1. Introduction

2. Implications for clinical

practice

Editorial

Antiangiogenesis therapy insecond line metastatic colorectalcancer: similar but differentMuhammad Wasif SaifTufts University School of Medicine, Experimental Therapeutics Program, Boston, MA, USA

Recent updates in the second-line treatment of patients with metastatic colo-

rectal cancer (mCRC) have indicated the benefit of adding aflibercept (plus

FOLFIRI) after an oxaliplatin-containing regimen (with or without bevacizu-

mab) or a bevacizumab-containing regimen after progression on a different

bevacizumab-containing regimen. This has led some oncologists to compare

the trials and equate the drugs, with the assumption that they confer equal

efficacy, but the background of this must be adequately assessed before

reaching this conclusion. In fact, the publication of these trial results has left

oncologists with much to consider for their mCRC patients who will eventu-

ally progress on a first-line chemotherapy/bevacizumab regimen. The author

comments on this issue and emphasizes the need for additional research

into antiangiogenic biomarkers to identify patients who are likely to respond

to one drug more than another.

Keywords: aflibercept, bevacizumab, colon cancer, VEGF

Expert Opin. Biol. Ther. (2013) 13(11):1489-1493

1. Introduction

Recent updates in the clinical guidance for second-line treatment of patients withmetastatic colorectal cancer (mCRC) have provided new options for patients, buthave also left some physicians stymied as to what to do with these choices. Specifi-cally, the National Comprehensive Cancer Network (NCCN) has added both anewly approved agent, aflibercept (known as ziv-aflibercept in the USA), and thewell-known agent bevacizumab as antiangiogenic therapy options for patientswith mCRC progressing on a first-line regimen that included antiangiogenic ther-apy with bevacizumab [1]. From a mechanistic standpoint, it is important to distin-guish these two antiangiogenic agents, in that unlike bevacizumab, which is amonoclonal antibody targeted specifically to vascular endothelial growth factor-A (VEGF-A), aflibercept acts as a soluble decoy receptor, which binds and inhibitsnot only VEGF-A, but also VEGF-B and placental growth factor (PlGF) [2-4]. Pre-viously, Phase III data supporting the use of aflibercept were not yet available, andbevacizumab was not recommended for patients with mCRC who progressed on afirst-line combination therapy that included bevacizumab (outside of a clinicaltrial) [5]. All of this changed in 2012 with the reporting of results from two well-designed trials; the VELOUR trial for aflibercept [6] and the ML18147 trial for bev-acizumab [7]. The trials had different objectives and varying designs, but muchattention has centered on the difference in overall survival between the experimentaland control arms of each trial, which, coincidentally happened to be identical in thefinal analysis [6,7]. This has led some oncologists to compare the trials and equate thedrugs, with the assumption that they confer equal efficacy [8], but the background ofthis must be adequately assessed before reaching this conclusion. In fact, the publi-cation of these trial results has left oncologists with much to consider for their

10.1517/14712598.2013.837881 © 2013 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 1489All rights reserved: reproduction in whole or in part not permitted

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mCRC patients who will, eventually, progress on a first-line chemotherapy/bevacizumab regimen.The results of VELOUR, published in 2012, demonstrate

that the addition of aflibercept to FOLFIRI chemotherapy(irinotecan with leucovorin, followed by infusional fluoroura-cil, repeated every 2 weeks) significantly improved overall sur-vival, progression-free survival and response rates comparedwith placebo for patients, inclusive of those who received priorbevacizumab, with mCRC and disease progression followingan oxaliplatin-containing regimen [6]. In the primary analysis,the hazard ratio (HR) for overall survival with aflibercept rel-ative to placebo was 0.817 (p = 0.0032) with a median sur-vival of 13.50 versus 12.06 months in the respective groups(net gain of 1.4 months) [6]. Of note, in VELOUR, a pre-specified subanalysis of patients with prior bevacizumab ther-apy compared with those with no prior bevacizumab therapydemonstrated no significant treatment interaction effects (i.e.,similar benefit of aflibercept therapy regardless of whether thepatients had, or had not, received prior bevacizumab) [3,9]. Inpatients who received no prior bevacizumab, the HR for overallsurvival was 0.788 (0.669 -- 0.927), whereas for those with priorbevacizumab use, the HR was 0.862 (0.673 -- 1.104). Impor-tantly, this was a subanalysis, and not sufficiently poweredto detect significant differences in overall or progression-freesurvival [9].The overall results of ML18147, published in early 2013,

demonstrated a significant improvement in overall as well asprogression-free survival for patients who continued bevacizu-mab treatment (with an accompanying change in chemother-apy regimen) following progression on a first-line regimenwhich included bevacizumab [7]. In the primary analysis, theHR for overall survival with continued bevacizumab, versuschemotherapy alone was 0.81 (p = 0.0062), with a mediansurvival of 11.2 and 9.8 months in the respective groups(net gain of 1.4 months) [7]. The NCCN 2013 guidancenow allows for either option, aflibercept or bevacizumab, asa component of therapy for patients who received a first-linebevacizumab-containing regimen [1].Before we evaluate results from these trials, we first must

understand differences in the drugs themselves. Bevacizumab,the first antiangiogenesis therapy to be used in mCRC, is amonoclonal antibody that specifically targets what is believedto be the most important mediator of tumor angiogenesis,VEGF-A [1,10]. Inhibition of VEGF-A interaction with its cel-lular receptor, VEGF receptor 2 (VEGFR2) is believed tocause both an inhibition of tumor vascularization, as well as‘normalization’ of the tumor vasculature, although the precisemechanism of its anti-tumor action when used in combina-tion with chemotherapy is not fully understood [11]. By com-parison, aflibercept is a recombinantly produced fusionprotein consisting of the high affinity ligand-binding domainsof VEGFR2, as well as VEGFR1, and, as noted earlier, acts asa soluble decoy receptor [2,10]. Aflibercept binds VEGF-A, andtwo additional related ligands that interact with VEGFR1,VEGF-B and PlGF. We now know that the pathways which

regulate angiogenesis are complex and dynamic, with multipleoverlapping pathways that are capable of crosstalk and regula-tory feedback mechanisms with each other [2]. Thus, onerationale behind the design of aflibercept is that in the faceof ongoing inhibition of the VEGF-A/VEGFR2 axis withbevacizumab, alternative adaptive mechanisms of angiogenesiscan emerge, some of which may be mediated through less-understood VEGFR1-mediated effects, including, amongother possible pathways, PlGF-mediated recruitment ofproangiogenic myeloid cells, PlGF-stimulated proliferationand/or migration of tumor cells and VEGFR1-mediated seed-ing at new metastatic sites [12]. Increased PlGF expression hasalso been associated with poor prognosis in CRC [13], andintriguingly, while the generalizability of the findings are lim-ited, it has been shown that PlGF levels are increased withbevacizumab treatment, with bevacizumab and chemotherapytreatment, and just prior to the onset of progressive disease inmCRC patients [14]. These findings raise the possibility of acontributing effect of PlGF to antiangiogenic escape, whichcould involve other factors in addition to VEGF-A. Addi-tional preclinical findings also point to some important differ-ences in binding to VEGF-A and corresponding inhibition ofVEGF-A-mediated biologic effects [15]. For example, afliber-cept’s binding to VEGF-A has been reported to be between10- and 100-fold more efficient than that of bevacizumab inin vitro studies [15,16], while fivefold greater concentrationsof bevacizumab than aflibercept were utilized for equivalentinhibition of VEGF-A-induced human endothelial-cellmigration [16]. The potential clinical relevance of these differ-ences has not been definitively determined. It could beargued, however, that patients who progress on a prior antian-giogenesis therapy (in this case bevacizumab) would benefitfrom an agent with a different mechanism of action (in thiscase aflibercept).

It may be inappropriate to conduct cross-study compari-sons when trial designs are different, but it is important totruly understand the substantial differences between them(Table 1). The purpose of the VELOUR trial was to evaluatethe safety and efficacy of aflibercept following disease progres-sion on a first-line oxaliplatin-containing regimen. Prior toVELOUR, no therapy had been shown to provide a signifi-cant survival benefit in the second line for patients receivinga prior oxaliplatin-containing regimen who were treatedwith FOLFIRI [6]. The main objective of ML18147 was toevaluate the effect on overall survival of continuing bevacizu-mab after progression on a bevacizumab-containing first-lineregimen. Rationale for the trial was in part provided by pre-liminary data from non-randomized observational cohortstudies (BRiTE and ARIES) suggesting a benefit of continu-ing bevacizumab therapy beyond progression [7]. This cleardistinction between the overall objectives of each trial areimportant to bear in mind when considering other aspectsof the trial design, as well as the results.

In line with its objective of being a first pivotal trial for afli-bercept in mCRC patients, VELOUR was designed as a

M. W. Saif

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randomized, double-blinded, parallel-arm, Phase III study inwhich patients were randomized (1:1) to treatment withFOLFIRI in combination with either aflibercept or placebo [6].Patients were stratified according to their prior bevacizumabuse, as well as Eastern Cooperative Oncology Group(ECOG) performance status; the primary end point was over-all survival, and the trial was also appropriately designed andpowered to assess secondary end points, includingprogression-free survival and adverse events [6]. The finalintent-to-treat (ITT) population in VELOUR (n = 1,226randomized) was consistent with that of a standard Phase IIIregistration trial population, and was reflective of an ‘all-takers’ recruitment approach. All patients had documentedprogression while on or following an oxaliplatin-containingregimen, but they were not selected based on the timing ofthat progression [6].

ML18147 was a randomized, prospective, intergroup, openlabel, Phase III trial. Because the objective was to comparecontinuation of bevacizumab versus no bevacizumab afterprogression, patients were randomized (1:1) to a change inchemotherapy with or without bevacizumab, with no placebocomparator. Most patients (~ 77%) were 42 days or less fromtheir last bevacizumab dose, and the distribution in use ofoxaliplatin-based (~ 42%) or irinotecan-based (~ 58%) first-line chemotherapy was balanced between the treatmentarms [7]. The choice of chemotherapy (to be used in combina-tion with bevacizumab, or not) was varied, and based on thepatient’s prior regimen, with all approved second-line treat-ments allowed at the investigator’s discretion. Although thedistribution of individual chemotherapy regimens was bal-anced between the treatment arms, a lack of uniformityamong the types of chemotherapy used (in as much as these

were at the investigator’s discretion) is an important limita-tion to recognize [7]. The primary end point was overall sur-vival, with secondary end points such as progression-freesurvival also assessed [7]. The final ITT population ofML18147 (n = 819) included adult patients with mCRCand progressive disease following first-line treatment withbevacizumab plus a standard chemotherapy regimen.

The ML18147 population had a number of notable exclu-sions, including those with progressive disease for > 3 monthsfollowing the last bevacizumab administration, those withfewer than 3 months of consecutive first-line bevacizumabtreatment, as well as those with a first-line progression-freesurvival of < 3 months [7]. In the latter excluded group, itcould be argued that the exclusion of this early recurrence or‘fast relapse’ group might have selected a more favorable out-come population who were more likely to respond to bevaci-zumab therapy. The trial would also, by virtue of thesecriteria, have excluded those unable to tolerate antiangiogenictherapy with bevacizumab [7].

2. Implications for clinical practice

The overall conclusions from VELOUR showed that thecombination of aflibercept with FOLFIRI significantlyimproved overall survival and other efficacy outcomes forpatients previously treated with an oxaliplatin-containing reg-imen who are receiving FOLFIRI [6]. Additional subanalysisfrom VELOUR showed a benefit of aflibercept regardless ofprior bevacizumab use, and thus, the results of VELOUR sup-port its use as a second-line therapy in patients receiving afirst-line bevacizumab-containing regimen [9]. The overallconclusions of ML18147 suggest that the continuation of

Table 1. VELOUR and ML18147 trials: key differences [6,7].

VELOUR trial ML18147 trial

Study design Prospective, randomized, double-blind,placebo control

Prospective, randomized, open label,no placebo control

Antiangiogenic study treatment Aflibercept versus placebo Bevacizumab versus no treatmentChemotherapy backbone Full dose FOLFIRI Physician’s discretion on dose and regimen

of chemotherapyStudy objective Evaluate the safety and efficacy of aflibercept

versus placebo in mCRC patients with progressionon a prior oxaliplatin-containing regimen

Evaluate whether bevacizumab could becontinued in patients progressing on afirst-line regimen containing bevacizumab

Study population ~ 30% bevacizumab experienced 100% bevacizumab experiencedStudy key exclusion criteria Prior irinotecan; history of major surgery

within 28 days; (no exclusion basedon timing of progression)

Progressive disease for > 3 months after lastbevacizumab dose; first line PFS < 3 months;first line (consecutive) bevacizumab treatmentof < 3 months

Study conclusions Addition of aflibercept to FOLFIRI improvedPFS and OS over placebo

Continuation of bevacizumab (with achange in CT) after 1st-progressionimproved PFS and OS over no treatment(with a change in CT)

CT: Chemotherapy; FOLFIRI: Folinic acid, fluorouracil, and irinotecan; mCRC: Metastatic colorectal cancer; OS: Overall survival; PFS: Progression-free survival;

VELOUR: A Multinational, Randomized, Double-blind Study, Comparing the Efficacy of Aflibercept Once Every 2 Weeks Versus Placebo in Patients With Metastatic

Colorectal Cancer (MCRC) Treated With Irinotecan/5-FU Combination (FOLFIRI) After Failure of an Oxaliplatin Based Regimen.

Second-line antiangiogenesis therapy in mCRC

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bevacizumab (with a change in chemotherapy) improves sur-vival over a change in chemotherapy alone in patients previ-ously receiving a bevacizumab-containing regimen [7]. Whileresults of both trials are welcomed and now provide for fur-ther options in the second line, the individual results of thetwo trials cannot be compared directly. It is important tonote that the coincidental 1.4-month gain in overall survivalthat occurred in both trials is actually the median of a vastnumber of different patient types (all takers) in the VELOURtrial while it is the median of a highly selected and relativelyhealthy population in ML18147. In fact, in a substudy(n = 1,102) of VELOUR which only included patients whoreceived oxaliplatin as first-line for mCRC and excludedpatients who received oxaliplatin as adjuvant therapy andwho progressed within 6 months (n = 124), the median over-all survival (95% confidence interval) for placebo/FOLFIRIwas 11.9 months compared with 13.8 months for afliber-cept/FOLFIRI; a difference of 1.9 months [17]. Lastly, interms of safety, the data show that aflibercept appears tohave an adverse event profile similar to that of bevacizumaband consistent with VEGF inhibition (e.g., hypertension, pro-teinuria) [4,18]. Any increase in toxicity, for example increaseddiarrhea in VELOUR over that of ML18147, was likelyrelated to VELOUR patients having had an oxaliplatin regi-men followed by a full dose of FOLFIRI, while in theML18147 trial, initial starting doses as well as subsequentmodification of the chemotherapy backbone were at thephysician’s discretion. Because the two trials were not con-ducted on the same chemotherapy backbone, there is no basisto conclude that one agent is superior to the other with respectto safety.With the current range of available therapies, the median

survival for unresectable mCRC has improved to 24 monthsor longer, and by optimizing the sequential use of these treat-ments, there is room for further improvement [2,3]. Ulti-mately, decisions regarding second-line therapy must beindividualized based on prior therapy and other patient fac-tors. Although a benefit of continuing bevacizumab past firstprogression was demonstrated in ML18147, we should notassume that continuing bevacizumab is the best option forall patients with first-line progression. One certainly shouldconsider a change in antiangiogenic therapy for the ‘fast-relapse’ patients with fewer than 3 months of progression-free survival on a first-line bevacizumab-containing regimen;

a population that was entirely excluded from ML18147 [7]

or even those who may have had a modest progression-free survival (~ 6 months) on a first-line chemotherapy-beva-cizumab regimen. And, while continuing bevacizumab with achange in chemotherapy backbone would be a viable optionfor many of these patients, a switch to aflibercept, by virtueof its distinct mechanism of action and higher affinity bindingto VEGF-A than bevacizumab, could allow for continuedantiangiogenesis therapy and the potential for additional sur-vival benefit. Unfortunately, bevacizumab is used in combina-tion with chemotherapy, and it is not possible at present tounequivocally discern, through the use of biomarkers or oth-erwise, which patients will continue to respond to antiangio-genic therapy with bevacizumab, and which patients mayhave developed bevacizumab resistance [2]. In the latter case,such patients would be better candidates for aflibercept treat-ment as the second-line antiangiogenic therapy. In this regard,there is an urgent need for continued research into biomarkersto help identify in advance those patients who are likely torespond to one antiangiogenesis therapy versus another, andindeed there is precedent for success using such anapproach [3]. For example, while initially used in unselectedpopulations, we now know that a benefit of epidermal growthfactor receptor targeted therapies (i.e., cetuximab and panitu-mumab) is observed only in mCRC patients with wild typeKRAS status, and thus recommendation for their use is nowlimited to this subset of patients [1-3]. One can envision a com-parative trial of bevacizumab or aflibercept in the second linesetting, in a population of high-risk mCRC patients, forexample, those with early progression (fewer than 3 monthson first line), utilizing biomarkers to identify patient subsetswhich might benefit from one therapy versus the other. Inthe absence of such data, however, we must rely on a fairassessment of the available data from VELOUR andML18147, which both show the benefit of continuing antian-giogenesis in the second line, albeit in two very different trialswith varying patient populations.

Declaration of interest

The author has been part of speaker’s bureaus for Genentechand Sanofi, no funding was received in preparation ofthis article.

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AffiliationMuhammad Wasif Saif MD

Director, GI Oncology Program, Leader,

Experimental Therapeutics Program,

Tufts University School of Medicine,

800 Washington Street, Suite 7S-7099,

Boston, MA 02111, USA

Tel: +1 617 636 8077;

Fax: +1 617 636 7060;

E-mail: WSaif@tuftsmedicalcenter.org

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