Anti-Angiogenic Therapy for the Treatment of Lung Cancer

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 (&ge; 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 &ge; 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 &ldquo;triple angiokinase inhibition.&rdquo; 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-na&iuml;ve 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 &ge; 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) 1&alpha;, 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.

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