET-1, and ET-2 Other inducers Ang1, integrins, hypoxia, hypoglycemia, NOS, and COX-2 VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; TGF-␣, transforming growth factor alpha; PDGF, platelet-derived growth factor; G-CSF, growth colony stimulating factor; TNF-␣, tumor necrosis factor alpha; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; ET, endothelin; Ang, angiopoietin; NOS, nitric oxide synthase; and COX-2, cyclooxygenase-2.

supported by several data: VEGF is a potent mitogenic agent for endothelial cells while it has no mitogenic activity to other cell types [8]. Furthermore, inactivation of even one allele of the VEGF gene (any of VEGF subtypes) is lethal in mouse embryos, and newly formatted vessels require the presence of VEGF in order to remain viable [7,9]. Although VEGF is recognized by two receptors expressed on the surface of endothelial cells [VEGFR-1 (FLT-1) and VEGFR-2 (KDR)], VEGFR-2 is considered as the critical component in the activation of endothelial cells [9]. A third receptor VEGFR-3 is associated with lymphangiogenesis. VEGF binding to VEGFR-2 induces the dimerization of the receptor. Dimerization results in activation of the receptor via autophosphorylation of the intracellular tyrosine kinase domain, which initiates an intracellular signal transduction cascade crucial to the process of angiogenesis (Fig. 1) [7]. VEGF is expressed by most types of human cancer cells, among them, NSCLC cells [10]. This expression is induced in several genetic (activation of ongogenes or inactivation or loss of tumor suppressor genes) and epigenetic (hypoxia, low pH, interleukin-6 and other inflammatory cytokines, growth factors such as basic fibroblast growth factor) ways [10]. In the tumor angiogenesis process, VEGF is secreted by tumor cells in response to hypoxia [11]. In NSCLC VEGF expression is associated with increased tumor microvasculature and probably poor prognosis [12,13]. It should be noted that tumor vasculature has morphological differences when compared to the normal one; tumor blood vessels are highly permeable, more dilated and more convoluted, resulting in abnormalities in blood flow [14].

132

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

Fig. 1. VEGF and VEGFR molecular pathway. VEGF = vascular endothelial growth factor; VEGFR = VEGF receptor.

Given the amount of data supporting the prominent role of VEGF pathway in the development of tumor vasculature, inhibition of this pathway has been proposed as a potential antitumor treatment. Two strategies have been pursued in clinical practice in order to restrict tumor vasculature development; either the use of monoclonal antibodies (mAbs) against VEGF or small molecule tyrosine kinase inhibitors (TKIs) to target the tyrosine kinase domain of VEGFRs [15].

3. Monoclonal antibodies 3.1. Bevacizumab Bevacizumab is a recombinant, humanized, monoclonal antibody against VEGF, and is the most extensively studied antiangiogenic agent. A key phase III trial, Eastern Cooperative Oncology Group (ECOG) 4599 trial demonstrated prolongation of median overall survival (OS) (hazard ratio [HR], 0.79; 95% confidence interval [CI] 0.67–0.92; and p-value = 0.003) by two months for the combination of bevacizumab and paclitaxel/carboplatin followed by bevacizumab until disease progression compared to the same chemotherapy regimen plus placebo [16]. Progression free survival (PFS) and overall response rate (ORR) were also higher in the bevacizumab arm. Subsequently, the European Avastin

in Lung (AVAiL) [17] phase III trial, evaluated chemotherapy in combination with two doses of bevacizumab. It should be noted that the study was designed to compare both bevacizumab arms with placebo, but not between each other. In this trial also patients in the bevacizumab arm received bevacizumab until progression after the completion of chemotherapy. This study failed to yield OS prolongation (HR, 0.93; 95% CI 0.78–1.11, p-value = 0.420 and HR, 1.03; 95% CI 0.86–1.23, p-value = 0.761; for the 7.5 and 15 mg/kg groups, respectively, vs placebo), although PFS and ORR were significantly longer for either dose of the drug [17,18] (Table 2). It is not clear why this discrepancy in OS was observed. It could be attributed to post study therapies, as the median survival of the AVAiL trial was >13 months for all treatment groups [18]. Furthermore, the AVAiL study enrolled a significant number of Asians who had never smoked; these patients were likely to had EGFR-activating mutations, and thus subsequent anti-EGFR treatment would have had a considerable effect on their OS [18]. Other potential explanations are a hypothetical smaller effect size of bevacizumab when combined with more effective chemotherapy or statistical power. Bevacizumab was registered in the United States based on the results of ECOG 4599 study and the drug was registered in Europe based on the data from both trials. Subsequent subgroup analysis of the ECOG 4599 study reported that elderly (≥70 years) patients did not derive any

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

133

Table 2 Phase III trials of bevacizumab in combination with chemotherapy, as first-line treatment in NSCLC. ECOG 4599 [16] CMT* ORR PFS OS 1-Year survival 2-year survival

15% 4.5 mo 10.3 mo 44% 15%

AVAiL [17,18]

CMT + Bev

p-Value

CMT**

CMT + Bev (7.5 mg/kg)

CMT + Bev (15 mg/kg)

35% 6.2 mo 12.3 mo 51% 23%

<0.001 <0.001 0.003

20.1% 6.1 mo 13.1 mo

34.1% 6.7 mo (p-value: 0.003) 13.6 mo (p-value: NS)

30.4% 6.5 mo (p-value: 0.03) 13.4 mo (p-value: NS)

CMT, chemotherapy; CMT*, carboplatin/paclitaxel; and CMT**, cisplatin/gemcitabine. mo, months; ORR, overall response rate; OS, overall survival; and Bev, bevacizumab.

survival benefit from the addition of bevacizumab, while they experienced significantly higher toxicity, when compared to their younger counterparts [19]. Seven treatment-related deaths were observed among elderly patients treated in the bevacizumab arm compared with only two deaths in the chemotherapy alone arm. A similar analysis of the AVAiL study reported similar OS in all treatment arms, regardless of age and more clinical problems related to bleeding for older (≥65 years of age) patients when compared to young in the placebo and bevacizumab 7.5 mg/kg arms [20]. Finally, an interim analysis to assess safety in older patients (≥65 years) of a phase IV study (SAIL study [21]) failed to demonstrate any difference in the incidence of serious adverse events between older and younger patients [22]. The discrepancies observed between these studies could be due to the lower cut-off age for elderly in AVAiL and SAIL trials as compared to ECOG trial (70 years), or better selection of patients in the former studies. In an unplanned subgroup analysis of the ECOG trial overall survival in women did not improve significantly with bevacizumab treatment, despite significant progression-free survival difference [23]. This finding has not been observed in the AVAiL study [17]. The ECOG 4599 study reported significantly higher toxicity for patients receiving bevacizumab. Indeed, the rates of hypertension, proteinuria, bleeding, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache were significantly higher in the paclitaxel–carboplatin–bevacizumab group than in the paclitaxel–carboplatin group [16]. Importantly, there were only two treatment related deaths in the chemotherapy arm and 15 in the bevacizumab arm [16]. Similarly, in the AVAiL study, treatment related deaths were higher in the 15 mg/kg bevacizumab arm (1% higher death rate due to serious adverse events) while it was similar in the 7.5 mg/kg bevacizumab arm and chemotherapy alone arm [17]. Incidence of neutropenia, vomiting, hypertension, and epistaxis were also higher with either dose of bevacizumab [17]. Moreover, squamous histology, metastases to central nervous system (CNS), history of hemoptysis, and history of documented hemorrhagic diathesis were reported as exclusion criteria in both studies, raising concerns about limited potential use of bevacizumab to selected NSCLC patients. Two large phase IV studies have confirmed that bevacizumab is safe and feasible in combination with chemotherapy in 1st line NSCLC

treatment [SAIL [21] and ARIES [24]]. The SAIL study enrolled 1065 NSCLC patients receiving chemotherapy in combination with bevacizumab. Only 64 of the 299 serious adverse events (16%) were bevacizumab related. Additionally, only 17% of the enrolled patients experienced a bleeding event (all were less than grade III) and only 14% of the patients reported hypertensive events [21]. ARIES is a phase IV trial assessing bevacizumab efficacy and safety among a broader population of NSCLC patients in a real-world setting [24]. The study enrolled almost 2000 patients with advanced NSCLC whose first-line therapy included bevacizumab. Only 3% of patients experienced a grade III–V bleeding event, and 0.1% a central nervous system grade III–V bleeding event. Finally, a serious arteriothrombotic event was reported in only 2% of patients. The PASSPORT trial, a phase II trial with 115 patients evaluated the safety of bevacizumab in patients with brain metastases [25]. The study reported no CNS bleeding events (≥grade II). However there were two were grade V events (pulmonary hemorrhages), and one grade IV, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event. A small phase II trial (BRIDGE trial) evaluated bevacizumab in patients with squamous histology [26]. Only one of the 31 enrolled patients (3.2%) developed pulmonary hemorrhage (≥grade III). These data suggest that bevacizumab might be safe and feasible in patients with brain metastases although in patients with squamous histology it should still be considered as experimental. 3.2. AVE0005 (VEGF-trap) AVE0005 is a chimeric, fusion molecule that combines the extracelluler domains of VEGFR-1 and VEGFR-2, fused to the Fc domain of the IgG1 human immunoglobulin. It binds with high affinity to all isoforms of circulating VEGF and prevents its binding to the cell membrane receptor. This agent has been tested in the context of a phase II trial as a single agent at a dose of 4.0 mg/kg every 2 weeks in platinum- and erlotinibresistant NSCLC adenocarcinoma patients [27]. The ORR was 2.0%, while median PFS and median OS were 2.7 months and 6.2 months, respectively. Six- and twelve-month survival rates were 54% and 29%, respectively. Common grade III and IV toxicities included dyspnea (21%), hypertension (23%), and proteinuria (10%). Two cases of grade V hemoptysis were

134

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

reported, and one case each of tracheoesophageal fistula, decreased cardiac ejection fraction, cerebral ischemia, and reversible posterior leukoencephalopathy. A phase III randomized trial comparing docetaxel vs docetaxel + VEGF-trap in second line setting is ongoing.

4. VEGF-receptors tyrosine kinase inhibitors The second approach tested in clinical practice for the inhibition of the VEGF downstream pathway is VEGFR small molecule tyrosine-kinase inhibitors (TKIs). A growing number of TKIs are being tested in NSCLC (Table 3). 4.1. Sorafenib Sorafenib inhibits VEGFR-2, raf-kinases, platelet derived growth factor beta (PDGFR-␤), and c-kit [28]. Two phase II trials evaluated sorafenib as single-agent in chemo-naïve [29] or previously treated [30] patients with NSCLC and its activity was considered as moderate. Furthermore, a randomized phase II trial of sorafenib vs placebo in 97 NSCLC patients who had received at least two prior treatment lines, demonstrated a significant prolongation of PFS (3.6 months vs 1.9 months; p-value:0.01) [31]. A randomized, placebo-controlled phase III trial of single-agent sorafenib as third/fourth line of treatment, is currently ongoing (NCT00863746). The combination of sorafenib with platinum-based doublets was well tolerated with diarrhea and rash being the most common side effects and with encouraging results [32,33]. On the basis of this trial three phase III studies of sorafenib in combination with chemotherapy (two with carboplatin/paclitaxel and one with gemcitabine/cisplatin [NExUS trial]) were initiated. However, the largest of these trials (ESCAPE trial, carboplatin/paclitaxel ± sorafenib) has been prematurely closed, after interim analysis showed that the study would not meet its primary end-point of improved survival [34]. The ESCAPE trial allowed for the inclusion of patients with squamous histology. In subset analysis, more treatment related deaths were observed in patients with squamous histology in the sorafenib arm [34]. As a consequence the NExUS trial was amended and squamous histology was considered as an exclusion criterion. Recently, results of NExUS trial were also reported; the trial failed to demonstrate a significant prolongation of OS, although a significant prolongation of PFS was observed [35]. Some recent data suggest that sorafenib may be more effective in patients with NSCLC who have KRAS mutations [36,37]. 4.2. Sunitinib Sunitinib has been tested in the context of phase II trials, in previously treated NSCLC patients. The drug was administered either in a 4 weeks on and 2 weeks off schedule [38], or continuously [39]. Response rate were 11.1%

and 2.1% with the two schedules, respectively. Patients with brain metastases and significant hemoptysis were excluded from both trials. Fatigue, dyspnea and nausea were the most common adverse events. Two treatment-related deaths due to hemorrhage were observed with the 4 weeks on–2 weeks off schedule [38] while two additional fatal events (disseminated intravascular coagulation, pneumothorax) were considered as possibly related to sunitinib. One treatment-related death due to congestive heart failure was observed with the continuous administration [39]. A randomized phase II trial evaluated the addition of sunitinib to carboplatin/paclitaxel/bevacizumab triplet. The addition of sunitinib was not feasible to the triplet due to toxicities [40]. A phase III trial is evaluating the erlotinib-sunitinib doublet vs single-agent erlotinib in the second-line setting (NCT00457392). Furthermore, another phase III trial is evaluating sunitinib as maintenance treatment (NCT00693992) in patients who have not progressed after chemotherapy with platinum-based doublet (with or without bevacizumab). 4.3. Pazopanib Pazopanib is an oral small-molecule TKI that inhibits VEGFR-1, -2 and -3, PDFGR-␣ and -␤ and c-kit [41]. In phase I testing the drug was in general well-tolerated [42] with hypertension, fatigue and gastrointestinal disorders beeing the main adverse events [42]. Pazopanib has been tested as neoadjuvant treatment in a phase II trial in 35 treatmentnaive NSCLC patients with stage I/II disease [43]. Five patients (14.3%) achieved a response, while the most common adverse events were hypertension, diarrhea and fatigue. An increase in pazopanib target genes was observed after treatment (VEGFR-1, PDGFR-␣, and PDGFR-␤) [43]. A randomized phase II trial is evaluating the combination of erlotinib/pazopanib vs erlotinib in previously treated NSCLC patients with stage IIIB/IV disease (NCT01027598), while a placebo-controlled, randomized phase II/III trial is testing pazopanib as adjuvant treatment in patients with stage I disease who have undergone surgical excision. Several clinical trials are evaluating pazopanib in combination with chemotherapy as first or second line treatment. 4.4. Cediranib Cediranib, is a small-molecule TKI that targets the VEGFR-1, -2, -3, and PDGFR␣ and -␤ [44]. The combination of cediranib with carboplatin/paclitaxel was found feasible and active as first-line of advanced NSCLC [45]. The most common grade III/IV toxicities were fatigue, hypertension, diarrhea, anorexia, mucositis, and thrombosis. On the basis of these results a randomized phase II/III trial (BR.24) of cediranib (30–45 mg/day) plus carboplatin/paclitaxel vs chemotherapy alone as first-line therapy was initiated. Although this trial demonstrated a significant ORR benefit in favor of cediranib (38% vs 16%; p < 0.0001), did not proceed to phase III due to significant toxicity

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

135

Table 3 Antiangiogenesis tyrosine kinase inhibitors in clinical development. Agent

Target

Phase

Sorafenib [34,89]

VEGFR2/3, C-RAF, B-RAF, PDGFR-β, c-kit

Phase III (1st line TXL/Carbo ± sorafenib prematurely stopped 1st line GMB-CDDP ± sorafenib negative for OS)

Sunitinib [38,39]

VEGFR1/2/3, FLT PDGFR-β, c-kit

Phase III maintenance, after platinum-based CMT:ongoing erlotinib ± sunitinib 2nd line setting: ongoing

Pazopanib [43]

VEGFR1/2/3, PDGFR-α/β, c-kit

Phase II (2nd line erlotinib ± pazopanib:ongoing) Phase II/III (adjuvant in stage I:ongoing)

Cediranib [46]

VEGFR1/2/3 PDGFR-β, c-kit

Phase II (1st line TXL/Carbo ± cediranib; stopped due to toxicity) Phase II (1st line TXL/Carbo ± cediranib:ongoing)

BIBF1120 [90]

VEGFR1/2/3,PDGFR-α, -β FGFR-1,-2,-3

Phase III 2nd line: docetaxel ± BIBF1120: ongoing 2nd line: pemetrexed ± BIBF1120: ongoing

Axitinib [52]

VEGFR1/2/3, PDGFR-α, c-kit

Phase II (single agent ORR:9.4%) Phase II (in combination with TXL/Carbo ORR:29%; in combination with GMB/CDDP ORR: 26%)

Motesanib [55]

VEGFR1/2/3, PDGFR, c-kit

Phase III (TXL/Carbo ± motesanib:negative for OS)

Vatalanib [91]

VEGFR1/2/3, PDGFR-β, c-kit

Phase II (2nd line monotherapy, ORR: 2% with once daily dosing; 5% with twice daily dosing)

ABT-869

VEGFR1/2/3,PDGFR

Phase II (2nd line monotherapy, ORR: 0% for 0.10mg/kg daily dosing; 7% for 0.10 mg/kg daily dosing)

CMT, chemotherapy; TXL, paclitaxel; Carbo, carboplatin; GMB, gemcitabine; CDDP, cisplatin; DLT, dose limiting toxicity; ORR, overall response rate; and OS, overall survival. VEGFR, vascular endothelial growth factor receptor; c-KIT, stem cell factor receptor; FGFR, fibroblast growth factor receptor; and PDGFR, platelet- derived growth factor receptor.

considerations in the cediranib arm [46]. A new phase III has initiated (BR.29 trial; NCT00795340) with a lower dose of cediranib (20 mg/day). A phase II trial of cediranib in combination with pemetrexed as second/third treatment is ongoing. Preliminary analysis for the first 31 patients yielded an ORR of 16% and a disease control rate of 71% [47]. Most common toxicities were neutropenia, fatigue and diarrhea.

daily. Dose-limiting toxicities (≥grade III) comprised of transaminase elevations, fatigue, anorexia, confusion, and gastrointestinal disorders. BIBF 1120 is being evaluated in the context of two randomized phase III trials in combination with chemotherapy as second line treatment: the first is testing the docetaxel/BIBF1120 vs docetaxel (LUME-Lung 1; NCT00805194) and other pemetrexed/BIBF1120 vs pemetrexed (LUME-Lung 2; NCT00806819).

4.5. BIBF 1120 4.6. Axitinib BIBF 1120 is an oral TKI that inhibits VEGFR-1, -2, and -3, PDGFR-␣ and -␤, and FGFR-1, -2, and -3 [48]. BIBF 1120 has been tested in the context of a phase II trial (two different doses of 150 mg and 250 mg), in 73 pretreated NSCLC patients with encouraging results (median PFS and OS of 11.6 weeks and 37.7 weeks, respectively, in patients with performance status of 0–1) and a very favorable toxicity profile [49]. Most common grade III/IV adverse events included reversible liver toxicity, diarrhea and nausea. BIBF 1120 has also been evaluated in combination with pemetrexed as second line therapy for the treatment of NSCLC [50]. The maximum tolerated dose of BIBF 1120 in combination with full dose pemetrexed was 200 mg twice

Axitinib, is a TKI that blocks VEGFR-1, -2, -3 and PDGFR-␣ and -␤ [51]. An open-label, single-arm, multicenter, phase II study of axitinib as first/second line in 32 patients with advanced NSCLC [52] demonstrated encouraging results with an ORR of 9%, median PFS of 4.9 months and median OS of 14.8 months. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Most common grade III treatment-related adverse events comprised of fatigue (22%), hypertension (9%), and hyponatremia (9%). Axitinib has also been evaluated in combination with chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) [53].

136

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

Dose-limiting toxicities were fatigue, proteinuria, and rash. Of 43 patients evaluable for response, the ORR was 29% with axitinib plus carboplatin/paclitaxel (n = 24) and 26% with axitinib plus cisplatin/gemcitabine (n = 19). 4.7. Motesanib Motesanib, is an antiangiogenic TKI that inhibits VEGFR1, -2, and -3 and PDGFR [54]. A phase III trial tested motesanib as first-line treatment in 1009 NSCLC patients with non-squamous histology, in combination with carboplatin/paclitaxel [55]. The addition of motesanib did not significantly improved the primary end-point of OS (13 months vs 11 months for the motesanib and placebo arms, respectively; p-value: 0.137). A significant although clinically irrelevant PFS prolongation was observed (5.6 months vs 5.4 months for the motesanib and placebo arms, respectively; p-value: 0.0006). Grade ≥III adverse events occurring more frequently in motesanib and placebo arms included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade V toxicity was higher in the motesanib arm (14% vs 9%; p-value: not-reported) [55].

5. Vascular disrupting agents (VDAs) While angiogenesis inhibitors prevent the formation of new blood vessels another category of agents that target tumor vasculature, the so called vascular disrupting agents (VDAs), target the endothelial cells of established tumor blood vessels and result in failure of the tumor vascular structure leading to blood and oxygen deprivation and ischemia in the central component of the tumor [56]. 5.1. Vadimezan (ASA404) Vadimezan is an analog of flavone acetic acid and is one of the most widely studied VDAs [57]. Encouraging results were observed in NSCLC in combination with chemotherapy in the context of a phase II trial [58]. Unfortunately these results were not confirmed in phase III trials. A recent large phase III trial by Lara et al. evaluated vadimezan in combination with the carboplatin/paclitaxel doublet as first line treatment in NSCLC [59]. No significant difference in OS (study’s primary end-point) was observed between vadimezan (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (HR: 1.01; 95% CI 0.85–1.19; p-value = 0.535). Because of these results and the negative results in the second-line setting, the development of vedimezan in lung cancer was stopped [60]. 5.2. ABT-751 ABT-751 is another VDA with potent preclinical anticancer activity. It has been tested as second line treatment

in NSCLC in combination with pemetrexed, in the context of a randomized phase II trial [61]. Although the trial failed to meet its primary end-point (median PFS: 2.3 months for ABT-751 vs 1.9 for placebo; p-value = 0.819) however, differences in PFS (p-value = 0.112) and OS (p-value = 0.034; median 3.3 months vs 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup.

6. Inhibition of multiple pathways Given the heterogeneity of NSCLC cases and the potential crosstalk between multiple pathways, multiple inhibition of intracellular pathways crucial for tumor growth and angiogenesis might offer an additional clinical benefit. The most widely studied combination of targeted agents is the dual inhibition of the VEGF and the epidermal growth factor receptor (EGFR) pathways. Early clinical data of phase II trials demonstrated that the combination of bevacizumab and erlotinib (an EGFR TKI) is feasible and with encouraging results [62–64]. Unfortunately a phase III trial comparing erlotinib vs erlotinib + bevacizumab (BETA-Lung trial) in second-line setting failed to reach its primary end-point of OS prolongation although it demonstrated a PFS prolongation, reducing the enthusiasm for this promising approach [65]. On the contrary, the ATLAS phase III trial demonstrated a significant PFS prolongation in favor of the bevacizumab plus erlotinib combination as maintenance therapy following first-line treatment with chemotherapy plus bevacizumab, compared to maintenance therapy with bevacizumab plus placebo [66] (Table 4). This trial failed to demonstrate an OS benefit but it should be noted that it was not powered to detect OS difference. Rather than using two different single-agents to individually block different targets, another interesting approach is to use a single-agent that inhibits multiple targets. Vandetanib is an orally available TKI that inhibits multiple kinases (VEGFR-2, -3, EGFR, RET). In phase II trials vandetanib has shown promising results [67,68] and on the basis of these results three phase III trials were initiated (Table 5). However all these trials were negative or with moderate results and the development of vandetanib for the treatment of NSCLC was discontinued [69].

7. Biomarkers of response to antiangiogenic treatment One of the major challenges in the field of anti-cancer treatment is to develop predictive biomarkers that will allow for the selection of patients who are likely to benefit from a particular agent (or combination) while saving others from the toxicity of an ineffective therapy and health-care systems from the costs of expensive but non-beneficial drugs. Although several biomarkers have emerged in the field of antiangiogenic therapies none of these has been

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

137

Table 4 Phase III trials of the bevacizumab/erlotinib combination. Trial

N

ORR

PFS

OS

Primary end-point

BeTa [65] Erlotinb/placebo Erlotinib/bevacizumab

Double-blind, placebo-controlled, phase III, recurrent or refractory NSCLC

637

6%13%

1.7 mo 4.3 mo

9.2 mo 9.3 mo

OS

ATLAS [66,92] Bevacizumab/placebo Bevacizumab/Erlotinib

Double-blind, placebo-controlled, phase III, maintenance treatment, following bev + platin-containing doublet chemo

768

NR

3.7 mo 4.8 mo p = 0.0012

13.3 mo 14.4 mo p = 0.56

PFS

NR, not reported; and bev, bevacizumab.

prospectively validated and widely accepted as a reliable tool for the selection of patients who will benefit from antiangiogenic treatment. 7.1. Blood pressure Hypertension is a common side effect of antiangiogenic therapy. The grade of hypertension has been proposed as a potential predictive biomarker in patients treated with antiangiogenic therapy. A subgroup analysis of the pivotal ECOG 4599 trial of bevacizumab in NSCLC suggested that onset of high blood pressure (>150/100 mmHg) during treatment with bevacizumab may be associated with improved outcomes [70]. In a multivariate Cox model comparing patients on bevacizumab treatment with high blood pressure (HBP) with those on placebo arm gave an OS hazard ratio (HR) of 0.60 (p-value = 0.001); comparing those on bevacizumab without HBP with those on chemotherapy alone, the OS HR was 0.86 (p-value = 0.05). Comparing the bevacizumab HBP group with chemotherapy alone arm gave an adjusted PFS HR of 0.54 (p-value < 0.0001) and comparing those on bevacizumab without HBP to those on placebo arm, the HR was

0.72 (p-value < 0.0001) [70]. Similarly, a pooled analysis of six phase II trials of axitinib with 307 patients with various tumor types (among them 32 patients with NSCLC) demonstrated that the occurrence of diastolic blood pressure > 90 mmHg might be associated with longer OS [71]. However, these observations should be further validated in larger prospective trials. 7.2. VEGF as a biomarker As expected the expression of VEGF has been one of the most extensively studied predictive biomarkers. Low baseline circulating levels of VEGF could be predictive of PFS advantage in NSCLC patients treated with vandetanib [72]. On the other hand immunohistochemical expression of VEGFA and VEGFR-2 had no prognostic impact in 102 operated NSCLC patients [73]. Similarly, a phase II/III trial examining chemotherapy plus bevacizumab in patients with advanced NSCLC failed to demonstrate a predictive role for highbaseline circulating plasma VEGF in connection with PFS and OS, despite a correlation with better ORR [74]. These discrepancies between the reported results underline the need

Table 5 Phase III trials of vandetanib in the treatment of NSCLC. Trial

n

ORR

PFS

OS

ZODIAC [93] Docetaxel/Vandetanib Docetaxel/Placebo

Phase III, placebo-controlled Second line treatment Primary end-point: PFS

694 697

17% 10% p = 0.001

4.0 mo 3.2 mo p < 0.001

HR:0.91 p = 0.196

ZEAL [94] Pemetrexed/Vandetanib Pemetrexed/Placebo

Phase III, placebo-controlled Second line treatment Primary end-point: PFS

56 278

19% 8% p < 0.001

17.6 weeks 11.9 weeks p = 0.108

10.5 mo 9.2 mo p = 0.219

ZEST [95] Erlotinib Vandetanib

Phase III Second line treatment Primary end-point: PFS

617 623

12% 12% p = NS

2.0 mo 2.6 mo p = 0.721

7.8 mo 6.9 mo p = NS

ZEPHYR [96] Vandetanib Placebo

Phase III, placebo-controlled ≥third-line treatment after failure of primary CMT and EGFR TKI Primary end-point: OS

617 307

2.6% 0.7% p = 0.028

HR 0.63 p < 0.0001

8.5 mo 7.8 mo p = 0.527

ZODIAC, Zactima in combination with docetaxel in NSCLC; ZEST, Zactima efficacy when studied versus Tarceva; ZEAL, Zactima efficacy with Alimta in lung cancer; ZEPHYR, Zactima efficacy trial for NSCLC patients with history of EGFR-TKI chemo-resistance; CMT, chemotherapy; ORR, overall response rate; PFS, progression free survival; OS, overall survival; and NS, non-significant.

138

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

for further studies regarding the role of VEGF as predictive biomarker. While the use of circulating VEGF and VEGF expression as a predictive biomarker remains to be elucidated there is also increasing interest about the role of VEGF genotype and VEGF single nucleotide polymorphisms (SNPs). It has been reported that the variant C allele of the VEGF +405G>C polymorphism has been associated with significantly improved survival in early stage NSCLC [75]. 7.3. Other biomarkers Several other proteins such as placental-derived growth factor (PIGF), VEGF receptors, inflammatory cytokines, and blood circulating cells have been studied as potential biomarkers, but limited data are available about NSCLC yet [76]. Similarly, several imaging techniques have been proposed and tested as predictive factors, such as magnetic resonance imaging (MRI) and computerized tomography (CT)-based assessment of changes in blood flow, blood volume, vessels permeability or vascular density, but again limited data are available [76].

8. Resistance to antiangiogenic treatment Development of resistance to antiangiogenic treatment represents a significant problem that is faced in routine clinical practice. With respect to intrinsic resistance, nonresponsive tumors, not pre-treated with chemotherapy, are characterized by a preexisting infiltration of bone marrowderived cells, principally CD11b+Gr1+ myeloid cells, which were shown to express a number of pro-angiogenic factors [77]. When sensitive tumor cells were mixed with cells that are resistant to anti-VEGF antibodies and transplanted into other mice, the transplanted tumors resist anti-VEGF therapy [10]. On the contrary, responsive tumor types had low levels of such inflammatory cells. Pharmacological impairment of myeloid cell recruitment rendered the otherwise resistant tumors responsive to the VEGF blockade [77]. It has been observed that late-stage tumors express a plethora of proangiogenic factors, including fibroblast growth factor 2 (FGF2), compared to earlier disease stages that preferentially expressed VEGF [78]. It is supported that preexisting pro-angiogenic factors such as FGF2 and others in late-stage metastatic tumors could enable continuing angiogenesis even in the presence of bevacizumab therapy and inhibition of VEGF pathway could not sufficiently block angiogenesis [78]. Intrinsic resistance can also occur as a result of tumor activation and enhancement of invasion and metastasis that facilitates access to normal tissue vasculature without obligate neovascularization, in vasculature rich organs such as the lungs [79]. Finally, another mechanism of inherent resistance that has been proposed is the absence of

VEGF and VEGFR in metastatic tumors growing in certain organ sites [80]. Anti-angiogenic therapy itself may also trigger escape mechanisms that rescue tumor vascularization. VEGFR2 blockade in tumor-bearing mice has been reported to up-regulate the expression of several angiogenesis stimulators such as PlGF, VEGF, angiopoietin-1, FGF and basic fibroblast growth factor (bFGF) [81,82]. This observation occurred in patients with glioblastoma where plasma levels of FGF-2 and stromal-derived factor 1 (SDF1) were increased when disease progression occurred under VEGF-targeted therapy [83], and in colorectal and renal cancer patients whereas PlGF and VEGF were also upregulated after treatment with antiangiogenic treatment [84,85]. Another mechanism that has been involved in resistance to antiangiogenic treatment involves mutations of genes such as p53. A very interesting study by Yu et al. demonstrated that tumor cells deficient in p53 present a reduced rate of apoptosis under hypoxic conditions, a condition that might reduce their reliance on vascular supply, and therefore their sensitivity to antiangiogenic therapy [86]. According to their work mice bearing tumors derived from p53(−/−) HCT116 human colorectal cancer cells were less responsive to antiangiogenic therapy compared to mice bearing isogenic p53(+/+) tumors. Therefore, genetic alterations might decrease the vascular dependence of tumor cells and could potentially influence the therapeutic response of tumors to antiangiogenic therapy [86]. Also prompt vascular remodeling of tumor-associated vasculature as a result of antiangiogenic treatment has been reported as another mechanism of resistance to this kind of treatment [87].

9. Future challenges The introduction of antiangiogenic therapy has led to some progress in the treatment of NSCLC. However, despite this progress several important issues remain challenging for the future. First of all we need to identify reliable predictive factors which will allow the selection of patients who are most likely to benefit from a particular agent and save others from toxicity of ineffective treatments. Anti-EGFR TKIs represent one of the best paradigms of treatment that had evolved on the basis of a reliable predictive factor [88]. It is obvious that limited therapeutic benefit will be achieved with targeted therapies in cases when a “clear target” has not been identified, while a significant benefit is obtained in cases of identification of patients’ subsets to whom these therapies are effective. Another major challenge is to find out the way to most effectively combine these targeted agents to conventional therapies. We need to find out the best way to combine or sequence cytotoxic therapies, radiotherapy and antiangiogenic agents, in order to achieve the maximum clinical benefit. Furthermore, it is challenging to evaluate the role of antangiogenic treatments in other disease settings (adjuvant,

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

neo-adjuvant, and maintenance). Several clinical trials are currently testing this issue. NSCLC development is a multistep process linked to several intracellular pathways and several genetic alterations. So we need to further improve our understanding regarding molecular alterations in different lung cancer histologies in order to develop more efficient and less toxic treatments and successfully tailor targeted therapies to individual tumor and patient characteristics. Additionally, based on the heterogeneity of NSCLC and the potential crosstalk between multiple pathways, using a single targeted agent may not be the optimal strategy to substantially improve clinical outcome and multiple inhibition of intracellular pathways might offer an additional clinical benefit. Therefore, another significant challenge for future research in the field of antiangiogenic therapy is to develop combinations of agents blocking several different pathways, or single-agents that target more than one pathway. The evolution of antiangiogenic treatment has reached an interesting point. An improved and more thorough understanding of the molecular mechanisms determining tumor angiogenesis and response and resistance to antiangiogenic therapies is required to further improve the benefits of such drugs.

Conflict of interest No conflict of interest to declare.

Reviewers Dr. Martin Barr, Institute of Molecular Medicine, St. James Hospital, Thoracic Oncology Research, Dublin 8, Ireland. Dr. Markus Joerger, Cantonal Hospital, Medical Oncology & Clinical Pharmacology, Rorschacherstr. 95, CH-9007 St. Gallen, Switzerland.

References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer Journal for Clinicians 2011;61:69–90. [2] Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and metaanalysis of individual patient data from 16 randomized controlled trials. Journal of Clinical Oncology 2008;26:4617–25. [3] Carney DN. Lung cancer – time to move on from chemotherapy. The New England Journal of Medicine 2002;346:126–8. [4] Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nature Medicine 2000;6:389–95. [5] Folkman J. Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery 2007;6:273–86. [6] Folkman J. Role of angiogenesis in tumor growth and metastasis. Seminars in Oncology 2002;29:15–8.

139

[7] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature Medicine 2003;9:669–76. [8] Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–9. [9] Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocrine Reviews 1997;18:4–25. [10] Kerbel RS. Tumor angiogenesis. The New England Journal of Medicine 2008;358:2039–49. [11] Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocrine Reviews 2004;25:581–611. [12] Fontanini G, Vignati S, Boldrini L, et al. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clinical Cancer Research 1997;3:861–5. [13] Yuan A, Yu CJ, Kuo SH, et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. Journal of Clinical Oncology 2001;19:432–41. [14] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58–62. [15] Pallis AG, Serfass L, Dziadziusko R, et al. Targeted therapies in the treatment of advanced/metastatic NSCLC. European Journal of Cancer 2009;45:2473–87. [16] Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England Journal of Medicine 2006;355:2542–50. [17] Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. Journal of Clinical Oncology 2009;27:1227–34. [18] Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatingemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Annals of Oncology 2010;21:1804–9. [19] Ramalingam SS, Dahlberg SE, Langer CJ, et al. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. Journal of Clinical Oncology 2008;26:60–5. [20] Leighl NB, Zatloukal P, Mezger J, et al. Efficacy and safety of bevacizumab-based therapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer in the phase III BO17704 study (AVAiL). Journal of Thoracic Oncology 2010;5: 1970–6. [21] Crino L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncology 2010;11:733–40. [22] Jager E, Wu Y, Mezger J, et al. Safety of first-line bevacizumab (bv) plus chemotherapy in elderly patients (pts) with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): MO19390 (SAIL) study group. Annals of Oncology 2008;19, abstr 240P. [23] Brahmer JR, Dahlberg SE, Gray RJ, et al. Sex differences in outcome with bevacizumab therapy: analysis of patients with advanced-stage non-small cell lung cancer treated with or without bevacizumab in combination with paclitaxel and carboplatin in the Eastern Cooperative Oncology Group Trial 4599. Journal of Thoracic Oncology 2011;6:103–8. [24] Wozniak A, Garst J, Jahanzeb M, et al. Clinical outcomes (CO) for special populations of patients (pts) with advanced non-small cell lung cancer (NSCLC): results from ARIES, a bevacizumab (BV) observational cohort study (OCS). Journal of Clinical Oncology 2010;28, abstr 7618. [25] Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. Journal of Clinical Oncology 2009;27:5255–61.

140

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

[26] Hainsworth JD, Fang L, Huang JE, et al. BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer. Journal of Thoracic Oncology 2011;6:109–14. [27] Leighl NB, Raez LE, Besse B, et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinumand erlotinib-resistant adenocarcinoma of the lung. Journal of Thoracic Oncology 2010;5:1054–9. [28] Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Research 2004;64:7099–109. [29] Dy GK, Hillman SL, Rowland Jr KM, et al. A front-line window of opportunity phase 2 study of sorafenib in patients with advanced nonsmall cell lung cancer: North Central Cancer Treatment Group Study N0326. Cancer 2010;116:5686–93. [30] Blumenschein Jr GR, Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. Journal of Clinical Oncology 2009;27:4274–80. [31] Schiller HJ, Lee JW, Hanna NH, Traynor AM, Carbone DP. A randomized discontinuation phase II study of sorafenib versus placebo in patients with non-small cell lung cancer who have failed at least two prior chemotherapy regimens: E2501. Journal of Clinical Oncology 2008:26. [32] Okamoto I, Miyazaki M, Morinaga R, et al. Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Investigational New Drugs 2010;28:844–53. [33] Flaherty KT, Schiller J, Schuchter LM, et al. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clinical Cancer Research 2008;14:4836–42. [34] Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. Journal of Clinical Oncology 2010;28:1835–42. [35] Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. Journal of Clinical Oncology 2012;30:3084–92. [36] Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discovery 2011;1:44–53. [37] Smit EF, Dingemans AM, Thunnissen FB, Hochstenbach MM, van Suylen RJ, Postmus PE. Sorafenib in patients with advanced non-small cell lung cancer that harbor K-ras mutations: a brief report. Journal of Thoracic Oncology 2010;5:719–20. [38] Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. Journal of Clinical Oncology 2008;26:650–6. [39] Novello S, Scagliotti GV, Rosell R, et al. Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. British Journal of Cancer 2009;101: 1543–8. [40] Socinski M, Scappaticci FA, Samant M, Kolb MM, Kozloff M. Safety and efficacy of combining sunitinib with bevacizumab + paclitaxel/carboplatin in non-small cell lung cancer. Journal of Thoracic Oncology 2010;5:354–60. [41] Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Current Oncology Reports 2007;9:115–9. [42] Schutz FA, Choueiri TK, Sternberg CN, Pazopanib:. Clinical development of a potent anti-angiogenic drug. Critical Reviews in Oncology/Hematology 2011;77:163–71. [43] Altorki N, Lane ME, Bauer T, et al. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. Journal of Clinical Oncology 2010;28:3131–7.

[44] Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Research 2005;65:4389–400. [45] Laurie SA, Gauthier I, Arnold A, et al. Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. Journal of Clinical Oncology 2008;26:1871–8. [46] Goss GD, Arnold A, Shepherd FA, et al. Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. Journal of Clinical Oncology 2010;28:49–55. [47] Gadgeel SM, Wozniak A, Edelman M, et al. Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2009;27, abstr e19007. [48] Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Research 2008;68:4774–82. [49] Reck M, Kaiser R, Eschbach C, et al. A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Annals of Oncology 2011;22:1374–81. [50] Ellis PM, Kaiser R, Zhao Y, Stopfer P, Gyorffy S, Hanna N. Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clinical Cancer Research 2010;16:2881–9. [51] Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clinical Cancer Research 2008;14:7272–83. [52] Schiller JH, Larson T, Ou SH, et al. Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. Journal of Clinical Oncology 2009;27:3836–41. [53] Martin L, Kozloff M, Krzakowski M, et al. Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors. Journal of Clinical Oncology 2009;27, abstr 3559. [54] Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Research 2006;66:8715–21. [55] Scagliotti G, Vynnychenko I, Ichinose Y, et al. An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2012;30:2829–36. [56] Thorpe PE. Vascular targeting agents as cancer F therapeutics. Clinical Cancer Research 2004;10:415–27. [57] Head M, Jameson MB. The development of the tumor vasculardisrupting agent ASA404 (vadimezan, DMXAA): current status and future opportunities. Expert Opinion on Investigational Drugs 2010;19:295–304. [58] McKeage MJ, Von Pawel J, Reck M, et al. Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer. British Journal of Cancer 2008;99:2006–12. [59] Lara Jr PN, Douillard JY, Nakagawa K, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. Journal of Clinical Oncology 2011;29: 2965–71. [60] Novartis discontinues ASA404 clinical trial program and shifts focus to other cancer compounds in early and late

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69] [70]

[71]

[72]

[73]

[74]

[75]

stage development. Basel, Switzerland: Novartis; 2010 http://www.novartis.com/newsroom/media-releases/en/2010/1461276.shtml Rudin CM, Mauer A, Smakal M, et al. Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology 2011;29:1075–82. Herbst RS, O’Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. Journal of Clinical Oncology 2007;25:4743–50. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. Journal of Clinical Oncology 2005;23:2544–55. Zappa F, Droege C, Betticher D, et al. Bevacizumab (B) and erlotinib (E) as first-line therapy in metastatic nonsquamous non-small cell lung cancer (NSCLC) followed by platinum-based chemotherapy (CT) at disease progression (PD): a multicenter phase II trial, SAKK 19/05. Journal of Clinical Oncology 2011;79, abstr 7651. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011;377:1846–54. Kabbinavar F, Miller VA, Johnson BE, O’Connor P, Soh C, for the Ai. Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2010;28, abstr 7526. Heymach JV, Johnson BE, Prager D, et al. Randomized, placebocontrolled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. Journal of Clinical Oncology 2007;25:4270–7. Natale RB, Bodkin D, Govindan R, et al. Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase ii study. Journal of Clinical Oncology 2009;27:2523–9. Commander H, Whiteside G, Perry C. Vandetanib: first global approval. Drugs 2011;71:1355–65. Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. Journal of Clinical Oncology 2010;28:949–54. Rini BI, Schiller HJ, Fruehauf JP, et al. Association of diastolic blood pressure (dBP) > 90 mmHg with overall survival (OS) in patients treated with axitinib (AG-013736). Journal of Clinical Oncology 2008;26, abstr 3543. Hanrahan EO, Ryan AJ, Mann H, et al. Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clinical Cancer Research 2009;15:3600–9. Bonnesen B, Pappot H, Holmstav J, Skov BG. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: relation to prognosis. Lung Cancer 2009;66:314–8. Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab – an Eastern Cooperative Oncology Group Study. Clinical Cancer Research 2008;14: 1407–12. Heist RS, Zhai R, Liu G, et al. VEGF polymorphisms and survival in early-stage non-small-cell lung cancer. Journal of Clinical Oncology 2008;26:856–62.

141

[76] Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nature Reviews Clinical Oncology 2009;6:327–38. [77] Shojaei F, Wu X, Malik AK, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnology 2007;25:911–20. [78] Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Research 1997;57:963–9. [79] Leenders WP, Kusters B, Verrijp K, et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clinical Cancer Research 2004;10:6222–30. [80] Karashima T, Inoue K, Fukata S, et al. Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice. International Journal of Clinical Oncology 2007;30:937–45. [81] Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299–309. [82] Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007;131:463–75. [83] Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83–95. [84] Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006;24:16–24. [85] Willett CG, Boucher Y, Duda DG, et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. Journal of Clinical Oncology 2005;23: 8136–9. [86] Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS. Effect of p53 status on tumor response to antiangiogenic therapy. Science 2002;295:1526–8. [87] Glade Bender J, Cooney EM, Kandel JJ, Yamashiro DJ. Vascular remodeling and clinical resistance to antiangiogenic cancer therapy. Drug Resistance Updates 2004;7:289–300. [88] Shepherd FA. Molecular selection trumps clinical selection. Journal of Clinical Oncology 2011;29:2843–4. [89] Bayer Healthcare Pharmaceuticals Inc., Onyx Pharmaceuticals Inc. Phase 3 trial of Nexavar in first-line advanced non-small cell lung cancer does not meet primary endpoint of overall survival; June 14, 2010. Available from: http://wwwonyx-pharmcom/viewcfm/685/ Phase-3-Trial-of-Nexavar-in-First-Line-Advanced-Non-Small-CellLung-Cancer-Does-Not-Meet-Primary-Endpoint-of-Overall-Survival [accessed 29.09.11]. [90] Reck M. BIBF 1120 for the treatment of non-small cell lung cancer. Expert Opinion on Investigational Drugs 2010;19:789–94. [91] Gauler TC, Besse B, Mauguen A, et al. Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Annals of Oncology 2011;23:678–87. [92] Miller VA, O’Connor P, Soh C, Kabbinavar F, for the Ai. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2009;27:LBA8002. [93] Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced

142

A.G. Pallis, K.N. Syrigos / Critical Reviews in Oncology/Hematology 86 (2013) 130–142

non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncology 2010;11:619–26. [94] de Boer RH, Arrieta O, Yang CH, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. Journal of Clinical Oncology 2011;29:1067–74. [95] Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. Journal of Clinical Oncology 2011;29:1059–66. [96] Lee J, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): a randomized, double-blind phase III trial (ZEPHYR). Journal of Clinical Oncology 2010;28, abstr 7525.

Biographies Dr. Athanasios Pallis, M.D., M.Sc., Ph.D. graduated from School of Medicine, University of Crete, in 1997. He was trained in medical oncology at the Medical Oncology Department of the University General Hospital of Heraklion, Crete (University of Crete). In 2003 he got his Ph.D. degree from the School of Medicine, in University of Crete. He has served as an EORTC fellow in 2008–2009. Dr. Pallis has served as a reviewer for several international journals. He has published more than 70 peer-reviewed, international articles and contributed in 7 chapters in international books. His main fields of interest are lung cancer, targeted therapies, and geriatric oncology. Konstantinos Syrigos, M.D., Ph.D. Assc. Professor and Head, Oncology Unit GPP, Athens School of Medicine, Visiting Professor of Thoracic Oncology, Yale School of Medicine, CT, USA. graduated from Athens School of Medicine in 1988. He was trained in internal medicine at the Laikon University Hospital (Athens University) and in medical oncology at the Hammersmith Hospital (London University). He got his M.D. thesis with

distinction from the Athens School of Medicine, in 1995 and his Ph.D. thesis from the Imperial College of Science, Technology and Medicine, London University, in 2000. He worked as Medical Oncologist Senior Registrar at the Hammersmith and St. Bartholomew’s Hospitals, in London and as consultant at the Sotiria General Hospital, in Athens. In 2002 he was appointed Assc. Professor of Oncology in Medicine and Head of the Sotiria Oncology Unit. From 2006 he is also visiting professor of Thoracic Oncology at Yale University, CT, USA. His main fields of interest are targeted therapies, drugs development as well as thoracic and head & neck oncology. Dr Syrigos participated in several international clinical trials Phase I–IV in lung, colon, head & neck and pancreatic cancer. He is a member of numerous scientific societies, including the European Society of Medical Oncology (ESMO), the European Respiratory Society (ERS), the American Society of Clinical Oncology (ASCO), the American Association of Cancer Research (AACR) and the International Association for the Study of Lung Cancer (IASLC). He is a manuscript reviewer for 18 scientific journals and currently serves on the editorial board of 5 scientific journals. He is the editor of 8 International Scientific Volumes. He has contributed 80 chapters in international books and he is the author of 290 peer-reviewed, international articles, with more than 4900 citations. He is currently sitting as member of the ESMO Translational Research Group and of the MASCC Board of Directors.