Anti-Angiogenic Therapy for the Treatment of Lung Cancer

The Journal of Targeted Therapies in Cancer, February 2014, Volume 3, Issue 1

Anti-angiogenic therapy aims to disrupt blood supply to tumors and has proven clinical benefit in nonsquamous non-small cell lung cancer (NSCLC).

Hongbin Chen, MD, PhD

Department of Medicine, Roswell Park Cancer Institute,

Buffalo, NY; hongbin.chen

@roswellpark.org

Anti-angiogenic therapy aims to disrupt blood supply to tumors and has proven clinical benefit in nonsquamous non-small cell lung cancer (NSCLC). Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the only antiangiogenic agent approved by the United States Food and Drug Administration. In clinical trials, bevacizumab significantly improved survival when added to several standard first-line chemotherapy regimens in nonsquamous NSCLC. Its role in the adjuvant chemotherapy setting and in small cell lung cancer treatment is yet to be defined. Other antibody-based treatment and multitargeted small molecules have been evaluated in lung cancer but have not been proven successful so far. Strategies to overcome resistance to VEGF inhibition through dual targeting and to identify predictive biomarkers should be research priorities. This article reviews the updated data from clinical trials of anti-angiogenic therapy in the treatment of lung cancer, with a focus on bevacizumab, multitargeted tyrosine kinase inhibitors, and other agents under investigation.

Lung cancer is the leading cause of cancer death in both men and women in the United States.1Lung cancer is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for about 85% of all lung cancer cases. It is further divided into squamous cell carcinoma and nonsquamous cell carcinoma— the latter includes adenocarcinoma, large cell carcinoma, and other cell types. Combination chemotherapy is commonly used for the first-line treatment of advanced/metastatic SCLC and NSCLC.2,3For nonsquamous cell histology, the cisplatin/pemetrexed combination has demonstrated better efficacy and improved survival with less toxicity than the cisplatin/ gemcitabine combination in treating NSCLC.4More recently, patients whose tumors harbor sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocation are recommended to receive either EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and afatinib, or ALK inhibitors, such as crizotinib, as the first-line therapy.5

Bevacizumab as Anti-Angiogenic Therapy in Advanced/Metastatic NSCLC

First-line setting

Cancer growth depends on angiogenesis (the formation of new blood vessels) to maintain the source of nutrition and oxygen.6Vascular endothelial growth factor (VEGF) is a cytokine that plays a key role in tumor angiogenesis.7VEGF binds to its receptors, VEGF receptor (VEGFR)-1 and VEGFR-2, leading to proliferation and migration of endothelial cells. Tumors usually produce VEGF, and high serum levels of VEGF are correlated with poor prognosis in patients with lung cancer.8Anti-angiogenic therapy aims to disrupt blood supply to tumors and has proven clinical benefit in nonsquamous NSCLC and other solid tumors. Bevacizumab, an anti-VEGF monoclonal antibody (mAb), is the only anti-angiogenic agent approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency for use in NSCLC. This article reviews the recent data from clinical trials of anti-angiogenic therapy in the treatment of both NSCLC and SCLC, with a focus on bevacizumab, multitargeted TKIs, and other agents under investigation.Bevacizumab is the most commonly tested agent for the efficacy and safety of anti-angiogenic therapy in lung cancer. Bevacizumab is a recombinant humanized mAb that targets circulating VEGF, thereby preventing its binding to VEGFR.9It has been extensively studied in various cancer sites and is the most widely investigated anti-angiogenic agent in advanced/metastatic NSCLC (Table 1). A randomized, phase II study published in 2004 showed that bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent NSCLC.10Bleeding was the most prominent adverse event (AE), and major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels.

Clinical Pearls

  • Bevacizumab, an anti-VEGF monoclonal antibody, is the only anti-angiogenic agent approved by the FDA after it significantly improved survival when added to several standard first-line chemotherapy regimens in nonsquamous non-small cell lung cancer.
  • Clinicians should be mindful of its potential side effects and choose appropriate patient populations.
  • Other antibody-based treatment and multitargeted TKIs have been evaluated in lung cancer but have not been proven successful so far.

Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks. Subsequently, the phase III, randomized Eastern Cooperative Oncology Group (ECOG) 4599 trial demonstrated that the addition of bevacizumab (15 mg/kg) to chemotherapy with the carboplatin/paclitaxel combination for six cycles in patients with advanced/metastatic nonsquamous NSCLC significantly improved response rate (RR, 15% to 35%), increased time to progression (4.5 to 6.2 months), resulted in an increase in overall survival (OS) from 10.3 to 12.3 months, and an increase in 2-year survival from 15% to 23%, compared with chemotherapy alone.11The survival benefit was even more evident among patients with adenocarcinoma: Overall survival increased from 10.3 to 14.2 months.12 However, female patients13or patients 70 years of age or older14did not seem to benefit from bevacizumab in the retrospective subgroup analysis. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or ECOG performance status >1 were excluded from this study. There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage (PH). The rates of hypertension, proteinuria, neutropenia, bleeding, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache were also much higher in the bevacizumab arm.

The phase III AVAiL trial, conducted outside of the United States, used a different chemotherapy regimen of cisplatin and gemcitabine as the backbone and evaluated two dosage levels of bevacizumab (7.5 mg/kg and 15 mg/kg).15Combining bevacizumab with chesmotherapy significantly improved progression- free survival (PFS, the primary endpoint) and objective RR at both dosage levels of bevacizumab, compared with chemotherapy alone. However, OS, a secondary endpoint, was not prolonged in this large study, possibly because of high use of efficacious second-line therapies.16Incidence of grade 3 or greater AEs was similar across arms. Grade >3 PH rates were < 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. In a retrospective subgroup analysis in elderly patients aged 65 years or older, bevacizumab-based therapy improved outcomes with no particular safety signals of concern.17

Table 1. Efficacy Results of Landmark Phase III Trials of Bevacizumab in the Treatment of Advanced/Metastatic NSCLC

ECOG 4599 was the first study to illustrate that adding an anti-angiogenic agent to chemotherapy resulted in OS exceeding the 1-year landmark. The positive results of the AVAiL trial provided additional evidence to support adding bevacizumab to standard chemotherapy in the first-line treatment of advanced/ metastatic nonsquamous NSCLC. Most practicing oncologists in the United States have adopted the ECOG 4599 regimen of bevacizumab (15 mg/ kg) with carboplatin/paclitaxel every 21 days up to six cycles, followed by maintenance bevacizumab until disease progression. Pemetrexed-based regimens are becoming widely used in patients with advanced/ metastatic nonsquamous NSCLC because of its efficacy and safety profile.4,18

A single-arm, phase II study showed encouraging survival and toxicity data with carboplatin/ pemetrexed/bevacizumab regimen.19The randomized, phase III PointBreak trial directly compared carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab with carboplatin/ paclitaxel/bevacizumab followed by maintenance bevacizumab.20Both regimens had similar OS but PFS favored the pemetrexed arm.21Toxicity profiles differed, although both regimens demonstrated tolerability, with more grade 3/4 anemia, thrombocytopenia, and fatigue in the pemetrexed arm, and more neutropenia, febrile neutropenia, sensory neuropathy, and alopecia in the paclitaxel arm. Therefore, the carboplatin/pemetrexed/bevacizumab combination is an acceptable alternative regimen in this setting. The randomized, phase III PRONOUNCE trial22directly compared a commonly used firstline chemotherapy regimen of carboplatin/pemetrexed with ECOG 4599 trial regimen of carboplatin/ paclitaxel/bevacizumab.The primary endpoint of PFS without grade 4 toxicity (G4PFS) was not met for superiority in the pemetrexed arm. The 2-drug regimen was not better (or worse) than the 3-drug regimen, with different but tolerable toxicity profiles.23This begs the question of the additional clinical utility of bevacizumab in the era of contemporary pemetrexed-based chemotherapy for nonsquamous NSCLC. The randomized, phase III ERACLE trial24in Italy compared quality of life (QOL) as its primary endpoint between cisplatin/pemetrexed and carboplatin/ paclitaxel/bevacizumab.The two-drug regimen showed a better health profile at 12 weeks.25

Second-line and maintenance settings

Several phase II studies evaluated bevacizumab as second-line therapy for advanced nonsquamous NSCLC but did not meet the primary endpoints.26,27Addition of bevacizumab to erlotinib did not improve survival in patients with recurrent or refractory NSCLC in the double-blind, placebo-controlled, randomized, phase III BeTa trial, either (Table 1).28It should be noted that both ECOG 4599 and AVAiL were among the first phase III trials in lung cancer treatment containing a continuation maintenance component with single-agent bevacizumab following the combination chemotherapy in the experimental arms, with the intention of prolonging the benefits and delaying the development of resistance. In patients with responsive or stable disease after initial combination chemotherapy, continuation or switch maintenance with pemetrexed or erlotinib is an option.29-32Most recently, the Avastin Tarceva Lung Adenocarcinoma Study (ATLAS) showed significantly improved PFS but not OS, with increased toxicity when adding maintenance erlotinib to bevacizumab after a first-line chemotherapy regimen with bevacizumab for advanced NSCLC.33The AVAPERL study evaluated the safety and efficacy of bevacizumab (7.5 mg/kg) with or without pemetrexed as continuation maintenance treatment.34In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinumbased chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance (7.4 months) was associated with a significant PFS benefit compared with bevacizumab alone (3.7 months), and was well tolerated. The OS has not yet been reached. The ongoing ECOG 5508 trial (NCT01107626) compares three arms of maintenance therapy: bevacizumab versus pemetrexed versus bevacizumab plus pemetrexed, in patients who have achieved stable or better response after 4 cycles of induction chemotherapy for stage IIIB/IV nonsquamous NSCLC.

Bevacizumab as Anti-Angiogenic Therapy in Early-Stage NSCLC

The open-label, phase IV SAiL study assessed the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in 2212 patients with untreated, locally advanced metastatic, or recurrent nonsquamous NSCLC across 40 countries.35The results confirmed that most AEs were manageable, with no new safety signals reported. In the phase II PASSPORT trial, adding bevacizumab to various chemotherapy agents or to erlotinib in patients with NSCLC and treated brain metastases seemed to be safe and was associated with a low incidence of central nervous system (CNS) hemorrhage.36Among patients with untreated, asymptomatic brain metastasis ineligible for surgery or radiosurgery, the phase II, noncomparative BRAIN study demonstrated promising efficacy and acceptable safety.37Only one grade 1 intracranial hemorrhage event was reported in the bevacizumab arm with first-line chemotherapy and none in the second- line with erlotinib. The phase II BRIDGE trial was designed to determine whether or not delaying initiation of bevacizumab treatment and selecting patients without baseline risk factors for PH would lower the incidence of severe PH among patients with squamous NSCLC.38The rate of PH was low (1/31 = 3.2%) in this small study, but treatment of squamous NSCLC with bevacizumab should still be considered experimental. Although no clinical or radiologic features (including cavitation and central tumor location) reliably predict severe PH in bevacizumab- treated patients, major blood vessel infiltration and bronchial vessel infiltration, encasement, and abutting may predict PH.39Because standardized radiologic criteria for defining infiltration have not been established, an individualized risk assessment should be done in all patients with NSCLC in whom bevacizumab is being considered.Given its efficacy in advanced/metastatic nonsquamous NSCLC, bevacizumab has been tested in early- stage NSCLC, usually in a multimodality fashion. A phase I/II study investigated incorporating bevacizumab and erlotinib with a complex sequence of induction chemotherapy and then concurrent chemoradiotherapy followed by consolidation therapy in stage III NSCLC.40Substantial risk of esophageal toxicity (29% grade 3/4 esophagitis, with one grade 3 tracheoesophageal fistula) was observed, with a lack of efficacy signal. Combining bevacizumab and chemoradiotherapy was associated with a relatively high incidence of tracheoesophageal fistula formation and related morbidity and mortality in both NSCLC and SCLC that prompted early trial closures, FDA warnings, and a change in bevacizumab labeling.41Therefore, bevacizumab should not be prescribed when planning for combination treatment for stage III NSCLC.

Other Anti-Angiogenic Antibodies

A recently reported phase II clinical trial assessed the effects of adding bevacizumab to neoadjuvant chemotherapy of cisplatin and docetaxel in resectable nonsquamous NSCLC.42The rate of downstaging (38%, primary endpoint), response to chemotherapy (45%), and perioperative complications (12%) were comparable with historical data, but the study failed to meet the primary endpoint. No partial response was observed to single-agent bevacizumab, but 18% of the patients developed new intratumoral cavitation, which may be a potential clinical biomarker. A major pathologic response (≥ 90% treatment effect) was associated with improved OS at 3 years (100% vs 49%). Perioperative complications potentially attributable to bevacizumab included gastrointestinal bleeding and bronchopleural fistulization. After induction treatment and surgery, the delivery of bevacizumab was not feasible, with approximately half of eligible patients receiving any adjuvant therapy. The ongoing ECOG 1505 trial (NCT00324805) is evaluating the efficacy of bevacizumab in the adjuvant setting among patients with resected stage IB (tumor ≥ 4 cm), stage II, or stage IIIA NSCLC. Patients are randomized to receive a total of 4 cycles of cisplatin-based adjuvant chemotherapy (with vinorelbine, docetaxel, pemetrexed, or gemcitabine) or four cycles of chemotherapy plus bevacizumab (every 21 days for up to 1 year). The results are eagerly awaited.Aflibercept is a recombinant fusion protein consisting of portions of human VEGFR extracellular domains fused to the Fc portion of human immunoglobulin G1 (IgG1). It binds vascular endothelial growth factor-A (VEGF-A) by acting as a high-affinity ligand trap to prevent binding to its endogenous receptor VEGFR-2, thereby inhibiting VEGF-induced angiogenesis in preclinical models.43Aflibercept has been approved for treatment in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for patients who have progressed on an oxaliplatin-containing regimen.44Aflibercept has been tested as a single agent and in combination with standard chemotherapy in the systemic therapy of NSCLC. In a single-arm, phase II study in platinum- and erlotinib-resistant adenocarcinoma of the lung, aflibercept monotherapy demonstrated objective responses in heavily pretreated patients.45The randomized, controlled, phase III VITAL trial compared aflibercept plus docetaxel with placebo plus docetaxel for the second-line treatment in 913 patients with locally advanced/metastatic nonsquamous NSCLC.46The aflibercept arm demonstrated significantly improved PFS (5.2 vs 4.1 months) and RR (23.3% vs 8.9%) compared with the placebo arm. However, this trial did not meet its primary endpoint of OS (10.1 vs 10.4 months), probably because of the confounding effect of subsequent therapy, as 47% of study patients went on to receive third-line systemic therapy. This study regimen was associated with increased toxicities, which were consistent with known anti-VEGF and chemotherapy-induced events.

Cross section of a human lung. The white area in the upper lobe is cancer, the black areas indicate the patient was a smoker.

SOURCE: The Web site of the National Cancer Institute (http://www.cancer.gov)

A phase I, dose-escalation study that combined aflibercept with cisplatin/pemetrexed in 18 patients with advanced solid tumors determined the recommended dose of aflibercept (6 mg/kg every 21 days) to be used in a phase II trial.47Subsequently, a single- arm, open-label, multicenter, phase II trial was conducted to test the 3-drug combination of aflibercept/ cisplatin/pemetrexed in the first-line treatment of patients with advanced/metastatic nonsquamous NSCLC.48The study was terminated prematurely after enrolling 42 patients because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). It should be noted that no RPLS was reported in the phase I study that used the same combination regimen of aflibercept/cisplatin/pemetrexed in 18 patients with advanced solid tumors,47nor in another phase I combination study of aflibercept/cisplatin/ docetaxel.49The syndrome may be related to declining renal function and/or to hypertension associated with anti-angiogenic therapy, but it is also likely that the development of RPLS depends on the specific chemotherapy regimen rather than its dosage or schedule. This phase II study was underpowered for efficacy evaluation, and this 3-drug combination will not be explored further in NSCLC.

Ramucirumab is a fully human IgG1 mAb targeting the VEGFR-2 binding and signaling.50A randomized, phase II study recently reported the efficacy of combining ramucirumab (10 mg/kg every 21 days) with standard first-line chemotherapy of platinum/ pemetrexed followed by maintenance therapy in stage IIIb/IV NSCLC.51The primary endpoint of PFS among nonsquamous patients was not met: 7.2 months in the ramucirumab arm versus 5.6 months in the control arm. Another phase II study tested ramucirumab in combination with carboplatin/paclitaxel in the first-line treatment of patients with stage IIIb/IV NSCLC.52Preliminary results of 31 patients did not highlight any unusual safety concerns, with one patient discontinuation because of the AE of pneumothorax. Preliminary efficacy data are encouraging, with RR of 67% and PFS of 5.7 months. The randomized, double-blind, phase III REVEL study (NCT01168973) is under way to compare docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV NSCLC after disease progression after one previous platinumbased therapy.53

Multitargeted TKIs in NSCLC

Bavituximab is a chimeric IgG1 mAb directed against the membrane phospholipid phosphatidylserine that triggers vascular disruption, enhances antitumor immune response, and causes selective shutdown of pre-existing tumor blood vessels.54As a vascular disrupting agent (VDA), bavituximab was well tolerated at dosages ranging up to 3 mg/ kg weekly, and pharmacokinetic studies support a weekly dosing regimen.55A randomized, open-label, phase II trial of paclitaxel/carboplatin with or without bavituximab in first-line treatment of advanced/ metastatic nonsquamous NSCLC reported no significant difference in the primary endpoint, RR (32% in the bavituximab arm vs 31% in the control arm), with similar overall safety profile of mostly hematologic AEs.56Another randomized, blinded, placebocontrolled, phase II trial of docetaxel and bavituximab as second-line therapy in advanced/metastatic nonsquamous NSCLC also reported no significant difference in the primary endpoint, RR (17.1% in the bavituximab arm vs 11.3% in the control arm).57Median OS was 11.7 months and 7.3 months, respectively. Based on a positive trend in this phase II trial, the large multicenter, phase III SUNRISE trial (NCT01999673) is under way to compare bavituximab plus docetaxel versus docetaxel alone in the second-line setting, using OS as the primary endpoint.Multitargeted TKIs exhibit anti-angiogenic effects by inhibiting VEGF pathway in addition to targeting other signaling pathways. They have been tested extensively in NSCLC and demonstrated some activities with no overall survival benefits shown to date (Table 2). In the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study, sorafenib demonstrated clinical activity in NSCLC, with an 8-week disease control rate (DCR) of 58.2%, especially with wild-typeEGFR.58However, sorafenib has failed to show OS improvement in the first-line setting when combined with standard chemotherapy of carboplatin/ paclitaxel in the phase III ESCAPE trial59or of cisplatin/ gemcitabine in the phase III NExUS trial.60In the third- or fourth-line setting, sorafenib improved PFS and RR but not OS in the recently completed placebo-controlled, phase III MISSION trial (NCT0863746).

Sunitinib did not improve OS when added to erlotinib in patients with refractory NSCLC, but the toxicities were greater with combination therapy.61Maintenance therapy with sunitinib monotherapy after frontline carboplatin/paclitaxel did not improve the 1-year OS.62The randomized, phase II Cancer and Leukemia Group B (CALGB) 30704 trial (NCT00698815) compared pemetrexed, sunitinib, and their combination as second-line therapy in patients with stage IIIB/IV NSCLC.63The 18-week PFS rate (the primary endpoint) was not significantly different between the arms. Cediranib (30 mg daily) was not tolerable when added to carboplatin/paclitaxel as first-line treatment in the phase II/III, double- blind BR24 study.64Subsequently, the randomized, double-blind, phase III BR29 study used a lower dosage (20 mg daily) of cediranib added to firstline carboplatin/paclitaxel.65The study was terminated for futility with increased RR and toxicity, but not survival. Similarly, limited activity but increased toxicity were observed when cediranib (30 mg daily) was added to first-line carboplatin/gemcitabine in a randomized, phase II study.66

Vandetanib is a small-molecule TKI that targets both VEGFR and EGFR.67It has been systematically evaluated in the second-line treatment of NSCLC in several large phase III trials. Although vandetanib significantly improved PFS when added to docetaxel in the ZODIAC trial68and when compared to placebo in the ZEPHYR trial,69it did not meet the primary endpoint of PFS when combined with pemetrexed in the ZEAL trial70or when compared with erlotinib in the ZEST trial.71The phase II vandetanib study from the BATTLE trial reported an 8-week DCR of 33%.72No OS benefit was reported in these trials, but increased toxicities occurred with the vandetanib arms. As a result, vandetanib is no longer in development in NSCLC. BMS-690514 is a reversible oral inhibitor of EGFR/HER-1, HER-2, and HER-4 and of VEGFRs-1 to -3, offering targeted inhibition of tumor growth and vascularization in a single agent. A phase I—IIa study suggests that BMS-690514 has a manageable safety profile and antitumor activity (RR of 3.3 %) in patients with NSCLC.73

Another TKI, motesanib, did not significantly improve OS when combined with carboplatin/paclitaxel in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset in the randomized, placebo-controlled, double-blind, phase III MONET1 study.74Pazopanib showed single-agent activity in patients with early-stage NSCLC in a phase II proof-of-concept study.75A randomized, open-label, phase II study recently reported some antitumor activity but unacceptable levels of toxicity when pazopanib was combined with pemetrexed in the first-line therapy of NSCLC.76Axitinib demonstrated single-agent activity and was well tolerated with manageable toxicities in patients with advanced NSCLC in an openlabel, phase II study.77In a randomized, phase II study comparing first-line axitinib/paclitaxel/carboplatin with bevacizumab/paclitaxel/carboplatin (ECOG 4599 regimen) in advanced nonsquamous NSCLC, the axitinib arm did not improve efficacy and was less well tolerated.78Similarly, a randomized, phase II study combining axitinib with another commonly used first-line regimen of cisplatin/ pemetrexed in advanced nonsquamous NSCLC did not improve efficacy.79

Dual Targeting

Nintedanib is an oral inhibitor of VEGF, fibroblast growth factor receptor (FGFR), and plateletderived growth factor receptor (PDGFR), so-called “triple angiokinase inhibition.” The phase III LUMELung 1 trial assessed the addition of nintedanib to docetaxel in second-line treatment of NSCLC.80The combination significantly improved PFS (3.4 vs 2.7 months) in all patients and improved OS (12.6 vs 10.3 months) in patients with adenocarcinoma. The phase III LUME-Lung 2 trial assessed the addition of nintedanib to pemetrexed in second-line treatment of nonsquamous NSCLC.81Even though the study was halted prematurely because of interim futility analysis, the primary endpoints of centrally reviewed PFS favored the nintedanib arm (4.4 vs 3.6 months), with no difference in OS or RR.Preclinical data suggest that EGFR activation may promote angiogenesis and an association between acquired resistance to EGFR blockade and increased VEGF expression.82,83Therefore, dual targeting of EGFR and VEGF pathways may increase efficacy compared with single-pathway inhibition alone. However, as mentioned above, the results of phase III trials so far combining an EGFR TKI such as erlotinib and an anti-VEGF mAb such as bevacizumab are disappointing. Combination of bevacizumab and erlotinib did not improve OS compared with erlotinib alone in the second-line setting BeTa trial,28or compared with bevacizumab alone in the maintenance setting ATLAS trial.33Vandetanib is another agent with dual inhibition but with disappointing results, as discussed above.

Table 2. Efficacy Results of Phase III Trials of Multitargeted TKIs in the Treatment of Advanced/Metastatic NSCLC

Cetuximab is a mAb targeting the EGFR pathway and has shown survival benefit when added to cisplatin and vinorelbine in the phase III FLEX trial,84although another phase III BMS 099 trial of chemotherapy with or without cetuximab failed to meet the primary endpoint of improved PFS.85A randomized, phase II study of cetuximab and bevacizumab in combination with two regimens of paclitaxel and carboplatin in chemo-naïve patients with stage IIIB/IV NSCLC showed expected PFS and numerically comparable OS.86Quality of life was similar in the two arms, and both regimens were well tolerated. The phase II South West Oncology Group (SWOG) S0536 trial evaluated carboplatin, paclitaxel, cetuximab, and bevacizumab followed by maintenance cetuximab and bevacizumab in advanced nonsquamous NSCLC.87The regimen was determined to be safe, with 2% grade ≥ 4 hemorrhage (primary endpoint), feasible, and effective as a frontline treatment. The median PFS was 7 months, OS was 15 months, and RR 56%, comparable with other phase III trials discussed above. In addition, no detrimental effect of KRAS mutation status was observed on the efficacy parameters in this study, in contrast to its effect with cetuximab-based therapy in colorectal cancer.88It provides the basis for the ongoing phase III SWOG S0819 trial to compare OS in patients with stage IV or recurrent NSCLC treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with cetuximab versus without cetuximab.89

Anti-Angiogenic Therapy in SCLC

Cabozantinib is a potent ATP-competitive inhibitor of MET and VEGFR2 as well as rearranged during transfection (RET) and fms-like tyrosine kinase 3 (FLT3).90Hepatocyte growth factor (HGF), the ligand of MET, and VEGF act synergistically to promote angiogenesis. Targeting the VEGF pathway can induce hypoxia and upregulate hypoxia-inducible factor (HIF) 1α, resulting in increased expression of both VEGF and MET and development of resistance to anti-VEGF therapy. Therefore, simultaneously inhibiting MET and VEGFR2 with cabozantinib is intended to overcome the development of MET-driven resistance to agents targeting the VEGF pathway alone and to provide a more sustained antitumor effect. A phase II, randomized discontinuation trial (RDT) evaluated cabozantinib in patients who received prior EGFR and VEGF pathway-targeted therapy for NSCLC.91It showed activity in this group of heavily pretreated patients, with PFS of 4.2 months and RR of 10%. Cabozantinib is also being investigated in patients with RET fusion-positive lung adenocarcinomas.92The randomized, phase II ECOG 1512 trial (NCT01708954) is investigating cabozantinib, erlotinib, and their combination as second- or thirdline therapy in stage IV NSCLC.Anti-angiogenic therapy, including bevacizumab and TKIs, has also been tested in SCLC. For extensive- stage (ES) SCLC, the addition of bevacizumab to cisplatin and etoposide in the phase II ECOG 3501 trial93resulted in improved PFS and OS relative to historical controls, who received this chemotherapy regimen without bevacizumab.Based on this encouraging data, the placebo-controlled, double-blind, randomized, phase II SALUTE trial94was designed to assess the efficacy and safety of adding bevacizumab to first-line standard chemotherapy of cisplatin or carboplatin plus etoposide for treatment of ESSCLC. The addition of bevacizumab improved PFS, with an acceptable toxicity profile, but no improvement in OS was observed. Adding bevacizumab to another first-line chemotherapy of carboplatin/irinotecan achieved favorable response.95However, the phase II CALGB 30306 study adding bevacizumab to cisplatin/irinotecan did not yield promising efficacy.96In the second-line setting, adding aflibercept to topotecan improved 3-month PFS from 9% to 26% in a randomized, phase II trial.97

Predictive Biomarkers

Conclusions

In the double-blind, randomized, phase II BR20 trial,98vandetanib failed to demonstrate efficacy as maintenance therapy for SCLC. Sunitinib did not seem to maintain disease stability after response to chemotherapy with platinum plus etoposide in a phase II study,99but achieved an encouraging 1-year OS of 54% after six cycles of irinotecan and carboplatin in patients with newly diagnosed ES-SCLC in another study.100 The randomized, placebo-controlled, phase II CALGB 30504 (ALLIANCE) study101 met its primary endpoint of PFS (3.8 months in the sunitinib arm vs 2.3 months in the placebo arm), although OS was not significant, probably because of crossover design. It should be pointed out that initially sunitinib was combined with platinum and led to severe toxicities such as neutropenia and sepsis in some studies,100,101resulting in the subsequent modification to maintenance-alone designs. Similarly, sorafenib in conjunction with cisplatin and etoposide and as maintenance therapy in ES-SCLC caused significant toxicity with disappointing efficacy data.102Meanwhile, single-agent sorafenib in platinum- treated patients with ES-SCLC failed to achieve disease control in the phase II SWOG 0435 trial.103Patient selection for anti-angiogenic therapy is now mostly based on exclusion for toxicity. Predictive biomarkers for anti-angiogenic therapy in general are still elusive. Among patients in the ECOG 4599 trial, baseline levels of soluble intercellular adhesion molecule (ICAM) were prognostic for survival and predictive of response to chemotherapy with or without bevacizumab (lower levels of ICAM associated with better results), while VEGF levels were predictive of response to bevacizumab but not survival (higher levels of VEGF with better response).104A baseline measurement of cytokine and angiogenic factors (CAF) consisting of HGF and interleukin (IL)-121 was associated with tumor response to pazopanib, an oral angiogenesis inhibitor of VEGFR, PDGFR, and c-kit.105Hypertension is one of the most common AEs during anti-angiogenic therapy. Clinically, retrospective analysis suggested improved outcomes associated with bevacizumab in patients developing hypertension on therapy,106but available evidence does not suggest hypertension as a surrogate for the efficacy of anti-angiogenic therapy in advanced NSCLC.107Exploring this area in biomarker- driven prospective studies will eventually help to identify patients who can benefit most from antiangiogenic therapy and avoid its use that is otherwise not likely cost-effective. It was estimated that the financial cost of bevacizumab plus chemotherapy compared with chemotherapy alone can incur an incremental cost-utility ratio of more than $500,000 per quality-adjusted year of life.108The antifungal drug itraconazole has a well-established safety profile and is relatively inexpensive. It has demonstrated preclinical anti-angiogenic activity109and was well tolerated in combination with pemetrexed as second-line therapy in NSCLC with a trend toward improved disease control in a phase II study.110Anti-angiogenic therapy is one of the earliest targeted therapies adopted in the treatment of lung cancer. Bevacizumab, an anti-VEGF monoclonal antibody, is the only anti-angiogenic agent approved by the FDA for the treatment of nonsquamous NSCLC because it has significantly improved survival when added to several standard first-line chemotherapy regimens. Clinicians should be mindful of its potential for side effects and select an appropriate patient population. Continuation maintenance with bevacizumab should be considered, but the optimal regimen is still under investigation. Its roles in the adjuvant chemotherapy setting and in SCLC treatment are yet to be defined. Other antibody-based treatment and multitargeted TKIs have been evaluated in lung cancer but have not been proven successful so far. Strategies to overcome resistance to VEGF inhibition via dual targeting and to identify predictive biomarkers should be priorities on the research agenda for antiangiogenic therapy.

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013.CA Cancer J Clin. 2013;63(1):11-30.
  2. Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer.J Clin Oncol. 1994;12(10):2022-2034.
  3. Schiller JH, Harrington DP, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002;346(2):92-98.
  4. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol. 2008;26(21):3543-3551.
  5. Chen H. Afatinib for EGFR mutation-positive, advanced non-small cell lung cancer.Int J Targeted Ther Cancer. 2013;2(5):37-48.
  6. Folkman J. Clinical applications of research on angiogenesis.N Engl J Med. 1995;333(26):1757-1763.
  7. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4-25.
  8. Korpanty G, Smyth E, Sullivan LA, et al. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway.Exp Biol Med. 2010;235(1):3-9.
  9. Ferrara N, Hillan KJ, Gerber H-P, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.Nat Rev Drug Discov. 2004;3(5):391-400.
  10. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.J Clin Oncol. 2004;22(11):2184-2191.
  11. Sandler AB, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006;355(24):2542-2550.
  12. Sandler A, Yi J, Dahlberg S, et al. Treatment outcomes by tumor histology in Eastern Cooperative Oncology Group study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer.J Thorac Oncol. 2010;5(9):1416-1423.
  13. Brahmer JR, Dahlberg SE, Gray RJ, et al. Sex differences in outcome with bevacizumab therapy: analysis of patients with advanced-stage nonsmall cell lung cancer treated with or without bevacizumab in combination with paclitaxel and carboplatin in the Eastern Cooperative Oncology Group Trial 4599.J Thorac Oncol. 2011;6(1):103-108.
  14. 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.J Clin Oncol. 2008;26(1):60-65.
  15. 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.J Clin Oncol. 2009;27(8):1227-1234.
  16. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin/ gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL).Ann Oncol. 2010;21(9):1804-1809.
  17. 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).J Thorac Oncol. 2010;5(12):1970-1976.
  18. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004;22(9):1589- 1597.
  19. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer.J Clin Oncol. 2009;27(20):3284-3289.
  20. Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the PointBreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.Clin Lung Cancer. 2009;10(4):252-256.
  21. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIb or IV nonsquamous non-small-cell lung cancer.J Clin Oncol. 2013;31(34):4349-4357.
  22. Zinner RG, Saxman SB, Peng G, et al. Treatment rationale and study design for a randomized trial of pemetrexed/carboplatin followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with advanced nonsmall- cell lung cancer of nonsquamous histology.Clin Lung Cancer. 2010;11(5):352-357.
  23. Zinner RG, Ross HJ, Weaver R, et al. PRONOUNCE: randomized, openlabel, phase III study of pemetrexed plus carboplatin (PemC) followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab (PCB) followed by maintenance bevacizumab in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).J Clin Oncol. 2013;31(suppl; abstr LBA8003).
  24. Galetta D, Pisconti S, Cinieri S, et al. Induction pemetrexed and cisplatin followed by maintenance pemetrexed versus carboplatin plus paclitaxel plus bevacizumab followed by maintenance bevacizumab: a quality of life-oriented randomized phase III study in patients with advanced non-squamous non-small-cell lung cancer (ERACLE).Clin Lung Cancer. 2011;12 (6):402-406.
  25. Galetta D, Pisconti S, Cinieri S, et al. Induction pemetrexed and cisplatin followed by pemetrexed vs carboplatin-paclitaxel and bevacizumab followed by bevacizumab as maintenance: multicenter randomized phase III study in patients with advanced non-squamous non-small-cell lung cancer (NSCLC): a quality of life oriented phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale) ERACLE.J Clin Oncol. 2013;31(suppl;abstr 8071).
  26. Herbst RS, O&rsquo;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.J Clin Oncol. 2007;25(30):4743- 4750.
  27. Adjei AA, Mandrekar SJ, Dy GK, et al. Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients with advanced nonsmall- cell lung cancer: NCCTG and SWOG Study N0426.J Clin Oncol. 2010;28(4):614-619.
  28. 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(9780):1846-1854.
  29. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for nonsmall- cell lung cancer: a randomised, double-blind, phase 3 study.Lancet. 2009;374(9699):1432-1440.
  30. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial.Lancet Oncol. 2012;13(3):247-255.
  31. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.J Clin Oncol. 2013;31(23):2895-2902.
  32. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.Lancet Oncol. 2010;11(6):521-529.
  33. Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIb trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer.J Clin Oncol. 2013;31(31):3926-3934.
  34. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089).J Clin Oncol. 2013;31(24):3004-3011.
  35. 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 Oncol. 2010;11(8):733- 740.
  36. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases.J Clin Oncol. 2009;27(31):5255-5261.
  37. Besse B, Le Moulec S, Senellart H, et al. Final overall survival (OS) results of a noncomparative phase II study of bevacizumab (B) plus first-line chemotherapy or second-line erlotinib (E) in nonsquamous NSCLC (NSNSCLC) patients with asymptomatic untreated brain metastases (BM) (BRAIN).J Clin Oncol. 2013;31(suppl; abstr 8059).
  38. 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.J Thorac Oncol. 2011;6(1):109-114.
  39. Reck M, Barlesi F, Crino L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts.Ann Oncol. 2012;23(5):1111- 1120.
  40. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial.J Clin Oncol. 2012;30(32):3953-3959.
  41. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab.J Clin Oncol. 2010;28(1):43-48.
  42. Chaft JE, Rusch V, Ginsberg MS, et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers.J Thorac Oncol. 2013;8(8):1084-1090.
  43. Lassoued W, Murphy D, Tsai J, et al. Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors.Cancer Biol Ther. 2010;10(12):1326-1333.
  44. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.J Clin Oncol. 2012;30(28):3499-3506.
  45. Leighl NB, Raez LE, Besse B, et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (aflibercept) in platinum- and erlotinibresistant adenocarcinoma of the lung.J Thorac Oncol. 2010;5(7):1054- 1059.
  46. Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial.J Clin Oncol. 2012;30(29):3640-3647.
  47. Diaz-Padilla I, Siu LL, San Pedro-Salcedo M, et al. A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.Br J Cancer. 2012;107(4):604-611.
  48. Chen H, Modiano MR, Neal JW, et al. A phase II multicentre study of zivaflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer [published online ahead of print Nov 28, 2013].Br J Cancer. 2014.
  49. Freyer G, Isambert N, You B, et al. Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours.Br J Cancer. 2012;107(4):598-603.
  50. Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2.J Clin Oncol. 2010;28(5):780-787.
  51. Doebele R, Spigel DR, Tehfe M, et al. A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): results from non-squamous (NSQ) pts (NCT01160744).J Thorac Oncol. 2013;8(suppl 2;S290, abstr MO06.08).
  52. Camidge DR, Ballas MS, Dubey S, et al. A phase II, open-label study of ramucirumab (IMC-1121B), an IgG1 fully human monoclonal antibody (MAb) targeting VEGFR-2, in combination with paclitaxel and carboplatin as first-line therapy in patients (pts) with stage IIIb/IV non-small cell lung cancer (NSCLC).J Clin Oncol. 2010;28(15s;abstr 7588).
  53. Garon EB, Cao D, Alexandris E, et al. A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): treatment rationale and study design.Clin Lung Cancer. 2012;13(6):505-509.
  54. DeRose P, Thorpe PE, Gerber DE. Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment: immunotherapy.Immunother. 2011;3(8):933-944.
  55. Gerber DE, Stopeck AT, Wong L, et al. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors.Clin Cancer Res. 2011;17(21):6888-6896.
  56. Dragnev KH, Attili SV, Gagua R, et al. A randomized, open-label, phase 2 trial of paclitaxel/carboplatin with or without bavituximab in patients with previously untreated locally advanced or metastatic non-squamous non-small-cell lung cancer.J Thorac Oncol. 2012;7(suppl;abstr 180).
  57. Shtivelband M, Spigel DR, Gerber DE, et al. Randomized, blinded, placebo- controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer.J Clin Oncol. 2013;31(suppl;abstr 8095).
  58. Blumenschein GR, Saintigny P, Liu S, et al. Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. Clin Cancer Res. 2013;19(24):6967-6975.
  59. 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.J Clin Oncol. 2010;28(11):1835-1842.
  60. Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, doubleblind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous nonsmall- cell lung cancer.J Clin Oncol. 2012;30(25):3084-3092.
  61. Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial.J Clin Oncol. 2012 ;30(17):2070-2078.
  62. Gervais R, Hainsworth JD, Blais N, et al. Phase II study of sunitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer.Lung Cancer. 2011;74(3):474-480.
  63. Heist RS, Wang X, Hodgson L, et al. CALGB 30704 (ALLIANCE): a randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non-small-cell lung cancer.J Thorac Oncol. 2014;9(2):214-221.
  64. 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(1):49-55.
  65. Laurie SA, Solomon BJ, Seymour L, et al. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29 [published online ahead of print Dec 17, 2013].Eur J Cancer. 2014.
  66. Dy GK, Mandrekar SJ, Nelson GD, et al. A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.J Thorac Oncol. 2013;8(1):79-88.
  67. Morabito A, Piccirillo MC, Falasconi F, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEFGR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions.Oncologist. 2009;14(4):378-390.
  68. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced nonsmall- cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial.Lancet Oncol. 2010;11(7):619-626.
  69. Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double- blind phase III trial (ZEPHYR).J Clin Oncol. 2012;30(10):1114-1121.
  70. de Boer RH, Arrieta O, Yang C-H, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2011;29(8):1067-1074 .
  71. 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.J Clin Oncol. 2011;29(8):1059-1066.
  72. Tsao AS, Liu S, Lee JJ, et al. Clinical and biomarker outcomes of the phase II vandetanib study from the BATTLE trial.J Thorac Oncol. 2013;8(5):658-661.
  73. Soria J-C, Baselga J, Hanna N, et al. Phase I/IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.Eur J Cancer. 2013;49(8):1815-1824.
  74. Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/ paclitaxel in patients with advanced nonsquamous non-smallcell lung cancer: MONET1.J Clin Oncol. 2012;30(23):2829-2836.
  75. 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.J Clin Oncol. 2010;28(19):3131-3137.
  76. Scagliotti GV, Felip E, Besse B, et al. An open-label, multicenter, randomized, phase II study of pazopanib in combination with pemetrexed in firstline treatment of patients with advanced-stage non-small-cell lung cancer.J Thorac Oncol. 2013;8(12):1529-1537.
  77. 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.J Clin Oncol. 2009;27(23):3836-3841.
  78. Twelves C, Chmielowska E, Havel L, et al. Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as firstline therapy for patients with advanced non-small-cell lung cancer.Ann Oncol. 2014;25(1):132-138.
  79. Belani CP, Yamamoto N, Bondarenko I, et al. A randomized phase II study of axitinib in combination with pemetrexed/cisplatin (pem/cis) as firstline therapy for nonsquamous non-small cell lung cancer (NSCLC).J Clin Oncol. 2012;30(suppl):abstr 7551.
  80. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-smallcell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.Lancet Oncol. 2014;15(2):143-155.
  81. Hanna N, Kaiser R, Sullivan RN, 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.J Clin Oncol. 2013;31(suppl):abstr 8034.
  82. Ellis LM. Epidermal growth factor receptor in tumor angiogenesis: angiogenesis and anti-angiogenic therapy.Hematol Oncol Clin North Am. 2004;18(5):1007-1021.
  83. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer.N Engl J Med. 2008;359(13):1367-1380.
  84. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet. 2009;373(9674):1525-1531.
  85. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/ carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.J Clin Oncol. 2010;28(6):911-917.
  86. Bonomi PD, Mace J, Mandanas RA, et al. Randomized phase II study of cetuximab and bevacizumab in combination with two regimens of paclitaxel and carboplatin in chemonaive patients with stage IIIB/IV nonsmall- cell lung cancer.J Thorac Oncol. 2013;8(3):338-345.
  87. Kim ES, Moon J, Herbst RS, et al. Phase II trial of carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab in advanced nonsquamous non-small-cell lung cancer: SWOG S0536.J Thorac Oncol. 2013;8(12):1519-1528.
  88. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab.JAMA. 2010;304(16):1812-1820.
  89. Redman MW, Crowley JJ, Herbst RS, et al. Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819.Clin Cancer Res. 2012;18(15):4004-4012.
  90. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.Mol Cancer Ther. 2011;10(12):2298-2308.
  91. Hellerstedt B, Edelman G, Vogelzang NJ, et al. Activity of cabozantinib (XL184) in metastatic NSCLC: results from a phase II randomized discontinuation trial (RDT).J Clin Oncol. 2012;30(suppl):abstr 7514.
  92. Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas.Cancer Discovery. 2013;3(6):630-635.
  93. Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group study E3501.J Clin Oncol. 2009;27(35):6006-6011.
  94. Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial.J Clin Oncol. 2011;29(16):2215-2222.
  95. Spigel DR, Greco FA, Zubkus JD, et al. Phase II trial of irinotecan, carboplatin, and bevacizumab in the treatment of patients with extensive-stage small-cell lung cancer.J Thorac Oncol. 2009;4(12):1555-1560.
  96. Ready NE, Dudek AZ, Pang HH, et al. Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study.J Clin Oncol. 2011;29(33):4436-4441.
  97. Allen JW, Moon J, Gadgeel SM, et al. SWOG 0802: a randomized phase II trial of weekly topotecan with and without AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small cell lung cancer (ESCLC).J Clin Oncol. 2012;30(suppl;abstr 7005).
  98. Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR20.J Clin Oncol. 2007;25(27):4278-4284.
  99. Schneider BJ, Gadgeel SM, Ramnath N, et al. Phase II trial of sunitinib maintenance therapy after platinum-based chemotherapy in patients with extensive-stage small cell lung cancer.J Thorac Oncol. 2011;6(6):1117-1120.
  100. Spigel DR, Greco FA, Rubin MS, et al. Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer.Lung Cancer. 2012;77(2):359-364.
  101. Ready NE, Pang HH, Gu L, et al. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small cell lung cancer: a randomized, placebo controlled phase II study CALGB 30504 (ALLIANCE).J Clin Oncol. 2013;31(suppl;abstr 7506).
  102. Sharma N, Pennell N, Nickolich M, et al. Phase II trial of sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive- stage small cell lung cancer [published online ahead of print Jan 15, 2014].Invest New Drugs. 2014.
  103. Gitlitz BJ, Moon J, Glisson BS, et al. Sorafenib in platinum-treated patients with extensive stage small cell lung cancer: a Southwest Oncology Group (SWOG 0435) phase II trial.J Thorac Oncol. 2010;5(11):1835-1840.
  104. Dowlati A, Gray R, Sandler AB, et al. 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.Clin Cancer Res. 2008;14(5):1407-1412.
  105. Nikolinakos PG, Altorki N, Yankelevitz D, et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib.Cancer Res. 2010;70(6):2171-2179.
  106. Dahlberg SE, Sandler AB, Brahmer JR, et al. 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.J Clin Oncol. 2010;28(6):949-954.
  107. Evans T. Utility of hypertension as a surrogate marker for efficacy of antiangiogenic therapy in NSCLC.Anticancer Res. 2012;32(11):4629-4638.
  108. Goulart B, Ramsey SD. A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer.Value Health. 2011;14(6):836-845.
  109. Aftab BT, Dobromilskaya I, Liu JO, et al. Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer.Cancer Res. 2011;71(21):6764-6772.
  110. Rudin CM, Brahmer JR, Juergens RA, et al. Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer.J Thorac Oncol. 2013;8(5):619-623.