Targeting Angiogenesis in Advanced Non-Small Cell Lung Cancer

Authors: Philip E. Lammers MD, MSCI1 and Leora Horn MD, MSc1
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  • 1 From Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee

Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer.

Lung cancer is the leading cause of cancer-related mortality in the United States, with an estimated 228,190 new cases and 159,480 deaths in 2013.1 More than two-thirds of patients with lung cancer will present with advanced disease.2 The 5-year survival rate is approximately 15%. Standard platinum-based chemotherapy regimens are associated with survival of approximately 1 year in patients with advanced lung cancer.3 Approximately 60% of patients with stage IIIB/IV adenocarcinoma have a molecular mutation thought to drive tumor growth.4 However, only patients with epidermal growth factor receptor (EGFR) mutations (approximately 10%-15%) or anaplastic lymphoma kinase (ALK) rearrangements (approximately 5%) have an FDA-approved therapy available. Other potential targets have been identified, such as c-ros oncogene 1 (ROS1) gene fusions and BRAF mutations, and clinical trials using targeted agents are ongoing. Alternative targets continue to be investigated, one of which is angiogenesis, a necessary process in the growth and metastasis of solid tumors.5 Bevacizumab is the only antiangiogenic therapy FDA-approved for NSCLC,6 but other agents have been tested in advanced NSCLC. Currently, NCCN recommends that bevacizumab be considered in the first-line treatment setting for stage IV disease in combination with a platinum doublet, with continuation of bevacizumab until progression.2

The use of antiangiogenic agents is a rational approach to treating lung cancer, but must be balanced against the potential risks involved, which can be life-threatening. Researchers have been searching for potential biomarkers to identify patients for whom therapy with antiangiogenic inhibitors may be most beneficial. The current data for antiangiogenic agents vary widely among the studied drugs, and safety data are especially limited for many of the agents studied. This review summarizes the available efficacy and safety/tolerability data from clinical trials of antiangiogenic agents in advanced NSCLC. (For consistency, efficacy data have been converted to months using the following: 1 month = 4.2 weeks for data reported in weeks; 12 months = 365 days for data reported in days. For consistency, where necessary, progression-free and overall survivals have been rounded to the nearest tenth, and hazard ratio, confidence interval, and P values have been rounded to 2 decimal places.)

Efficacy and Safety of Antiangiogenic Agents for NSCLC

Antibody-Based Therapeutics

Bevacizumab: Bevacizumab is a humanized monoclonal antibody with a high affinity for vascular endothelial growth factor (VEGF).7 Bevacizumab binds to circulating VEGF, preventing it from binding to the VEGF receptor (VEGFR) and thereby inhibiting downstream signaling. The sites of action of bevacizumab and other antiangiogenic agents described in this article are depicted in Figure 1. Bevacizumab has been studied extensively in various malignancies, and certain adverse events (AEs), such as bleeding and thrombosis, are known to be associated with its use. In addition, hypertension and proteinuria are common throughout treatment, although these are generally manageable with antihypertensive therapies.

Figure 1
Figure 1

Targeting angiogenesis in lung cancer. Receptors and downstream signaling pathways involved in angiogenesis and sites of action of antiangiogenic antibody-based therapies and multitargeted tyrosine kinase inhibitors.

Abbreviations: AKT, protein kinase B; c-KIT, stem cell factor receptor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; FLT-3, fms-like tyrosine kinase 3; MEK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase; RAF, v-raf 1 murine leukemia viral oncogene homolog 1; RAS, retrovirus-associated DNA sequences; RET, rearranged during transfection; SRC, v-src sarcoma viral oncogene homolog; TKIs, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0146

Bevacizumab is the most studied antiangiogenic agent in advanced NSCLC (Tables 1 and 2). After promising results from a phase II study,8 ECOG 4599 was conducted as a randomized phase III trial comparing carboplatin/paclitaxel with or without bevacizumab in 878 patients with recurrent or advanced nonsquamous NSCLC.9 Improvements in median overall survival (OS), median progression-free survival (PFS), and response rate (RR) occurred in patients treated with bevacizumab compared with those in the chemotherapy arm: 12.3 versus 10.3 months; 6.2 versus 4.5 months; and 35% versus 15%, respectively. In an unplanned subset analysis, median PFS and RR were significantly improved with bevacizumab versus chemotherapy for both sexes; however, median OS was not improved in the female cohort but was improved among men (11.7 vs 8.7 months with chemotherapy).10 In another unplanned subset analysis, elderly patients (age ≥70 years) had improved median PFS and RR but no improvement in median OS.11 The most common grade 3 or higher AEs in the bevacizumab arm were neutropenia (26%), hypertension (7%), febrile neutropenia (5%), and bleeding events (4%).9 Compared with chemotherapy alone, bevacizumab plus chemotherapy was associated with higher rates of grade 4 neutropenia (26% vs 17%) and thrombocytopenia (1.6% vs 0.2%), and grade 3/4 febrile neutropenia (4.0% vs 1.8%), hyponatremia (3.5% vs 1.1%), hypertension (7.0% vs 0.7%), headache (3.0% vs 0.5%), rash or desquamation (2.3% vs 0.5%), and bleeding events (4.4% vs 0.7%).

Table 1

Overall Survival and Response Rate Data Reported in Selected Phase II and III Trials of Antiangiogenic Agents in NSCLC

Table 1Table 1Table 1

The AVAIL trial was a similarly designed phase III trial conducted in Europe and Canada to evaluate the efficacy of cisplatin and gemcitabine with or without bevacizumab (7.5 or 15.0 mg/kg) in 1043 patients with advanced or recurrent nonsquamous NSCLC.12 Median PFS (6.7 months in the bevacizumab, 7.5-mg/kg arm and 6.5 months in the bevacizumab, 15.0-mg/kg arm vs 6.1 months in the placebo arm) and RR (38% in the bevacizumab, 7.5-mg/kg arm and 35% in the bevacizumab, 15.0-mg/kg arm vs 22% in the placebo arm) were significantly improved in both bevacizumab-containing arms, but OS was not improved in either bevacizumab-containing arm compared with placebo (13.6, 13.4, and 13.1 months, respectively).13 Grade 3/4 AEs in the bevacizumab, 15.0-mg/kg arm included hypertension (9%), vomiting (9%), neutropenia (36%), bleeding (4%), and proteinuria (1%). Grade 3/4 AEs in the bevacizumab, 7.5-mg/kg arm included hypertension (6%), vomiting (7%), neutropenia (40%), bleeding (4%), and proteinuria (<1%). Pulmonary hemorrhage was observed in 1.5% of patients in the bevacizumab, 7.5-mg/kg arm; 0.9% in the bevacizumab, 15.0-mg/kg arm; and 0.6% in the placebo arm.

A phase II study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed and bevacizumab showed impressive results14 and led investigators to conduct a large randomized phase III trial of 939 patients to evaluate for superiority of pemetrexed/carboplatin/bevacizumab followed by pemetrexed/bevacizumab maintenance compared with paclitaxel/carboplatin/bevacizumab followed by single-agent bevacizumab maintenance.15 Only PFS was statistically superior in the pemetrexed/carboplatin/bevacizumab arm (6.0 vs 5.6 months for paclitaxel/carboplatin/bevacizumab), but RR (34.1% vs 33.0%) and OS (12.6 vs 13.4 months) did not show superiority. The toxicities differed between arms; more grade 3/4 thrombocytopenia (23.3% vs 5.6%), anemia (14.5% vs 2.7%), and fatigue (10.9% vs 5.0%) were seen in the pemetrexed group, whereas more grade 3/4 neutropenia (40.6% vs 25.8%), febrile neutropenia (4.1% vs 1.4%), and sensory neuropathy (4.1% vs 0%) were seen in the paclitaxel group.

Several studies have evaluated bevacizumab in patients who have historically been excluded from other trials. The phase II BRIDGE trial studied carboplatin/paclitaxel and delayed bevacizumab in 31 previously untreated patients with advanced squamous NSCLC.16 Efficacy results have not been published, but the 4 most common grade 3/4 AEs were hypertension (16%), dyspnea (10%), deep vein thrombosis (7%), and arthralgia (7%). One patient had grade 3 or higher pulmonary hemorrhage and another had grade 1 pulmonary hemorrhage.

The phase II BRAIN trial evaluated the safety of bevacizumab given in the first-line setting with carboplatin/paclitaxel, or in the second-line setting in combination with erlotinib in patients with nonsquamous NSCLC and asymptomatic, untreated brain metastases. Grade 1 intracranial hemorrhage occurred in 1 of 67 patients in the first-line setting and 0 of 24 patients in the second-line setting, and the RR for intracranial metastases was 61% in first-line therapy and 21% in second-line therapy.17

Ramucirumab: Ramucirumab (IM-1121B), a human monoclonal anti-VEGFR-2 antibody,18 is currently being evaluated in patients with diverse histologic subtypes of NSCLC, including those with squamous cell histology and/or treated brain metastases. Results from a single-arm phase II trial of 40 patients treated with carboplatin, paclitaxel, and ramucirumab reported an RR of 55% and a median PFS of 7.9 months.19 Grade 3/4 AEs included thrombocytopenia (10%), febrile neutropenia (7.5%), peripheral neuropathy, and pulmonary embolism (5% each).

In a separate phase II randomized study in patients with nonsquamous NSCLC, ramucirumab plus pemetrexed was given in combination with either carboplatin or cisplatin versus single-agent pemetrexed in combination with carboplatin or cisplatin.20 An interim analysis showed an RR of 44% and aPFS of 6.3 months in the ramucirumab arm versus an RR of 37% and a PFS of 4.3 months in the chemotherapy-alone arm. Grade 3 AEs in the ramucirumab arm included thrombocytopenia (15%), neutropenia (13%), fatigue (12%), and nausea (10%).

Table 2

Ongoing Phase II and Phase III Trials in the United States of Approveda and Investigational Antiangiogenic Agents in Advanced or Metastatic NSCLCb

Table 2

Bavituximab: Bavituximab is a monoclonal antibody against phosphatidylserine that causes selective shutdown of existing tumor blood vessels.21 A randomized phase II study of 86 patients with non-squamous histology compared carboplatin/paclitaxel with or without bavituximab.22 In the bavituximab group, the RR was 32% and PFS was 5.8 months, and in the chemotherapy alone group, the RR was 31% and PFS was 4.6 months. OS was not yet reached at the time of reporting. The most common grade 3/4 AEs were anemia (6.8% with bavituximab vs 7.1% with chemotherapy alone), neutropenia (6.8% vs 9.5%), and thrombocytopenia (6.8% vs 2.4%).

Aflibercept: Aflibercept (AV0005), an angiogenesis inhibitor composed of portions of the extracellular domains of human VEGFR-1 and VEGFR-2 fused to the Fc portion of human immunoglobulin G, is currently being evaluated in NSCLC.23 In a single-arm, phase II trial, aflibercept was administered to 98 patients with platinum- and erlotinib-resistant lung adenocarcinoma, and results showed an RR of 2%, a median PFS of 2.7 months, and a median OS of 6.2 months.24 The most common grade 3/4 AEs were hypertension (23%), dyspnea (21%), proteinuria (10%), and fatigue (7%). A phase III trial (VITAL) of docetaxel plus aflibercept versus docetaxel alone as second-line therapy in advanced NSCLC showed an improvement in RR (23% vs 9%) and median PFS (5.2 vs 4.1 months), but OS was not improved (10.1 vs 10.4 months).25 The most common grade 3/4 AEs were neutropenia (28% in the aflibercept arm vs 21% in the chemotherapy-alone arm), fatigue (11% vs 4%), and stomatitis (9% vs 1%).

Tyrosine Kinase Inhibitors

Resistance to VEGF inhibition has been shown to be multifactorial.26 Receptor tyrosine kinase inhibitors (TKIs), many of which target several angiogenesis pathways, are a class of agents in clinical development for various malignancies. Many of the multitargeted agents will theoretically inhibit several angiogenesis pathways and may specifically overcome resistance to VEGF inhibition. Several of these multitargeted TKIs have been investigated for use in the treatment of NSCLC in clinical trials.

Sorafenib: Sorafenib is a multitargeted TKI that inhibits VEGFR-2, VEGFR-3, platelet-derived growth factor receptor-β (PDGFR-β), v-raf1 murine leukemia viral oncogene homolog 1 (Raf), fms-like tyrosine kinase 3 (FLT-3), and stem cell factor receptor (c-KIT).27 Sorafenib showed single-agent activity in several phase II trials in patients with previously treated advanced nonsquamous NSCLC,28,29 but large randomized phase III trials have been disappointing.30,31 A phase III trial (ESCAPE) of 926 patients with advanced nonsquamous and squamous cell NSCLC was halted because of lack of efficacy on interim analysis.30 Patients with squamous histology receiving sorafenib had a shorter median OS (8.9 vs 13.7 months) compared with patients receiving chemotherapy alone. The 4 most common grade 3/4 AEs in the sorafenib arm were neutropenia (9%), rash/desquamation (8%), hand-foot skin reaction (8%), and fatigue (5%), whereas in the chemotherapy arm, these were neutropenia (6%), fatigue (3%), and diarrhea, sensory neuropathy, vomiting, and nausea (2% each). Four of the 6 fatal hemorrhagic/bleeding events observed in the study occurred in patients with squamous histology (2 in each arm).

A second phase III trial (NEXUS) excluded patients with squamous cell histology, subsequent to a protocol amendment.31 This trial combined cisplatin/gemcitabine with or without sorafenib in 904 patients with advanced NSCLC, showing no difference in median OS with sorafenib versus placebo in nonsquamous disease (12.4 vs 12.5 months), but a statistically significant increase in median PFS (6.0 vs 5.5 months). Reported grade 3 or higher AEs attributable to sorafenib included thrombocytopenia (10%), hand-foot skin reaction (9%), fatigue (7%), and rash (6%).

Sunitinib: Sunitinib is a multitargeted TKI that inhibits VEGFR-2, PDGFR-β, rearranged during transfection (RET), c-KIT, and FLT-3.32 Sunitinib has shown single-agent activity in phase II trials in patients with previously treated NSCLC.33,34 A phase III trial of sunitinib plus erlotinib versus erlotinib alone as second- or third-line therapy in 960 patients (90% with unknown EGFR mutational status) showed no significant differences in the primary end point of OS (9.0 vs 8.5 months).35 The most common grade 3/4 toxicities with sunitinib plus erlotinib were rash/dermatitis (17%), diarrhea (16%), and hypophosphatemia (13%), all higher than with erlotinib alone (10%, 3%, and 4%, respectively).

Nintedanib: Nintedanib (BIBF 1120) is a multitargeted TKI that targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, fibroblast growth factor receptor (FGFR)-1, FGFR-2, and FGFR-3. In addition, nintedanib has activity against FLT-3 and the v-src sarcoma viral oncogene homolog (src) family.36 A phase II study of nintedanib dosed at either 250 mg twice daily or 150 mg twice daily in 73 patients with relapsed NSCLC showed mild activity.37 A phase III study (LUME-Lung 1) randomized 1314 patients with advanced or metastatic squamous and nonsquamous NSCLC that had progressed on first-line chemotherapy to either nintedanib or placebo in combination with docetaxel.38 An improvement was seen in median PFS (3.4 vs 2.7 months) but not in median OS (10.1 vs 9.1 months) in the nintedanib/docetaxel arm versus the docetaxel/placebo arm. Grade 3/4 AEs were similar in each arm, the most common included elevated alanine aminotransferase (ALT) (8% vs 1%) and diarrhea (7% vs 3%). A separate phase III study (LUME-Lung 2) comparing nintedanib or placebo in combination with pemetrexed in patients with advanced or metastatic nonsquamous NSCLC that had progressed on first-line chemotherapy was stopped early because of a signal for futility on an interim analysis.39 The analysis of 713 enrolled patients (initial enrollment planned for 1300 patients) showed an increase in median PFS (4.4 vs 3.6 months) but no difference in RR (9% vs 9%) or median OS (HR 1.03). Reported grade 3/4 AEs included elevated ALT (23% vs 7%), elevated aspartate aminotransferase (12% vs 2%), and diarrhea (3% vs 1%).

Cediranib: Cediranib inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α/β, FGFR-1, and c-KIT.40 A phase II/III trial comparing carboplatin/paclitaxel with or without cediranib, 30 mg, in 296 patients with advanced NSCLC was halted early because of imbalances in the number of deaths observed in cediranib-treated patients.41 The RR was 38%, median PFS was 5.6 months, and median OS was 10.5 months in the cediranib group compared with an RR of 16%, median PFS of 5.0 months, and median OS of 10.1 months in the placebo group. The 4 most common grade 3/4 AEs in the cediranib arm were neutropenia (49%), fatigue (29%), increased thyroid-stimulating hormone (27%), and hypertension (19%). A phase II trial evaluating pemetrexed and cediranib in 2 cohorts of patients (a bevacizumab-naïve group and a bevacizumab-pretreated group) has completed accrual of bevacizumab-naïve patients.42 Preliminary results in the bevacizumab-naïve group showed an RR of 29%, median PFS of 5.6 months, and median OS of 11 months. The 4 most common grade 3/4 AEs in the bevacizumab-naïve cohort were fatigue (22%), neutropenia (14%), diarrhea (14%), and infection (8%). Three treatment-related deaths have been reported.

Motesanib: Motesanib is a multitargeted TKI that targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, c-KIT, and RET.43 A phase II trial of motesanib in combination with doublet chemotherapy44 and a phase III trial of carboplatin and paclitaxel with or without motesanib (MONET1) were performed. The phase III study was initially suspended because of a higher incidence of hemoptysis and mortality in patients with squamous cell histology. The trial resumed in patients with only nonsquamous histology, and did not show a statistically significant improvement in median OS.45 The RR was 40%, median PFS was 5.6 months, and median OS was 13.0 months in the motesanib arm, versus 26%, 5.4 months, and 11.0 months, respectively, in the placebo arm. Grade 3 or higher AEs with motesanib included neutropenia (22% vs 15% with placebo), diarrhea (9% vs 1%), hypertension (7% vs 1%), and cholecystitis (3% vs 0%). The incidence of grade 5 AEs was 14% with motesanib versus 9% with placebo.

Pazopanib: Pazopanib is a multitargeted TKI that inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α/β, FGFR-1, FGFR-3, and c-KIT,46 and is currently being evaluated. In a phase II trial, 192 patients with advanced NSCLC for whom 1 to 2 prior lines of therapy failed were randomized to pazopanib plus erlotinib versus placebo plus erlotinib.47 A statistically significant improvement in PFS was seen in the combination arm (2.6 vs 1.8 months with erlotinib alone), but both arms showed similar RR (6% vs 0%) and OS (6.8 vs 6.7 months). Severe nonhematologic toxicities in the combination group were fatigue (20%), diarrhea (19%), and proteinuria (5%).

Axitinib: Axitinib is a multitargeted TKI that targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c-KIT.48 A phase II study of axitinib in 32 patients with NSCLC showed an RR of 9%, a median PFS of 4.9 months, and a median OS of 14.8 months.49 Grade 3 hypertension (9%) and diarrhea and vomiting (3% each) were reported. In a randomized phase II study of 2 dosing schedules (continuous or intermittent) of axitinib with first-line pemetrexed/cisplatin in 170 patients with nonsquamous NSCLC, the axitinib arms were associated with higher RRs versus chemotherapy alone (45.5% in the continuous arm and 39.7% in the intermittent arm vs 26.3% in the chemotherapy-alone arm), but with no significant prolongation of PFS (8.0, 7.9, and 7.1 months, respectively) or OS (16.6, 14.7, and 15.9 months, respectively).50 The most common grade 3 AEs were hypertension (20%), neutropenia (18%), and nausea (16%) with continuous axitinib, and hypertension (17%), fatigue (16%), and anemia (14%) with intermittent axitinib, and grade 4 asthenia (1%) and pulmonary embolism (1%) were also reported with the latter schedule.

A phase II randomized study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with nonsquamous NSCLC failed to show an improvement in RR (29% vs 43%, respectively), PFS (5.7 vs 6.1 months), or OS (10.6 vs 13.3 months) for axitinib versus bevacizumab. The most common grade 3/4 AE in both arms was neutropenia, and axitinib was associated with a higher rate of treatment discontinuation because of AEs compared with bevacizumab (41% vs 31%, respectively).51

Vandetanib: Vandetanib is a TKI that inhibits VEGFR signaling, EGFR signaling to a lesser extent, and RET tyrosine kinases.52 Vandetanib is no longer in development for the treatment of NSCLC. Several phase III trials failed to show a significant improvement in OS among previously treated patients with advanced NSCLC when vandetanib was combined with chemotherapy (ZEAL, ZODIAC),53,54 given as a single agent after failure of an EGFR TKI (ZEPHYR),55 or compared with erlotinib (ZEST).56

Linifanib: Linifanib (ABT-869) is a multitargeted TKI that is being evaluated in NSCLC. It inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, c-KIT, CSF-1R, and FLT-3.57 Results from a phase II trial evaluating 2 doses of linifanib (0.10 mg/d and 0.25 mg/d) in 139 patients with chemorefractory NSCLC showed an RR of 5.0%, median PFS of 3.6 months, and median OS of 9.0 months overall.58 The incidence of grade 3/4 hypertension was 1.5% in the 0.10-mg/d group and 24.3% in the 0.25-mg/d group; no other grade 3/4 AEs were observed in more than 10% of patients overall.

Vascular Disrupting Agents

Ombrabulin: Ombrabulin (AVE8062) is a vascular disrupting agent and analog of combretastatin A4 that damages tumor vasculature.59 The phase II DISRUPT trial randomized 176 patients with either squamous or nonsquamous histology to either therapy with ombrabulin or placebo combined with a chemotherapy backbone of either cisplatin/docetaxel or carboplatin/paclitaxel for 6 cycles.60 The RR was 32% in the ombrabulin arm versus 31% in the placebo group, PFS was 5.7 versus 5.5 months, and OS was 11.0 months in each arm. The safety profile was reported to be similar, with a 57% incidence of unspecified grade 3/4 AEs in the ombrabulin arm versus 52% in the placebo arm.

Vadimezan: Vadimezan (ASA404) is a vascular disrupting agent of the flavonoid class.61 After promising results in a phase II trial in untreated patients,62 it was tested in a phase III trial in advanced or metastatic NSCLC in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel alone. A total of 1299 patients were enrolled and the trial was stopped early because of futility. No statistical differences in OS (13.4 vs 12.7 months), PFS (5.5 vs 5.5 months), or RR (25% vs 25%) were seen in the vadimezan arm versus the chemotherapy-alone arm.63

Lack of Predictive Biomarkers for Antiangiogenic Therapy in Lung Cancer

Many antiangiogenic agents have shown an increase in RR or PFS when compared with placebo, but in most cases this has not translated into an OS benefit. Predictive biomarkers are greatly needed to identify the subset of patients who may benefit from antiangiogenic therapy or those likely to experience side effects, such as thrombosis and bleeding. Several molecular mediators of angiogenesis and inflammatory signaling have been investigated as potential biomarkers of antiangiogenic therapy in lung cancer, such as circulating VEGF,64 intercellular adhesion molecule (ICAM),64 IL-2,65 IL-8,66 IL-12,65 and IL-16,65 but no biomarker has yet been prospectively validated to correlate with outcomes.

Conclusions

As the field of lung cancer moves further into the age of personalized medicine, it will be imperative to target the entire milieu surrounding the tumor environment, and not merely the mutations within the cancer cell itself. Preclinical models and selected clinical trials have shown benefits for targeting angiogenesis in lung cancer. Currently, bevacizumab is the only antiangiogenic agent recommended by the NCCN for use in the treatment of advanced NSCLC. A significant knowledge deficit exists in the understanding of the molecular basis of antiangiogenic therapy and the AEs seen with these agents. A more thorough understanding of the mechanisms of benefit and AEs is needed to better predict who will benefit from this treatment strategy. Predictive biomarkers are needed to help select patients who will benefit most from or be least likely to experience the toxicities associated with these drugs.

Editorial assistance was provided by Allison Michaelis, PhD, of MedErgy, which was contracted by BIPI for these services.

Dr. Lammers is supported by the NIH (K12 CA 0906525). Financial support for editorial assistance was provided by Boehringer Ingelheim Pharmaceuticals, Inc. The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

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Correspondence: Leora Horn, MD, MSc, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232. E-mail: leora.horn@vanderbilt.edu
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    Targeting angiogenesis in lung cancer. Receptors and downstream signaling pathways involved in angiogenesis and sites of action of antiangiogenic antibody-based therapies and multitargeted tyrosine kinase inhibitors.

    Abbreviations: AKT, protein kinase B; c-KIT, stem cell factor receptor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; FLT-3, fms-like tyrosine kinase 3; MEK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase; RAF, v-raf 1 murine leukemia viral oncogene homolog 1; RAS, retrovirus-associated DNA sequences; RET, rearranged during transfection; SRC, v-src sarcoma viral oncogene homolog; TKIs, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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    • Export Citation
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    • Export Citation
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    • Export Citation
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    • Export Citation
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    • Export Citation
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    • Export Citation
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    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. Ann Oncol 2011;22:13741381.

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    • Export Citation
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    Reck M, Kaiser R, Mellemgaard A et al. . Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial [abstract]. J Clin Oncol 2013:31(Suppl):Abstract LBA8011.

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    Hanna NH, Sullivan RN, Aren RO et al. . Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy [abstract]. J Clin Oncol 2013:31(Suppl):Abstract 8034.

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    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 Res 2005;65:43894400.

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    • Export Citation
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    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. J Clin Oncol 2010;28:4955.

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    • Export Citation
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    Gadgeel SM, Ruckdeschel JC, Wozniak AJ et al. . Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl):Abstract 7564.

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    • Export Citation
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    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 Res 2006;66:87158721.

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