Emerging Data with Antiangiogenic Therapies in Early and Advanced Non–Small-Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related mortality in the United States. Patients treated with adjuvant chemotherapy have a 5-year survival rate of 25% to 70% depending on stage, whereas those with advanced disease have a median survival of approximately 8 months when treated with standard platinum-based therapy. Improvements in our understanding of cancer biology have led to the development of novel agents that more precisely affect the target of interest, allowing for a more rational approach to clinical trial design. Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is the most studied antiangiogenic agent in patients with non–small-cell lung cancer (NSCLC). There was an improvement in overall survival when bevacizumab was combined with paclitaxel and carboplatin in patients with advanced NSCLC that was not seen when bevacizumab was combined with cisplatin and gemcitabine. Studies with bevacizumab in the adjuvant and advanced setting are ongoing in patients with NSCLC. Small-molecule inhibitors targeting the VEGF receptor and the tyrosine kinase receptor have also shown promise when combined with standard chemotherapy, but their role in the treatment of patients with NSCLC remains to be determined. This article reviews clinical trials that have incorporated antiangiogenic agents in the treatment of patients with NSCLC.

Introduction

Lung cancer is the leading cause of cancer-related mortality in the United States, with 215,020 new cases and 161,840 deaths anticipated in 2008.¹ Non–small-cell lung cancer (NSCLC) accounts for 80%-85% of cases, with approximately 70% of patients presenting with advanced disease (stage IIIB with pleural effusion or stage IV) at the time of diagnosis.² Surgery remains the primary treatment modality for patients with early-stage disease; however, the majority of patients relapse with distant disease and chemotherapy is offered in an effort to improve survival. A recent meta-analysis showed a 5.4% improvement in overall survival (OS) and a 5-year survival rate of approximately 50% after adjuvant treatment with platinum-based chemotherapy.³ Patients with advanced disease have a median survival of approximately 10 months when treated with traditional platinum-based therapy.^4,5 Therefore, novel therapies are required for this all-too-common disease. Tumor growth and development is a complex multistep process requiring the transformation of a normal cell into a malignant cell. In the past 2 decades, there has been substantial interest in developing molecular-targeted agents that modulate growth factors and signaling cascades that are aberrant in tumor cells. Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in the transition of tumors from the dormant to malignant stage.^6,7 The secretion of proangiogenic factors, during tumor growth and progression, results in cell migration, proliferation, and capillary tube formation.^6,7 Tumor blood vessels also have abnormal structural arrangements. Antiangiogenic agents, in addition to inhibiting the growth of tumor vasculature, are believed to transiently normalize the tumor vascular supply resulting in improved drug delivery.^8,9 Angiogenesis has also been implicated in the growth of distant metastases.^5,10,11 Microvessel count as a measure of angiogenesis is a significant predictor of increased risk for metastatic disease and poorer OS in patients with NSCLC.^12,13 Therefore, angiogenesis has become a rational therapeutic target because of the important role it plays in tumor growth and development. Because of their nonoverlapping toxicity with chemotherapy agents, antiangiogenic agents have been combined with a variety of chemotherapy agents currently used in the treatment of patients with NSCLC. This article summarizes the data for antiangiogenic agents that have been approved and are in development for the treatment of patients with NSCLC. Tables 1-4^14-41 show details on the drug targets, routes of administration, treatment results, and toxicities.

Table 1. Antiangiogenic Agents Approved or in Development for the Treatment of Patients with Non–Small-Cell Lung Cancer.

Drug	Target	Route of Administration	Frequency of Administration	Clinical Status
Bevacizumab	VEGF ligand	I.V.	Every 3 weeks	Approved
Sorafenib	Raf, Kit, Flt-3, VEGFR-2, VEGFR-3, PDGFR-β	Orally	Twice daily	Phase III
Vandetanib	VEGFR-2, VEGFR-3, RET, EGFR	Orally	Daily	Phase III
Sunitinib	VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, Flt-3, c-Kit	Orally	Twice daily	Phase III
Cediranib	VEGFR-2, VEGFR-1, VEGFR-3, c-Kit, Flt-3	Orally	Daily	Phase III
Motesanib	VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, Ret, Kit	Orally	Daily	Phase III
Thalidomide	Unknown	Orally	Daily	Phase III
Axitinib	VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, Kit	Orally	Twice daily	Phase II
Pazopanib	VEGFR-2, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, c-Kit	Orally	Daily	Phase II
XL647	VEGFR-2, EGFR, ErbB2, EphB4	Orally	Daily/twice daily	Phase II

Abbreviations: EGFR = epidermal growth factor receptor; I.V. = intravenous; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor

Table 4. Open Trials of Adjuvant Chemotherapy with Antiangiogenic Agents in Patients with Non–Small-Cell Lung Cancer.

Trial/Protocol ID	Phase	Treatment
ECOG 1505	III	Cisplatin + vinorelbine or gemcitabine or docetaxel with or without bevacizumab 15 mg/kg
BEACON*	II	Docetaxel + cisplatin + bevacizumab 15 mg/kg
NCT00621049	II	Carboplatin + docetaxel + bevacizumab with or without erlotinib
NCT00675597	NS	Docetaxel + vinorelbine + bevacizumab
NCT00459121	II	Carboplatin + paclitaxel + vandetanib

^*Neoadjuvant trial of chemotherapy before surgery.

Abbreviations: BEACON = Bevacizumab and Chemotherapy for Operable NSCLC; ECOG = Eastern Cooperative Oncology Group; NCT = National Clinical Trial; NS = not specified

Anti–Vascular Endothelial Growth Factor Monoclonal Antibodies

Vascular endothelial growth factor (VEGF) is an important factor mediating proangiogenic effects. Many human cancer cells, including lung cancer cells, express VEGF receptors (VEGFRs).^42,43 Vascular endothelial growth factor expression has been found to significantly correlate with new vessel formation, disease-free survival (DFS), and OS in patients with NSCLC.^42,43,44 Bevacizumab is a monoclonal antibody with a high affinity for VEGF.^46,47 Bevacizumab exerts its antiangiogenic effects by binding to free, circulating VEGF, thereby inhibiting the binding of VEGF to its receptors, preventing VEGF ligand-receptor downstream signaling.⁴⁷ A randomized phase II trial of 99 patients with advanced or recurrent NSCLC compared carboplatin and paclitaxel with or without bevacizumab (7.5 or 15 mg/kg) and found the combination of bevacizumab 15 mg/kg with carboplatin and paclitaxel increased response rate (RR; 31.5% vs. 18.8%) and prolonged time to progression (TTP; 7.4 months vs. 4.2 months; P = .023) compared with chemotherapy alone. There was also a nonsignificant improvement in OS (17.7 months vs. 14.9 months). Although there were no objective responses, 1-year survival was 47% for patients (n = 19) who progressed and went on to receive single-agent bevacizumab 15 mg/kg.¹⁴

Based on these results, the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial (E4599) comparing carboplatin and paclitaxel with or without bevacizumab (15 mg/kg) in 878 patients with recurrent or advanced nonsquamous NSCLC. There was a significant improvement in OS, progression-free survival (PFS), and RR for patients treated with bevacizumab plus chemotherapy compared with chemotherapy alone: 12.3 versus 10.3 months (hazard ratio [HR], 0.79; P = .003), 6.2 versus 4.5 months (HR, 0.66; P < .001) and 35% versus 15% (P < .001), respectively. In an unspecified subset analysis the benefit of bevacizumab plus chemotherapy on OS was evident among men (11.1 months vs. 8.7 months) but not women (13.3 months vs. 13.1 months), whereas RR and PFS were significantly improved for both sexes. There was a significantly higher incidence of toxicities for patients treated with bevacizumab, although the incidence of grade 3 to 5 pulmonary hemorrhage was only 1.9% versus 0.27% in the chemotherapy-alone arm.¹⁵ An unspecified retrospective subset analysis of elderly patients (aged ≥ 70 years) found a trend toward higher RR and PFS but no improvement in OS for paclitaxel and carboplatin plus bevacizumab.⁴⁸

Based on the results of E4599, ECOG is conducting a phase III randomized trial (E1505) in 1500 patients with resected stage IB to III NSCLC evaluating the addition of bevacizumab to standard chemotherapy (cisplatin/gemcitabine, cisplatin/vinorelbine, or cisplatin and docetaxel) followed by maintenance bevacizumab. The combination of carboplatin and paclitaxel is not being used after the LACE metaanalysis demonstrated superior outcomes for patients treated with cisplatin-based regimens in the adjuvant setting.³ A review of the National Cancer Institute Web site identified 2 additional adjuvant trials in patients with resected NSCLC: docetaxel and vinorelbine plus bevacizumab and docetaxel and carboplatin plus bevacizumab followed by maintenance bevacizumab with or without erlotinib.⁴⁹ A second phase III randomized trial, conducted in Europe and Canada (AVAiL), compared cisplatin and gemcitabine with or without bevacizumab 7.5 mg/kg or 15 mg/kg in 1043 patients with recurrent or advanced nonsquamous NSCLC.¹⁶ Following the positive survival results of the ECOG trial, the primary endpoint of AVAiL was amended from OS to PFS. A significant improvement in PFS was seen at both bevacizumab doses, 6.7 months for 7.5 mg/kg (HR, 0.75; P = .003) and 6.5 months for 15 mg/kg (HR, 0.82; P = .03), compared with 6.1 months for the placebo group. Overall survival was not significantly different between treatment groups but has not been formally presented. Objective RRs were 34.1%, 30.4%, and 20.1% for bevacizumab 7.5 mg/kg, 15 mg/kg, and placebo, respectively. Although the trial was not powered to directly compare the 2 doses of bevacizumab, efficacy and safety data were similar for both doses.

Paclitaxel was replaced with albumin-bound paclitaxel in a phase II trial of 50 patients with advanced nonsquamous NSCLC. In this trial, patients received the combination of albumin-bound paclitaxel and carboplatin plus bevacizumab 15 mg/kg for 4 cycles followed by maintenance bevacizumab. Median PFS was impressive at 9.8 months, and OS is 15.8 months.⁵⁰ A phase II trial evaluated the combination of bevacizumab with carboplatin (area under the curve of 6) and docetaxel in 20 of a planned 50 patients with chemotherapy-naive advanced NSCLC and found a 74% partial response (PR).⁵¹ Preliminary results from 2 phase II trials evaluating bevacizumab with carboplatin and pemetrexed in patients with advanced NSCLC indicate response rates of 55% and 60%.^52,53 Two phase II trials used oxaliplatin plus bevacizumab with pemetrexed or gemcitabine in patients with untreated NSCLC and reported RRs of 26% and 31%.^17,18 The BEACON study is a randomized phase II trial evaluating preoperative chemotherapy (docetaxel and cisplatin) with or without bevacizumab in patients with nonsquamous histology stage IB to IIIA NSCLC. Preliminary results from 19 of an intended 70 patients have shown > 94% of patients completing preoperative chemotherapy. A similar rate of downstaging has been observed between treatment groups. No bevacizumab-related operative complications have been reported to date.⁵⁴

A phase II trial evaluated second-line therapy with pemetrexed and bevacizumab in 48 patients who had progressed following platinum-based chemotherapy. There were 5 PRs (10%) and 19 patients with stable disease (SD). Median PFS and OS were 4.1 months and 8.6 months, respectively.¹⁹ Although the PFS is longer, the RR and OS are similar to a previous study by Hanna et al evaluating treatment with pemetrexed alone.⁵⁵ A second randomized phase II trial in previously treated patients with NSCLC compared chemotherapy alone (docetaxel or pemetrexed) to chemotherapy plus bevacizumab or bevacizumab plus erlotinib. The RR was higher for the erlotinib/bevacizumab combination (17.9%) versus 12.2% for chemotherapy alone and 12.5% for chemotherapy plus bevacizumab. The median PFS, OS, and 1-year survival were superior for patients receiving bevacizumab: 3 versus 4.8 versus 4.4 months, and 8.6 versus 12.6 versus 13.7 months, and 33% versus 53.8% versus 57.4%, for chemotherapy versus chemotherapy plus bevacizumab versus erlotinib plus bevacizumab, respectively. Grade 3/4 toxicities were greater in the chemotherapy treatment arms, with a higher percentage of patients discontinuing treatment because of adverse events (24% for chemotherapy alone versus 28% for chemotherapy plus bevacizumab and 13% for erlotinib plus bevacizumab).²⁰

Based on the results of this study, 2 pharmaceutical-sponsored phase III trials were opened for previously treated patients with NSCLC: the BeTa Lung trial that is comparing treatment with erlotinib to erlotinib plus bevacizumab, and the ATLAS trial, which is now closed, evaluating the efficacy and safety of maintenance bevacizumab with or without erlotinib following 4 cycles of chemotherapy with bevacizumab.

Therefore, bevacizumab appears to be safe and well tolerated when combined with chemotherapy in patients with advanced NSCLC. Two large, randomized phase III studies have shown an improvement in PFS when bevacizumab was combined with chemotherapy compared with chemotherapy alone. The ECOG 4599 trial showed that the addition of bevacizumab to standard chemotherapy—carboplatin and paclitaxel—also results in an improvement in OS compared with chemotherapy alone. A subset analysis suggests there could be limited benefit in elderly patients. Several large trials have reported on the safety of bevacizumab in combination with chemotherapy in patients with advanced NSCLC. These trials have included patients with brain metastases, with hypertension, and on anticoagulation medication. The data to date suggest that it might be safe to administer bevacizumab to patients with NSCLC with treated brain metastases, that there is less of a safety concern for patients on anticoagulation medication than previously believed, and that hypertension can be managed. However, we await the final results of the study before recommendations can be made.^19,56-59 There are currently no data to support a role for bevacizumab as adjuvant therapy in patients with NSCLC outside of a clinical trial.

Small-Molecule Receptor Tyrosine Kinase Inhibitors

Sorafenib

Sorafenib is an oral multikinase inhibitor that has been found to inhibit tumor growth and angiogenesis when administered alone and/or in combination with chemotherapy or other targeted agents.^60-64 A phase II trial treated 54 patients with relapsed or refractory NSCLC with single-agent sorafenib. Patients with squamous cell histology and asymptomatic brain metastases were included and those with significant bleeding in the previous month were excluded. Median PFS was 11.9 weeks, and OS was 29.3 weeks. Although there were no confirmed PRs, tumor shrinkage was observed in 29% of patients, whereas 59% of patients had SD.²² Preliminary results from 15 patients with relapsed NSCLC treated with sorafenib reported 2 PRs (13%) and 7 patients with SD (46%). Patients were evaluated by dynamic contrast-enhanced magnetic resonance imaging, which showed a reduction in tumor permeability associated with reductions in tumor size.^21,65 Accrual to this trial is ongoing. ECOG conducted a phase II trial in 342 patients with NSCLC who had progressed following ≥ 2 chemotherapy regimens (E2501). In this trial, all patients were initially treated with sorafenib. Patients were evaluated after 2 cycles, and those who were responding continued on treatment with sorafenib, those with SD were randomized to sorafenib or placebo, and those with progression were taken off study. A total of 107 patients with SD were randomized and 83 were evaluable for response. Eight of 30 patients on placebo crossed over to treatment with sorafenib. An error in randomization was discovered by ECOG after 55 patients had been randomized. This was not believed to affect the primary endpoint of the study (the proportion of patients with disease control 2 months after randomization). There was a significantly higher number of patients with disease control (SD/PR/complete response [CR]) at 2 months in the sorafenib treatment group compared with placebo (47% vs. 19%; P = .01). Median PFS was also significantly longer (3.6 months vs. 2 months; P = .009), and there was a trend toward improvement in OS (11.9 months vs. 9 months).⁶⁶

In a first-line study, 25 patients with advanced NSCLC were treated with sorafenib before receiving standard chemotherapy. Although the study did not meet stage I efficacy criteria (only 1 confirmed PR in the first 20 patients), the authors concluded that the median survival of 8.8 months and objective RR of 12% suggests that single-agent sorafenib achieves similar activity compared with 2-drug combinations and should be considered for combination studies with standard chemotherapy regimens.²³ One study documented that single-agent sorafenib does not appear to adversely affect health-related quality of life in patients with advanced NSCLC.⁶⁷ In a phase I dose-escalation trial, 31 patients (12 with locally advanced or recurrent NSCLC) were treated with sorafenib 200 mg or 400 mg plus gefitinib. An additional 20 patients were treated with single-agent sorafenib and gefitinib followed by the combination of sorafenib and gefitinib. There was 1 PR, and 20 patients had SD of ≥ 4 months' duration.²⁴ In a phase I/II trial, carboplatin and paclitaxel were combined with sorafenib in patients with advanced NSCLC. An encouraging median PFS of 8.5 months was achieved; 29% of patients had a PR, and 50% had SD.²⁵ However, a randomized phase III trial (ESCAPE) comparing carboplatin and paclitaxel with or without sorafenib in 926 patients with advanced NSCLC who were chemotherapy naive was closed early after a planned interim analysis showed no difference in RR (30% vs. 24%), PFS (5.1 months vs. 5.4 months; HR, 1.0; P = .514), or OS (10.7 months vs. 10.6 months; HR, 1.16; P = .930) for patients receiving chemotherapy with sorafenib compared with chemotherapy alone. In a subset analysis, patients with squamous cell histology appeared to have a poorer OS when treated with the combination of chemotherapy and sorafenib compared with chemotherapy alone (8.9 months vs. 13.6 months; HR, 1.81). This was true for PFS as well.²⁶ A second large phase III trial, NExUS, remains open evaluating chemotherapy with gemcitabine and cisplatin with or without sorafenib in the same patient population; however, patients with squamous cell histology are no longer eligible for this study based on the data from the ESCAPE trial. Although single-agent sorafenib might be beneficial in patients with advanced NSCLC, these data would suggest that combination chemotherapy with sorafenib does not improve survival for patients with advanced NSCLC. Sorafenib is not currently being evaluated in the adjuvant setting in patients with NSCLC.

Vandetanib

Vandetanib inhibits both angiogenesis and tumor growth. Therapy with vandetanib (100, 200, or 300 mg daily) was evaluated in a randomized phase II dose-finding study of 53 Japanese patients with previously treated NSCLC.²⁷ Overall, there was a 13.2% PR rate. Time to progression was 8.3 weeks at the 100-mg dose and 12.3 weeks at both the 200-mg and 300-mg doses. In a randomized phase II trial of 168 patients with NSCLC, single-agent vandetanib was compared with gefitinib in patients after failure of first- or second-line platinum-based therapy.²⁸ Of note, patients with hemoptysis, thromboses, squamous cell carcinoma, and brain metastases were permitted to enter this trial. Median PFS was 11 weeks for vandetanib compared with 8.1 weeks for patients receiving gefitinib. Objective responses were seen in 8% of patients treated with vandetanib compared with 1% of patients treated with gefitinib. On progression, patients were permitted to switch to the alternative regimen. In patients who switched therapies, disease control > 8 weeks was seen in 16 of 37 (43%) patients who switched to vandetanib and 7 of 29 (24%) patients who switched to gefitinib. Overall survival was not significantly different between treatment arms.

Vandetanib 100 mg or 300 mg plus docetaxel was compared with docetaxel alone in a phase II randomized, placebo-controlled trial of 127 patients with advanced NSCLC who had experienced treatment failure with platinum-based chemotherapy. Patients with squamous cell histology were permitted to enter the trial, as were patients with clinically stable, treated brain metastases. A PR was seen in 12% of patients receiving docetaxel alone, 26% of patients receiving vandetanib 100 mg and docetaxel, and 18% of patients receiving vandetanib 300 mg and docetaxel. There was no statistically significant difference in OS (13.4 months vs. 13.1 months vs. 7.9 months, respectively).²⁹ The results of this study have led to a phase III trial comparing vandetanib plus docetaxel to docetaxel alone as a second-line therapy in patients with advanced NSCLC. In a second randomized phase II trial, 181 patients with advanced NSCLC who were chemotherapy naive were randomized to 1 of 3 treatments: single-agent vandetanib, vandetanib plus paclitaxel and carboplatin, or paclitaxel and carboplatin alone. Patients with central nervous system metastases and squamous cell histology were permitted to enter this trial. The objective RRs were 7% for vandetanib alone, 32% for combination therapy, and 25% for chemotherapy alone. Combination therapy with vandetanib with carboplatin and paclitaxel prolonged PFS compared with carboplatin and paclitaxel alone (24 weeks vs. 23 weeks; HR, 0.75; 95% CI, 0.05-1.15; P = .098). The vandetanib-alone arm was stopped early after a planned interim analysis of PFS met criteria for discontinuation. Overall survival was not significantly different for vandetanib plus chemotherapy versus chemotherapy alone. Contrary to the ECOG 4599 trial, an unplanned exploratory analysis suggested a benefit for female patients receiving vandetanib with chemotherapy compared with chemotherapy alone.^30,68 The preferential benefit in female patients with NSCLC might be attributable to vandetanib's dual inhibition of both epidermal growth factor receptor (EGFR) and VEGF pathways. Sex has been shown to correlate with response to EGFR inhibitors.^69,70 However, the dose of vandetanib when combined with chemotherapy is not believed to affect the EGFR axis.

It appears that single-agent vandetanib has shown promising activity in patients with advanced NSCLC. The improved RR and PFS compared with gefitinib might be attributable to vandetanib acting on both VEGF and EGFR pathways. Inhibition of VEGF pathways is believed to contribute to the mechanism of action of agents targeting EGFR,⁷¹ and increased activity of VEGF pathways is one of the mechanisms by which tumors develop resistance to EGFR inhibitors.⁷² Preclinical data have shown that dual EGFR and VEGF inhibition has additive effects and can overcome resistance in EGFR inhibitor–resistant cells.⁷³ Ongoing phase II and III clinical trials are evaluating single-agent vandetanib and vandetanib in combination with chemotherapy in the first-, second-, and third-line treatment of patients with NSCLC. A phase II trial is currently under way evaluating adjuvant vandetanib plus carboplatin and paclitaxel in patients with resected stage I/III NSCLC.⁴⁹

Sunitinib

Sunitinib inhibits tumor proliferation and angiogenesis.⁷⁴ Two phase II trials have evaluated sunitinib in patients with previously treated NSCLC and reported RRs of 11% and 2%, SD rates of 29% and 19% in patients, PFS of 12 weeks, and OS of 5.4 months and 8.6 months, respectively.^31,32 A phase I study in untreated patients with advanced NSCLC evaluated sunitinib 37.5 mg or 50 mg in combination with cisplatin and gemcitabine. No dose-limiting toxicities were seen at the sunitinib 37.5-mg dose, although 2 were noted (neutropenia and infection) at the 50-mg dose. Three patients had a PR at the 50-mg dose. Sunitinib 37.5 mg appears to be the recommended dose with this chemotherapy schedule.³³ A second phase I study in 37 patients with advanced solid tumors, including 13 patients with NSCLC, evaluated sunitinib in combination with docetaxel. Neutropenia (with or without fever) was seen in 5 patients. One patient had pulseless electrical activity and pulmonary hemorrhage. With > 50% SD seen, studies are ongoing.⁷⁵ Trials are investigating the addition of sunitinib to platinum-based chemotherapy in patients with untreated NSCLC. A phase III trial is evaluating sunitinib in combination with erlotinib versus erlotinib alone in patients with previously treated NSCLC.

Thalidomide

Thalidomide, a glutamic acid derivative, is an immunomodulatory agent with antiinflammatory and purported antiangiogenic effects.⁷⁶ Preliminary results from a phase II trial of thalidomide in combination with carboplatin and irinotecan in 36 patients with advanced NSCLC reported a response rate of 22% and a median survival of 7.3 months.³⁴ A large, randomized phase III control trial of 722 patients with advanced NSCLC demonstrated no benefit for carboplatin and gemcitabine with thalidomide compared with placebo (OS, 8.4 months vs. 8.9 months; HR, 1.13; 95% CI, 0.96-1.32; P = .14).³⁵ A small phase II trial evaluated thalidomide in combination with gemcitabine and irinotecan and included biologic correlates. With only 8 patients evaluable for response, the authors reported a correlation between serum hypoxia markers, including VEGF, and disease status, and reduction in these markers in a patient who had a response to therapy.³⁶ Accrual to this trial is ongoing. A phase I/II trial combined thalidomide and docetaxel in 26 patients with previously treated NSCLC and reported a 19% RR and an OS of 5.4 months, which is similar to treatment with docetaxel alone.^37,55 Despite ongoing trials, there is currently no evidence to support the use of thalidomide in patients with advanced NSCLC.

Other Therapies

Cediranib is a potent inhibitor of angiogenesis. Cediranib 20, 30, or 45 mg daily has been evaluated in phase I studies in combination with 4 chemotherapy regimens, including pemetrexed and docetaxel, 2 agents commonly used in the treatment of patients with NSCLC. Response rates were promising and cediranib did not appear to affect the pharmacokinetic profile of either agent.⁷⁷ Three phase I studies have evaluated cediranib in combination with erlotinib or chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine) and found the combinations to be well tolerated.^38,78,79 When cediranib was combined with carboplatin and paclitaxel in 20 patients with chemotherapy-naive NSCLC, there were 9 PRs (45%) and 11 patients with SD. Median TTP was 7.6 months.³⁸ These results led to a trial by the National Cancer Institute of Canada, BR24, a randomized, double-blind, placebo-controlled trial of cediranib in combination with carboplatin and paclitaxel. This trial has recently been closed because of excessive toxicities, raising the question of cediranib in combination with chemotherapy in the treatment of patients with advanced NSCLC.

Motesanib is a potent inhibitor of angiogenesis. A phase I study evaluated motesanib in 65 patients with advanced solid tumors. Of 56 evaluable patients, there was a 4% PR rate and 61% SD rate.⁸⁰ A phase I trial evaluated motesanib in combination with gemcitabine in 26 patients, including 2 with lung cancer. There were 2 unconfirmed PRs and 7 patients with SD.⁸¹ Further testing of this regimen has been recommended. A phase I study of 36 patients with advanced solid tumors, including 19 with NSCLC, combined motesanib with panitumumab, cisplatin, and gemcitabine. Of 29 patients evaluable for response there was 1 CR, a 31% PR rate (6 seen in patients with NSCLC), and a 59% SD rate.^82,83 The excessive rate of thrombosis of this trial is being investigated before further evaluation can be recommended. A phase II trial is currently ongoing comparing first-line motesanib plus carboplatin and paclitaxel to bevacizumab plus carboplatin and paclitaxel. A phase III double-blind, placebo-controlled trial will randomize patients with advanced NSCLC who are chemotherapy naive to carboplatin and paclitaxel with or without motesanib.

Axitinib is another angiogenesis inhibitor in early-stage development in NSCLC. A phase I dose-escalation study evaluated axitinib in 36 patients with solid tumors (including NSCLC) who were refractory to standard therapy. There were 3 confirmed PRs, with other evidence of antitumor activity. Cavitation of lung lesions, similar to what has been seen with bevacizumab, was observed in the 2 patients with NSCLC; both subsequently died with hemoptysis (one was believed to be axitinib related).⁸⁴ A phase II trial evaluated the activity and safety of axitinib in 32 patients with advanced NSCLC. A total of 13% of patients were treatment naive. There were 3 responses (10%), median duration of response was 9.4 months, PFS was 5.8 months, and OS was 12.8 months.³⁹

Pazopanib is another angiogenesis inhibitor in early-stage development in NSCLC. A phase I study in 43 patients with advanced solid tumors (including NSCLC) evaluated pazopanib in doses ranging from 50 mg 3 times weekly to 2000 mg daily. Tumor shrinkage was noted in patients with renal cell cancer. One patient with NSCLC was included in the 6 patients with SD who remained on therapy for ≥ 6 months.⁸⁵ Neoadjuvant pazopanib 800 mg was administered for 2 to 6 weeks before scheduled surgery for patients with stage IA and stage IB NSCLC. Tumor measurements and plasma cytokine/angiogenic factors were measured before and after treatment. Measurements from 19 paired samples demonstrated a decrease in serum VEGFR-2 and increases in additional cytokine/angiogenic factors. There was a strong correlation between serum VEGFR-2 and tumor shrinkage, making this a potential marker for treatment response.⁸⁶ However, the efficacy of pazopanib in the treatment of patients with NSCLC is still to be determined.

BIBF 1120 is an oral angiokinase inhibitor.⁸⁷ A phase I trial of 36 patients found twice-daily BIBF 1120 to be well tolerated while allowing increased drug exposure. Major toxicities were not the typical hypertension and palmar-plantar erythrodysesthesia noted with other multikinase inhibitors.⁸⁸ Also, a randomized phase II trial compared BIBF 1120 dose of 250 mg twice daily to 150 mg twice daily in 73 patients with previously treated NSCLC. Preliminary results showed no objective responses and similar SD (48%) and PFS (1.6 months) between treatment groups. Patients with a performance status (PS) of 0 to 1 appeared to have slightly improved SD (59%) and PFS (2.6 months) compared with PS 2 patients.⁸⁹ A phase I trial combined BIBF 1120 with pemetrexed in 26 patients with previously treated NSCLC. The RR was 11.5% (1 CR, 2 PRs), and 8 patients had SD.⁹⁰ Phase III trials with BIBF 1120 are ongoing.

XL647 is another oral small-molecule tyrosine kinase inhibitor (TKI). Initial phase I studies administered XL647 daily for 5 days of a 14-day schedule to 41 patients with advanced solid tumors. One patient with NSCLC had a PR, and an additional 14 patients had SD.^41,91,92 In a second phase I study by the same group, XL647 was administered on a continuous daily schedule to patients with advanced solid tumors. A total of 31 patients were enrolled. Nine patients remain on study, with the majority withdrawing for disease progression; 12 patients have had SD > 3 months.^92,93 In a Simon 2-stage study, XL647 was administered to 23 patients with NSCLC who relapsed after initial benefit from erlotinib or gefitinib. There was 1 PR and 7 patients with SD. Patients have reported improvement in symptoms while on study. Accrual continues with stage 2 of this study.⁴⁰ A second trial by the same investigators administered XL647 to 41 patients with NSCLC who were chemotherapy naive and meeting ≥ 1 of the eligibility criteria: Asian, female, minimal (< 15 pack-years) or no smoking history. Of 36 patients evaluable for response there was a 28% PR and 36% of patients had SD (≥ 3 months). Seventy percent of patients with a PR had an EGFR mutation detected in tumor tissue.⁴⁰ Phase II clinical studies with XL647 in patients with NSCLC are ongoing.

Neovastat (AE-941) is a shark cartilage extract that binds to VEGFR⁹⁴ as well as inhibits matrix metalloproteinases and stimulates apoptosis and tissue plasminogen–activating enzymes.⁹⁵ A phase I/II trial of 80 patients with advanced NSCLC evaluated neovastat at 2 doses (≤ 2.6 or > 2.6 mL/kg/day). Although both doses were well tolerated, the median survival was longer at the higher dose (6.1 months vs. 4.6 months).⁹⁶ Trials with neovastat in combination with chemotherapy and radiation therapy in patients with NSCLC are ongoing.

Conclusion

As our knowledge of cell biology improves, we are able to identify therapies that more precisely affect the target of interest, allowing for a more rational approach to clinical trial design. Inhibition of angiogenesis continues to be an attractive target in the treatment of patients with NSCLC. Based on randomized phase II and III trials, bevacizumab is the only antiangiogenic therapy approved to date for the treatment of patients with advanced NSCLC.^14,15 The multitude of ongoing clinical trials that have added bevacizumab to standard chemotherapy illustrates the continued interest in VEGF as a therapeutic target. The small-molecule receptor TKIs have several targets, including VEGF receptors. Although several of these agents have shown activity in phase II trials, the studies are small, and larger phase III trials that are currently under way will determine their role in the treatment of patients with NSCLC. An important aspect of several of these studies continues to be the inclusion of biologic correlates in order to determine indicators that are prognostic and predictive of a benefit from therapy. However, no definitive markers have been identified to date. The increased sophistication of preclinical models and the enrollment of patients in clinical trials that include measurements of potential biologic correlates will help identify patients who might benefit from therapy with angiogenesis inhibitors as well as determine potential mechanisms of resistance to therapy.

Table 2A. Summary of Toxicity Profiles of Antiangiogenic Agents.

Drug	Toxicity
Bevacizumab	Hypertension Proteinuria Venous or arterial thrombosis Bleeding* Tumor hemorrhage Complications with healing Fatigue
Additional toxicities when combined with chemotherapy	Neutropenia Febrile neutropenia Headache Hyponatremia Diverticulitis Gastrointestinal perforation Reversible posterior leukoencephalopathy syndrome
Additional toxicities when combined with erlotinib	Rash Diarrhea
Sorafenib	Hand-foot syndrome† Hypertension Fatigue Diarrhea Nausea Bleeding
Additional toxicities when combined with chemotherapy	Dyspnea Elevated ALT Neutropenia Thrombocytopenia Infection Thrombosis Cardiac ischemia
Vandetanib	Rash Diarrhea Hypertension Asymptomatic QTc prolongation Nausea Headache Dizziness
Additional toxicities when combined with chemotherapy	Neutropenia Bleeding
Sunitinib	Hypertension Hyperpigmentation and skin discoloration Hypothyroidism Diarrhea Fatigue/asthenia Pain/myalgia Nausea and vomiting Dyspnea Stomatitis/mucosal inflammation Hemorrhage Hair depigmentation
Thalidomide	Thrombosis Neuropathy Neutropenia Fatigue Nausea

All toxicities are reported to occur in > 10% of patients; rare events not mentioned.

^*Associated with squamous cell histology, tumor cavitation, central tumors, and disease location close to major blood vessels.¹⁴

^†Characterized by desquamation of skin on hands and feet as well as blisters and paresthesias.

Abbreviation: ALT = alanine aminotransferase

Table 2B. Summary of Toxicity Profiles of Antiangiogenic Agents.

Drug	Toxicity
Cediranib	Diarrhea Dysphonia Hypertension Fatigue
Additional toxicities when combined with erlotinib or chemotherapy	Rash Abdominal pain Anorexia Myalgias Neutropenia Hemoptysis Pulmonary emboli Neutropenia
Motesanib	Hypertension Fatigue Diarrhea Nausea and vomiting Headache Cholecystitis and gall bladder enlargement Lethargy Hypertension Thrombosis*
Axitinib†	Hypertension Fatigue Nausea and vomiting Diarrhea Headache Stomatitis Erythema Hyponatremia
Pazopanib	Nausea and vomiting Diarrhea Fatigue Hypertension Anorexia Hair depigmentation observed at higher doses
BIBF 1120	Nausea Vomiting Diarrhea
Additional toxicities when combined with chemotherapy	Elevated liver enzymes Fatigue Anorexia Gastrointestinal disorders
XL647	Diarrhea Fatigue Rash QTc prolongation Dysguesia

All toxicities are reported to occur in > 10% of patients; rare events not mentioned.

^*This rate was found to be excessive when motesanib was combined with panitumumab.

^†Complete toxicity profile is not known.

Table 3A. Summary of Clinical Trials Investigating Antiangiogenic Therapy in Patients with Non–Small-Cell Lung Cancer.

Study	Phase	Treatment	N	OS, Months	RR, %
Bevacizumab
Johnson et al14	II	Carboplatin AUC 6 + paclitaxel 200 mg/m2 every 3 weeks	32	14.9	19
		Carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab 7.5 mg/kg	32	11.6	28
		Carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab 15 mg/kg	35	17.7	31.5
Sandler et al15	III	Carboplatin AUC 6 + paclitaxel 200 mg/m2	433	10.3	15
		Carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab 15 mg/kg	417	12.3	35
Manegold et al16	III	Cisplatin 80 mg/m2 day 1 + gemcitabine 1250 mg/m2 days 1 and 8 every 3 weeks	347	NR	20
		Cisplatin 80 mg/m2 day 1 + gemcitabine 1250 mg/m2 + bevacizumab 7.5 mg/kg	345	NR	34
		Cisplatin 80 mg/m2 day 1 + gemcitabine 1250 mg/m2 + bevacizumab 15 mg/kg	351	NR	30
Davila et al17	II	Oxaliplatin 130 mg/m2 day 1 + gemcitabine 1000 mg/m2 days 1 and 8 + bevacizumab 15 mg/kg day 1	22	NR	31
Waples et al18	II	Oxaliplatin 120 mg/m2 + pemetrexed 500 mg/m2 + bevacizumab 15 mg/kg day 1	58	16.7	26
Herbst et al20	II	Pemetrexed 500 mg/m2 + bevacizumab 15 mg/kg	48	8.6	10
Adjei et al19	II	Docetaxel 75 mg/m2 or pemetrexed 500 mg/m2	41	8.6	12
		Docetaxel 75 mg/m2 or pemetrexed 500 mg/m2 + bevacizumab 15 mg/kg	40	12.6	13
		Erlotinib 150 mg + bevacizumab 15 mg/kg	39	13.7	18
Sorafenib
Gutierrez et al21	II	Sorafenib 400 mg	15	NR	13
Gatzemeier et al22	II	Sorafenib 400 mg	54	7	29
Adjei et al23	II	Sorafenib 400 mg	25	8.8	12
Schiller et al66	II	Sorafenib 400 mg	51	11.9	2
		Placebo	32	9	3
Adjei et al24	I	Gefitinib 250 mg + sorafenib 200-400 mg	31	NR	3
Schiller et al25	I/II	Carboplatin AUC 6 + paclitaxel 225 mg/m2 day 1 + sorafenib 400 mg twice daily days 2-18 every 3 weeks	15	NR	29
Scagliotti et al26	III	Carboplatin AUC 6 + paclitaxel 225 mg/m2 day 1 every 3 weeks	462	10.7	24
		Carboplatin AUC 6 + paclitaxel 225 mg/m2 day 1 + sorafenib 400 mg twice daily	464	10.6	30

Abbreviations: AUC = area under the curve; NR = not reported; OS = overall survival; RR = response rate

Table 3B. Summary of Clinical Trials Investigating Antiangiogenic Therapy in Patients with Non–Small-Cell Lung Cancer.

Study	Phase	Treatment	N	OS, Months	RR, %
Vandetanib
Kiura et al27	II	Vandetanib 100 mg/200 mg/300 mg	53	NR	13
Natale et al28	II	Vandetanib 300 mg daily	83	6.1	8
		Gefitinib 250 mg daily	85	7.4	1
Heymach et al29	II	Docetaxel 75 mg/m2	41	13.4	12
		Docetaxel 75 mg/m2 + vandetanib 100 mg	42	13.1	26
		Docetaxel 75 mg/m2 + vandetanib 300 mg	44	7.9	18
Heymach et al30	II	Carboplatin AUC 6 + paclitaxel 225 mg/m2 every 3 weeks	52	NR	25
		Carboplatin AUC 6 + paclitaxel 225 mg/m2 + vandetanib 300 mg daily	56	NR	32
		Vandetanib 300 mg daily	73	NR	7
Sunitinib
Socinski et al31	II	Sunitinib 50 mg daily	63	5.4	11
Brahmer et al32	II	Sunitinib 37.5 mg daily	47	8.6	2
Reck et al33	I	Cisplatin 80 mg/m2 day 1 + gemcitabine 1000 or 1250 mg/m2 days 1 and 8 every 3 weeks + sunitinib 37.5 mg or 50 mg daily	13	NR	23
Thalidomide
Miller et al34	II	Carboplatin AUC 5 day 1 + irinotecan 50 mg/m2 days 1 and 8 + thalidomide 200 mg/day to 1000 mg/day	36	7.3	22
Lee et al35	III	Carboplatin AUC 5 day 1 + gemcitabine 1200 mg/m2 day 1 and 8 every 3 weeks	350	8.9	42
		Carboplatin AUC 5 day 1 + gemcitabine 1200 mg/m2 day 1 and 8 every 3 weeks + thalidomide 100 mg/day during chemotherapy, then 200 mg/day	372	8.4	40
Flora et al36	II	Irinotecan 100 mg/m2 + gemcitabine 1000 mg/m2 days 1 and 8 + thalidomide 200-400 mg/day	8	NR	13
Seidler et al37	II	Docetaxel 75 mg/m2 + thalidomide 200 mg/day	26	5.4	20
Other Agents
Laurie et al38	I	Carboplatin AUC 6 + paclitaxel 200 mg/m2 day 1 every 3 weeks + cediranib 30 mg or 45 mg daily	20	NR	45
Schiller et al39	II	Axitinib 5 mg	32	12.8	10
Miller et al40	II	XL647	23	NR	4
Rizvi et al41	II	XL647	36	NR	28

Abbreviations: AUC = area under the curve; NR = not reported; OS = overall survival; RR = response rate