Despite recent therapeutic advances, NSCLC remains the leading cause of cancer-related death in the USA [1]. Most patients present with advanced disease and5-year overall survival remains dismal at 15% [2]. Standard frontline therapy forpatients with advanced or metastatic NSCLC consists of a platinum doublet chemo-therapy given for four to six cycles, then either maintenance treatment or a chemo-therapy break, with additional chemotherapy at progression [3,4]. Given the limitedefficacy and significant toxicities associated with cytotoxic chemotherapy, there areincreasing efforts to develop targeted therapies for the treatment of lung cancer.
One of the most important targeted treatments in NSCLC consists of agents aimedat the VEGF pathway. In 1971, Judah Folkman demonstrated that tumor growthdepended upon angiogenesis, which led the way for researchers to investigate anti-angiogenic agents for the treatment of various malignancies [5]. Angiogenesis signalingpathways include VEGF, platelet-derived growth factor (PDGF), fibroblast growthfactor (FGF), Notch/Delta-like ligand 4 (DLL-4), and tyrosine kinase with Ig andEGF homology domains-2 (Tie2)/angiopoietin, among others. The VEGF receptorpathway is felt to be one of the most potent mediators of tumor angiogenesis andconsists of four homologues (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) thatbind to three tyrosine kinase receptors: VEGF receptor 1 (VEGFR-1)/McDonoughfeline sarcoma oncogene -like tyrosine kinase I (flt1), VEGFR-2/kinase insert domainreceptor (KDR), and VEGFR-3/flt4 [6]. VEGF signals primarily through VEGFR-2,which undergoes dimerization, autophosophorylation and activation when boundby ligand [7]. Activation of downstream targets, including PI3K and src, leads toendothelial cell proliferation and migration [6].
Preclinical models have shown that VEGF inhibition prevents or slows tumorgrowth [8]. VEGF expression has also been found to be an independent prognosticfactor in various tumor types, including in NSCLC [9-11]. These findings providedthe rationale for developing anti-angiogenic agents in lung cancer, specifically toimprove upon the poor clinical outcomes for patients with advanced disease treatedwith traditional cytotoxic chemotherapy. Anti-angiogenic agents in developmentinclude those that are directed against the VEGF molecule itself and the VEGF
receptor tyrosine kinase, in addition to agents which work onother components of the pathway.
2. Bevacizumab
Bevacizumab is a monoclonal antibody against VEGF andremains the only angiogenesis inhibitor to date that hasbeen approved by the FDA for lung cancer, although thereare a number of other angiogenesis inhibitors in various stagesof clinical development that are discussed later in this review.In 2006, the FDA granted approval of bevacizumab in thetreatment of advanced NSCLC based upon the encouragingresults of a Phase III clinical trial (Table 1). The backgroundto this was a Phase II trial conducted by Johnson et al., inwhich 99 patients were randomized into three treatmentarms: chemotherapy (carboplatin/paclitaxel) alone, chemo-therapy plus bevacizumab (7.5 mg/kg), and chemotherapyplus bevacizumab (15 mg/kg). Patients in the bevacizumabplus chemotherapy arm were allowed to continue bevacizu-mab monotherapy for up to 18 cycles after completion ofthe chemotherapy, and patients in the chemotherapy alonearm who progressed were allowed to receive bevacizumab atthe time of progression. Results revealed that overall responserate (ORR) was higher in the high-dose bevacizumab armcompared with the chemotherapy-alone arm (31.5 versus18.8%), and progression-free survival (PFS) was also pro-longed in the high-dose bevacizumab arm comparedwith the chemotherapy-alone arm (7.4 months versus4.2 months, p = 0.023). However, overall survival (OS) wasnot statistically different between the high-dose bevacizumab
arm and chemotherapy alone arm (17.7 versus 14.9 months,p = 0.63), and low-dose bevacizumab was not found to conferany advantages over chemotherapy alone. Both the relativelysmall number of patients in this trial and the ability tocrossover to maintenance bevacizumab provide possibleexplanations for the lack of OS benefit seen. Importantly, pul-monary hemorrhage was observed in 6 out of 67 patients(9.0%), including 4 fatalities, which occurred mainly inpatients with squamous histology, and by chance thosepatients were more commonly in the low-dose bevacizumabarm [12]. Based upon the association of bleeding withsquamous histology, subsequent Phase III trials investigatingbevacizumab excluded patients with squamous histology.
Eastern Cooperative Oncology Group (ECOG) 4599 wasa Phase III study that randomized 878 patients with recurrentor advanced NSCLC to receive first-line chemotherapyconsisting of carboplatin/paclitaxel with or without bevacizu-mab (15 mg/kg) (with no crossover allowed). Therapy wasgiven every three weeks. Patients with squamous histology,brain metastases and significant hemoptysis were excludedfrom this trial. The primary endpoint of OS was signifi-cantly improved in patients receiving bevacizumab (12.3versus 10.3 months; hazard ratio (HR): 0.79; 95%CI: 0.67 -- 0.92; p = 0.003). In addition, ORR (35 versus15%, p < 0.001) and PFS (6.2 months versus 4.5 months,HR: 0.66; 95% CI: 0.57 -- 0.77; p < 0.001) were alsoimproved in those patients receiving bevacizumab comparedwith chemotherapy alone. The addition of bevacizumab wasassociated with significantly increased toxicity, including15 deaths, compared with 2 deaths in the chemotherapy-alone arm. The deaths in the bevacizumab arm involved fivepatients with pulmonary hemorrhage, five patients withfebrile neutropenia, two patients with gastrointestinal blee-ding, two patients with stroke, and one patient with probablepulmonary embolus [13]. Moreover, a subgroup analysisrevealed that patients over the age of 70 who received bevaci-zumab experienced significantly more grade 3 -- 5 toxicitiescompared with those receiving chemotherapy alone (87 versus61%, p < 0.001), though the ORR and PFS benefit was stillseen, arguing for caution with bevacizumab in this subgroupof patients [14]. Despite these limitations, ECOG 4599 wasthe first trial, to our knowledge, to demonstrate a survivalbenefit in patients with advanced NSCLC receiving ananti-angiogenic agent.
The Phase III Avastin in Lung (AVAiL) trial randomized1043 patients with recurrent or advanced NSCLC to receivecisplatin/gemcitabine with or without bevacizumab (7.5 or15 mg/kg). All three drugs were given on day 1 of each3-week cycle, with additional gemcitabine on day 8. The pri-mary endpoint of this trial was PFS and was found to be sig-nificantly improved in patients receiving bevacizumab at boththe low dose (6.7 months; HR: 0.75; p = 0.003) and the highdose (6.5 months; HR: 0.82, p = 0.03) compared with thosepatients receiving chemotherapy alone (6.1 months) [15].However, OS was not significantly prolonged in either the
Article highlights.
. Bevacizumab is the only anti-angiogenic agent approvedin the USA and in Europe for NSCLC. This is based uponimproved progression-free survival (PFS) and overallsurvival (OS) noted in the landmark ECOG 4599 trial,and improved PFS noted in the Avastin in Lung (AVAiL)trial, both studies conducted in patients with advancednon-squamous NSCLC.
. The role of bevacizumab in patients with early-stage NSCLC and the identification of biomarkers topredict benefit from bevacizumab are questions that arebeing explored in ongoing studies.
. Small-molecule tyrosine kinase inhibitors (TKIs) thattarget multiple angiogenic pathways, including VEGF,are being evaluated in NSCLC and include sorafenib,vandetanib, sunitinib, cediranib, pazopanib, motesanib,axitinib, BIBF 1120 and cabozantinib.
. Other anti-angiogenic agents, such as the recombinantfusion protein, aflibercept, and vascular-disrupting agents (VDAs), are also under investigationfor the treatment of NSCLC.
. Additional results are awaited from recently completedand ongoing studies in order to establish the exact roleof anti-angiogenic agents in the treatment of NSCLC.
This box summarizes key points contained in the article.
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low-dose (13.6 months; HR: 0.93; p = 0.420) or high-dose(13.4 months; HR: 1.03; p = 0.761) bevacizumab arm, com-pared with the chemotherapy alone arm (13.1 months) [16].The lack of OS benefit seen in this trial may be explainedby the fact that a high percentage (61 -- 65%) of patients inthe trial went on to receive additional treatment post-study [17]. Toxicity analysis revealed that severe pulmonaryhemorrhage occurred in eight patients receiving bevacizumab(with seven fatal events), as compared to in two patientsreceiving placebo (with one fatal event). Notably, 9% ofthe study population received therapeutic anticoagulationwith either warfarin or low-molecular-weight heparin afterinitiation of the trial, and none of these patients developedpulmonary hemorrhage, suggesting that bevacizumab can besafely administered in patients on full-dose anticoagulation,an observation supported by later trials.
Additional studies have further investigated the safety anduse of bevacizumab in a variety of other clinical settings.While neither ECOG 4599 nor AVAiL included patientswith brain metastases, the subsequent Study of Bevacizumabin Combination with First- or Second-line Therapy in Sub-jects with Treated Brain Metastases. Due to Non-squamousNSCLC (PASSPORT) study showed that bevacizumab canbe administered safely in patients with treated brain metasta-ses [18]. Bevacizumab has also been studied and found to beefficacious in combination with other commonly used plati-num doublets, including carboplatin/pemetrexed [19]. ThePhase IV Safety of Avastin in Lung (SAiL) trial evaluated bev-acizumab in combination with different chemotherapeuticagents and found that patients receiving cisplatin doubletsplus bevacizumab had improved OS (14.7 months) comparedwith patients receiving carboplatin doublets plus bevacizumab(14.3 months), non-platinum doublets plus bevacizumab(8.1 months), or single-agent chemotherapy plus bevacizu-mab (9.4 months). Only certain adverse events were reported,including grade ‡ 3 pulmonary hemorrhage noted in 1% ofpatients, as well as grade 3 -- 5 bleeding (excluding pulmonary
hemorrhage) noted in 3% of patients [20]. The Phase IIIPointBreak trial is underway comparing two arms: carbopla-tin/pemetrexed/bevacizumab induction followed by pemetre-xed/bevacizumab maintenance and carboplatin/paclitaxel/bevacizumab induction followed by bevacizumab mainte-nance in patients with advanced non-squamous NSCLC [21].Given the promising results seen with bevacizumab in patientswith advanced or metastatic NSCLC, there is additional inter-est in evaluating bevacizumab in earlier stage settings. ECOG1505 is an ongoing Phase III study randomizing patients withearly stage (stage I--III) resected NSCLC to receive 4 cycles ofadjuvant cisplatin-based chemotherapy with or without beva-cizumab. Although the study is still undergoing accrual, aninterim safety analysis revealed no unexpected toxicityconcerns [22].
Trials are also evaluating bevacizumab in combination withother targeted therapies, including erlotinib, an oral EGFRinhibitor, in both the maintenance and second-line setting.The randomized, double-blind, placebo-controlled, phaseIIIB ATLAS study randomized patients with advancedNSCLC who completed four cycles of platinum-based chemo-therapy to receive maintenance bevacizumab (15 mg/kg) pluserlotinib (150 mg daily) versus maintenace bevacizumabplus placebo. The primary endpoint of PFS was improvedin those patients receiving maintenance bevacizumab/erlotinib compared with those receiving maintenance bevaci-zumab/placebo (4.8 months versus 3.7 months; HR: 0.72;p = 0.0012) [23]. However, the secondary endpoint of OSwas not improved in the bevacizumab/erlotinib arm(14.4 months versus 13.3 months; 95% CI: 0.70 -- 1.21;p = 0.56) [24]. A Phase II randomized trial evaluating bevacizu-mab in the second-line setting compared three arms: erlotinibplus bevacizumab, chemotherapy (docetaxel or pemetrexed)plus bevacizumab, and chemotherapy alone. Results indicatedthat median PFS was improved with the addition of bevacizu-mab to either chemotherapy (4.8 months) or erlotinib(4.4 months) in comparison with chemotherapy alone
Table 1. Results from key first-line bevacizumab trials.
Trial Phase Schema n RR (%) PFS (months) OS (months)
Johnson et al. [12] II Carboplatin/paclitaxel 32 18.8 4.2 14.9Carboplatin/paclitaxel +bevacizumab (7.5 mg/kg)
(3 months) [25]. In the Phase III Bevacizumab plus Tarceva(BeTa) trial, 636 patients with progressive disease after front-line chemotherapy were randomized to receive erlotinib withor without bevacizumab. While PFS was prolonged with thecombination therapy (3.4 months versus 1.7 months; HR:0.62; p < 0.0001), there was no difference in OS, which wasthe primary endpoint of the trial (9.3 months versus9.2 months; HR: 0.97; p = 0.75) [26].Despite considerable knowledge that has been gained from
numerous studies, questions remain regarding the identifica-tion of biomarkers that can help predict which patients wouldderive the most benefit from the addition of bevacizumab.The biomarker studies included in ECOG 4599 suggestthat single nucleotide polymorphisms in VEGF, EGF, inter-cellular adhesion molecule-1 (ICAM-1) and WNK lysinedeficient protein kinase (WNK1) may predict response,although no single marker or set of markers have proven tobe ready for clinical use [27]. Hypertension has also been foundto be a marker of clinical benefit from bevacizumab in variousmalignancies [28,29], including lung cancer [30]. Changes incytokines and angiogenic factors (CAFs) have also been corre-lated with clinical outcome, suggesting that CAF profilingmay help identify drug-specific markers of activity and clinicalbenefit for anti-angiogenic treatments [31]. Ultimately, thegoal of personalized medicine is to identify reliable bio-markers and other specific characteristics within individualpatients to aid in tailoring therapy that will result in thegreatest clinical efficacy.
3. Small-molecule tyrosine kinase inhibitors
Several anti-angiogenic small molecule tyrosine kinase inhibi-tors (TKIs) are in current clinical development. An advantageof TKIs includes the fact that they inhibit multiple receptorssimultaneously, thereby potentially providing a higher like-lihood of single-agent activity. Another benefit is that theseagents are often available orally, offering patients greater con-venience. However, despite these advantages, toxicity remainsa concern given the multi-targeted kinase inhibition and theadditive adverse events that may be of particular concernwhen the agents are combined with chemotherapy. Belowwe review selected small-molecule TKIs that include VEGFas a target for the treatment of NSCLC (Table 2).
3.1 SorafenibSorafenib is an oral multi-kinase inhibitor of VEGFR-2and -3, platelet-derived growth factor receptor (PDGFR)-bRAF-kinase, c-Kit, Ret, and McDonough feline sarcomaoncogene-like tyrosine kinase receptor 3 (Flt-3). In Phase Istudies that included patients with NSCLC, sorafenib demon-strated activity both as a single agent [32] and in combinationwith chemotherapy [33]. Subsequently, sorefenib was investi-gated in two separate Phase III trials, one in previously treat-ment patients with metastatic renal cell carcinoma (RCC) [34]
and the other in patients with advanced hepatocellular
carcinoma (HCC) [35]. PFS was prolonged in both Phase IIIstudies when comparing sorafenib with placebo, leading toFDA approval of sorafenib in patients with metastatic RCCand advanced HCC. These trials also indicated that sorafenibwas generally well tolerated with main toxicities of diarrhea,rash, fatigue and hand--foot skin reactions. Based upon thesefindings, sorafenib is now being investigated in various othertumor types, including NSCLC.
In the Phase II ECOG 2501 trial, 342 patients with NSCLCwho had failed at least two prior chemotherapy regimensreceived sorafenib (400 mg twice daily) for two cycles. Thosepatients who were noted to have stable disease after two cycles(n = 97) were randomized to receive additional sorafenib orplacebo. Results indicated that sorafenib prolonged PFS com-pared with placebo (3.6 months versus 1.9 months,p = 0.01) [36]. In another Phase II trial, sorafenib was adminis-tered continuously at a dose of 400 mg twice daily as a singleagent to 52 patients with relapsed or refractory advancedNSCLC. Stable disease (SD) was achieved in 59% of evaluablepatients, and in those patients with SD, median PFS was5.5 months. The treatment-related toxicities were manageableand similar to the toxicities seen in previous trials with sorafe-nib, including hand-foot reaction seen in 10% of patients [37].An additional study found that in patients with advancedNSCLC who achieved a prolonged response or SD withsorafenib, sorafenib was able to be continued until diseaseprogression without major safety or tolerability issues [38].
The encouraging results seen in the Phase II setting led totwo large Phase III trials combining sorafenib with chemo-therapy. In the double-blind, placebo-controlled Phase IIIEvaluation of Sorafenib, Carboplatin and Paclitaxel Efficacyin NSCLC (ESCAPE) trial, sorafenib was studied in combi-nation with carboplatin/paclitaxel as first-line treatment inpatients with advanced NSCLC. The study was terminatedearly due to an interim analysis revealing that the primaryendpoint of OS was unlikely to be reached and due to toxicityconcerns in patients with squamous histology [39]. ThePhase III NSCLC Research Experience Utilizing Sorafenib(NEXUS) trial investigated sorafenib in combination with cis-platin/gemcitabine and demonstrated a PFS benefit, althoughthe primary endpoint of OS was not improved [40]. Althoughconcerns remain regarding the safety and efficacy of combi-ning sorafenib with chemotherapy in NSCLC, additionaltrials have revealed encouraging results combining sorafenibwith erlotinib in the Phase II setting, warranting furtherinvestigation [41,42]. Recently, the Biomarker-IntegratedApproaches of Targeted Therapy for Lung Cancer Elimina-tion (BATTLE) study was the first completed prospective,biomarker-based adaptively randomized study that rando-mized pretreated lung cancer patients to erlotinib, vandetanib,erlotinib plus bexarotene, or sorafenib based upon biomarkerresults obtained from individual patients. In comparingpatients in the adaptive randomization arm against the equalrandomization arm, results indicated that K-ras-mutantpatients treated with sorafenib had a non-statistically
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significant trend toward improved disease control rate (DCR)(61 versus 32%, p = 0.11), suggesting a preferential benefit ofsorafenib in K-ras-mutant patients, although this correlationwill need to further tested in additional clinical trials [43].
3.2 VandetanibVandetanib (ZACTIMA) is a VEGFR (VEGFR-2,VEGFR-3) TKI that also targets RET and EGFR [44].Phase I studies of vandetanib in patients with advanced solidtumors demonstrated a dose limiting toxicity of diarrheaand revealed other adverse side effects, including rash, nausea,hypertension, asymptomatic QTc prolongation andfatigue [45]. Vandetanib has been studied in combinationwith chemotherapy in various Phase II trials in patients withadvanced NSCLC. Vandetanib in combination with carbo-platin/paclitaxel resulted in prolonged PFS (56 weeks;HR = 0.76; p = 0.098) compared with carboplatin/paclitaxel alone (52 weeks) in previously untreated patientswith locally advanced or metastatic NSCLC. Although theprimary endpoint of PFS was met, the secondary endpointof OS was not significantly different between the twoarms [46]. Another trial showed that vandetanib in combina-tion with docetaxel was superior to docetaxel alone in previ-ously treated patients with NSCLC with regard to PFS(18.7 weeks versus 12 weeks; HR = 0.64; p = 0.037) [46].
Based upon these encouraging results, the Phase III ZAC-TIMA in Combination with Docetaxel In Non-SmallCell Lung Cancer (ZODIAC) trial was conducted, whichrandomized patients with advanced NSCLC to receive eitherdocetaxel/vandetanib or docetaxel/placebo as second-linetreatment. The addition of vandetanib improved ORR(17 versus 10%, p = 0.0001) and PFS (HR: 0.79,p < 0.0001), although the primary endpoint of OS was notmet (HR:0.91, p = 0.196) [47]. In the Phase III ZactimaEfficacy Study versus Tarceva (ZEST) trial, vandetanib wasinvestigated in combination with pemetrexed also in thesecond-line setting in patients with advanced NSCLC.Despite showing an improvement in ORR (19% for peme-trexed/vandetanib versus 8% for pemetrexed/placebo,p < 0.001) and delay in time to worsening of lung cancersymptoms (18.1 weeks for pemetrexed/vandetanib versus
12.1 weeks for pemetrexed/placebo, p = 0.0052), this studydid not meet its primary endpoint of PFS (HR: 0.86,p = 0.108) [48]. Finally, in the Phase III Zactima EfficacyStudy for NSCLC Patients with History of EGFR-TKI and Chemo-Resistance (ZEPHYR) study, patientswith advanced NSCLC who had progressed after chemo-therapy and erlotinib were randomized to receive vandetanibas a single agent versus placebo. PFS was improved in thosepatients receiving vandetanib (HR: 0.63, p < 0.0001),although the primary endpoint of OS was not met (HR:0.95, p = 0.527). The somewhat disappointing results ofthese three Phase III trials led to withdrawal of the applica-tion for approval of vandetanib and its future remainsuncertain for NSCLC.
3.3 SunitinibSunitinib is an oral TKI that inhibits VEGFR-1, -2, -3,PDGFR-a/b, c-kit, Flt-3, and RET and has gained FDAapproval for the treatment of advanced RCC and imatinib-resistant gastrointestinal stromal tumor. Sunitinib has beenstudied in advanced NSCLC in two separate Phase II trials. Inthe first study, 63 previously treated patients with advancedNSCLC received sunitinib (50 mg/day on a 4 weekson/2 weeks off schedule) given as a single agent.Results were encouraging, indicating ORR of 11.1% (95%CI: 4.6 -- 21.6%), median PFS of 12 weeks (95% CI: 10.0 --16.1) and median OS of 23.4 weeks (95% CI: 17.0 -- 28.3).The treatment was also well tolerated, with mostly grade1 and 2 toxicities [49]. A subsequent Phase II evaluated 47 previ-ously treated NSCLC patients on a continuous dosing scheduleof sunitinib (37.5 mg/day). Although the ORR was only 2.1%(95%CI: 0.1 -- 1.3%) in this study, median PFS was 11.9 weeks(95%CI: 8.6 -- 14.1) and median OS was 37.1 weeks (95%CI:31.1 -- 69.7), suggesting that sunitinib may be a potential ther-apeutic agent in patients with advanced NSCLC [50]. There areongoing studies investigating sunitinib in patients withNSCLC, including the Phase II CALGB 30704 trial evaluatingsunitinib as second-line therapy (ClinicalTrials.gov identifier:NCT00698815) [51] and the Phase III CALGB 30607study of sunitinib as maintenance therapy (ClinicalTrials.govidentifier: NCT00693992) [52].
Table 2. Anti-angiogenesis small molecule tyrosine kinase inhibitors and their targets.
Agent VEGFR-1 VEGFR-2 VEGFR-3 PDGFR c-Kit EGFR Other
Sorafenib x x x x x Raf, Flt-3Vandetanib x x x RetSunitinib x x x x x Ret, Flt-3Cediranib x x x x xPazopanib x x x x xMotesanib x x x x x RetAxitinib x x xBIBF 1120 x x FGFRCabozantinib x x MET, Ret, Flt-3
3.4 CediranibCediranib (AZD2171) is an oral inhibitor of VEGFR-1 and -2, PDGFR-b, and c-kit that has demonstrated activity incombination with chemotherapy in patients with NSCLC.In the Phase II/III BR24 trial, 296 patients were randomizedto receive carboplatin/paclitaxel with or without cediranib asfront-line treatment in patients with advanced NSCLC.Despite Phase II interim results indicating a higher ORRand PFS with cediranib, the study was discontinued earlydue to excessive toxicities associated with cediranib given atthe 30 mg dose, including severe hypertension, gastrointesti-nal toxicity and febrile neutropenia [53]. Based upon theseresults, the BR29 Phase II/III trial utilized cediranib at areduced dose of 20 mg daily combined with carboplatin/pac-litaxel, but was also halted due to an interim analysis revealingthat cediranib did not meet pre-specified PFS efficacy criteria(ClinicalTrials.gov identifier: NCT00795340) [54]. Cediranibis also being studied in combination with pemetrexed inrecurrent NSCLC in a Phase II setting (ClinicalTrials.govidentifier: NCT00410904) [55].
3.5 PazopanibPazopanib is an oral inhibitor of VEGFR-1, -2, and -3, as wellas of PDGFR-b and c-kit, which was FDA approved in2009 for the treatment of advanced RCC. Various studieswith pazopanib have completed or are in the process of accru-ing patients with NSCLC. A recently completed Phase II open-label multi-center randomized study compares pazopanib/pemetrexed with cisplatin/pemetrexed as frontline treatmentin patients with metastatic NSCLC, and results are nowawaited (ClinicalTrials.gov identifier: NCT00871403) [56].Other studies that remain active and have completed accrualinclude the Phase II randomized, placebo-controlled study ofpazopanib in combination with erlotinib in previously trea-ted patients with NSCLC (ClinicalTrials.gov identifier:NCT01027598) [57] and the Phase II study comparing pazopa-nib/paclitaxel with carboplatin/paclitaxel as first-line treat-ment in advanced NSCLC (ClinicalTrials.gov identifier:NCT00866528) [58].
3.6 MotesanibMotesanib (AMG 706) is a VEGFR-1, -2, and -3, PDGFR-b,c-kit, and RET inhibitor that was found to induce regression oftumor xenografts in preclinical models [59]. In a Phase II studyof motesanib or bevacizumab in combination with carboplatin/paclitaxel as frontline treatment for advanced non-squamous NSCLC, motesanib administered at a dose of125 mg/day resulted in similar efficacy compared with the bev-acizumab arm, with a median PFS of 7.7 months (comparedwith 8.3 months with bevacizumab) and a median OS of14.0 months (compared with 14.0 months with bevacizu-mab) [60]. However, the subsequent double-blind, placebo-controlled Phase III Motesanib NSCLC Efficacy andTolerability Study (MONET1) study of motesanib pluscarboplatin/paclitaxel in patients with non-squamous advanced
NSCLC did not meet its primary endpoint of improved OS(HR: 0.89, p = 0.137) [61], which has resulted in lessenthusiasm for further development of this agent for NSCLC.
3.7 AxitinibAxitinib (AG-013736) is a TKI of VEGFR-1, -2, and -3,PDGFR-b, and c-kit that has been studied in patients withmultiple different tumor types, including advanced NSCLC.A Phase II trial evaluated axitinib administered as a single-agent in patients with advanced NSCLC. In this trial, 28% ofpatients had received no prior chemotherapy. ORR was 9%,median PFS was 4.9 months (95% CI: 3.6 -- 7.0 months)and median OS was 14.8 months (95% CI: 10.7 -- not estima-ble), indicating that axitinib had favorable single-agent activityin NSCLC. Toxicities were also manageable, and includedgrade 3 fatigue (22%), hypertension (9%), and hyponatremia(9%) [62]. There are ongoing Phase II trials of axitinib inpatients with non-squamous NSCLC, including AGILE1030 comparing axitinib/carboplatin/paclitaxel to bevacizu-mab/carboplatin/paclitaxel (ClinicalTrials.gov identifier: NCT00600821) [63], and AGILE 1039 comparing axitinib/cis-platin/pemetrexed to cisplatin/pemetrexed (ClinicalTrials.govidentifier: NCT00768755) [64]. Axitinib is also being evaluatedin patients with advanced squamous NSCLC in the AGILE1038 trial, randomizing patients to axitinib/cisplatin/gemcitabine versus cisplatin/gemcitabine (ClinicalTrials.govidentifier: NCT00735904) [65].
3.8 BIBF 1120BIBF 1120 inhibits VEGFR-1, -2, and -3, in addition toPDGFR-a/b, and fibroblast growth factor receptors (FGFR)1 -- 3. A double-blind, multicenter Phase II trial of 73 patientswith relapsed advanced NSCLC found that BIBF 1120 givenas single agent resulted in a median PFS of 11.6 weeks,median OS of 37.7 weeks, and tumor stabilization rate (com-plete response, partial response, or stable disease) of 46% inpatients with an ECOG performance status of 0 or 1. BIBF1120 was well tolerated with the most common grade 3/4toxicities consisting of nausea, vomiting, diarrhea, and eleva-tion of liver function tests [16]. In two separate randomizedPhase III studies, BIBF 1120 is being further studied inthe second-line NSCLC setting in combination with doce-taxel (LUME-Lung 1) and in combination with peme-trexed (LUME-Lung 2) (ClinicalTrials.gov identifier:NCT00805194 [66] and NCT00806819 [67], respectively).The studies have both completed accrual and resultsare awaited.
3.9 CabozantinibCabozantinib (XL-184) is a TKI with potent activity againstMET and VEGFR-2, as well as other pathways includingRET, Kit, and Flt-3. In mouse studies, cabozantinib resultedin decreased tumor and endothelial cell proliferationwith associated increased apoptosis and dose-dependentinhibition of various tumor types, including lung cancer [68].
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A Phase Ib/II study of cabozantinib with or without erlotinibin previously treated patients with advanced NSCLC showedthat the combination of cabozantinib and erlotinib waswell tolerated with evidence of clinical activity in a largelyerlotinib pretreated patient cohort, including patients withEGFR T790M and MET amplification [69]. Additionalresults are awaited.
4. Other anti-angiogenic therapies
4.1 AfliberceptAflibercept (VEGF-Trap, ZALTRAP) is a recombinantfusion protein that binds VEGFR-1, VEGFR-2 and placentalgrowth factor (PlGF). This compound gained FDA approvalfor the treatment of macular degeneration, and is now beingexplored in various types of malignancies with encouragingresults. Recently, in the Phase III Aflibercept Versus Placeboin Combination With Irinotecan and 5-FU in Cancer AfterFailure of an Oxaliplatin Based Regimen (VELOUR) study,patients with metastatic colorectal cancer previously treatedwith oxaliplatin were randomized to receive the irinotecan-5-fluorouracil-leucovorin (FOLFIRI) regimen with or with-out aflibercept. The addition of aflibercept improved bothPFS (HR = 0.758, p = 0.00007) and OS (HR = 0.817,p = 0.0032) [70]. In lung cancer, aflibercept was studied in aPhase II study of heavily pretreated patients with advanceddisease. Aflibercept 4.0 mg/kg was administered as a single-agent, intravenously every two weeks and was found to havean ORR of 2% (95% CI: 0.2 -- 7.2%), PFS of 2.7 months,and OS of 6.2 months [71]. Subsequently, the Phase III Afli-bercept Versus Placebo in Patients With Second-Line Docetaxel for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (VITAL) trial compared afliberceptversus placebo in combination with docetaxel in patientswith locally advanced or metastatic NSCLC who had failedplatinum-based chemotherapy. Although the addition of afli-bercept to docetaxel was associated with improved ORR(23.3 versus 8.9%) and PFS (HR = 0.82, 95% CI:0.716 -- 0.937), the primary endpoint of OS (HR = 1.01,95% CI: 0.868 -- 1.174) was not statistically significantbetween the two arms [72].
4.2 Vascular-disrupting agents4.2.1 Vadimezan (ASA 404)There are other anti-angiogenesis pathways that do notinvolve inhibition of VEGF, including vascular-disruptingagents (VDAs), such as vadimezan (ASA 404). A randomizedPhase II trial found that patients with advanced NSCLCreceiving front-line carboplatin/paclitaxel with vadimezanhad improved OS compared to those receiving carboplatin/paclitaxel alone (14.0 months versus 8.8 months, HR 0.73,95% CI: 0.39 -- 1.38) [73]. However, the Antivascular TargetedTherapy: Researching ASA 404 in Cancer Treatment-1(ATTRACT-1) Phase III study of patients with advancedNSCLC who received frontline carboplatin/paclitaxel with
or without vadimezan failed to show an improvement in OS,leading to termination of any further clinical development ofthis agent [74].
CA4P)Fosbretabulin is another VDA that acts as a reversible tubulin-depolymerizing agent that selectively disrupts the vascularendothelial cell junctional protein, VE-cadherin. Fosbretabu-lin was studied in combination with carboplatin/paclitaxel/bevacizumab in the Phase II randomized Fosbretabulin inAdvanced Lung Oncology (FALCON) trial. Preliminaryresults from this trial indicate that fosbretabulin in combi-nation with standard frontline carboplatin/paclitaxel/bevacizumab was well tolerated with a trend toward improve-ment in RR, PFS and OS seen in the fosbretabulin arm [75].These encouraging results have led to consideration ofconducting a Phase III study.
4.2.3 Plinabulin (NPI-2358)Plinabulin is a VDA that destabilizes tumor vascular endothe-lial cell cohesion by acting on the cytoskeleton and was stu-died in a Phase I/II study in combination with docetaxel inpatients with advanced NSCLC. Early results indicate thatpatients receiving the combination of plinabulin/docetaxel had a higher incidence of PR (22%) compared tothe control arm of docetaxel alone (5%) [76]. Additionalresults are awaited.
5. Conclusion
Agents targeting VEGF have proven to be efficacious in thetreatment of NSCLC, including the monoclonal antibodybevacizumab, which has gained FDA approval in patientswith advanced non-squamous NSCLC. In the landmarkECOG 4599 study, bevacizumab was found to improveboth PFS and OS when given in combination with carbopla-tin/paclitaxel as front-line treatment in patients with advancedNSCLC. Small-molecule TKIs that include VEGF as a target,in addition to other anti-angiogenic agents such as afliberceptor VDAs, are in various stages of clinical development andhave shown promising results in the trials conducted so farin NSCLC. The exact role of anti-VEGF treatments inNSCLC, including how best to combine them with tradi-tional cytotoxic chemotherapy, needs to be determined andresults are eagerly anticipated from ongoing studies.
6. Expert opinion
In the landmark ECOG 4599 trial, patients with advancedNSCLC who received carboplatin/paclitaxel in combinationwith bevacizumab had improvements in ORR, PFS and OS.After many previous negative Phase III trials of agentsadded to first-line chemotherapy for NSCLC patients, theanti-VEGF antibody, bevacizumab, became the first agent to
Targeting VEGF in lung cancer
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improve OS when added to first-line chemotherapy inadvanced NSCLC. Bevacizumab remains approved onlyfor patients with non-squamous NSCLC due to the increasedbleeding risk seen with squamous cell histology, althoughthe eligibility profile of bevacizumab is continuing toexpand. Recent trials have shown that bevacizumab can besafely administered in patients with treated brain metastases,in elderly patients, and in patients receiving full-dose anticoagulation. An additional study, ECOG 1505, isalso evaluating bevacizumab in the curative setting in patientswith early-stage disease who have undergone resection. Theexciting results seen with bevacizumab have led to thedevelopment of other anti-angiogenic agents, includingsmall-molecule TKIs that target multiple angiogenic path-ways. Although disappointingly neither vandetanib, sorafenibnor motesanib improved the primary endpoint of OS whenadded to chemotherapy in Phase III trials, TKIs have shownconsiderable promise and additional data are awaited fromPhase II/III trials that are underway. Sunitinib, pazopaniband axitinib, have all shown exciting single-agent activity inpatients with NSCLC, while cediranib and BIBF 1120 havedemonstrated significant potential in improving outcomeswhen administered in combination with chemotherapy.Both sorafenib and cabozantinib have been combined witherlotinib with encouraging results seen to date. Other anti-angiogenic agents, such as the recombinant fusion proteinaflibercept and VDAs, are also being examined in the treat-ment of NSCLC. Anti-angiogenic therapy has proven benefitin patients with NSCLC and is rightfully continuing to beexplored in additional trials with the hope that we will beable to better identify those patients who are most likelyto benefit.The identification and validation of reliable biomarkers for
the anti-angiogenic agents has been an important goal and anarea of considerable research. A correlative study analysisperformed as part of ECOG 4599 found that plasma VEGFlevels were predictive of response to bevacizumab but notsurvival [77]. Another study found that low baseline VEGFlevels were predictive of PFS benefit in patients with advanced
NSCLC receiving vandetanib as compared to standard che-motherapy [78]. In patients with early-stage NSCLC receivingadjuvant therapy, increased VEGFR-2 gene copy number cor-related with greater resistance to chemotherapy and worsenedsurvival, suggesting that these potentially high-risk patientsmay benefit from VEGFR blockade [79]. The ongoingECOG 1505 study will provide 1500 tissue samples and mul-tiple time point serum measurements, with the hope ofvalidating biomarkers for patients who received bevacizumabin the adjuvant setting.
Clinical predictors, such as hypertension, have also beenevaluated and may prove to be useful when assessing responseto anti-angiogenic treatment. For example, in ECOG 4599,hypertension was associated with improved outcomes inpatients receiving carboplatin/paclitaxel/bevacizumab [30].More complex predictors, such as cytokines and angiogenicfactors (CAFs) have also been studied and hold promise inproviding additional insight into the molecular consequencesof anti-angiogenic therapies. In patients with metastatic renalcell carcinoma (mRCC) receiving treatment with sorafenib,CAF profiling allowed identification of a candidate genesignature for predicting PFS benefit and a platform formeasuring distinct marker changes occurring during treat-ment [80]. In addition to continuing to explore methodsthat will potentially help to stratify patients in future ran-domized trials, there is active research into developing newtechniques that will allow assessment of the vascular responseof tumors and in determining why certain patients developresistance to anti-angiogenic treatments, and discoveringways of overcoming that resistance. Despite these challenges,there is certainly optimism for the approval of other anti-angiogenic therapies in the horizon for the treatmentof NSCLC.
Declaration of interest
H Wakelee has received financial support from Arqule,AstraZeneca, Bayer Schering, Eli Lilly and Co., Exelixis,Genentech, Novartis and Pfizer.
M. Das & H. Wakelee
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AffiliationMillie Das1 MD & Heather Wakelee†2 MD†Author for correspondence1Staff Oncologist,
VA Palo Alto Heath Care System,
3801 Miranda Avenue,
Palo Alto, CA 94304, USA2Assistant Professor of Medicine,
