the trial results indicated differences
`in the toxicity profiles of the two
`regimens, with relatively more fre(cid:173)
`quent grade 3 or 4 mucositis, nausea
`and vomiting, and grade 2 alopecia
`with FOLFIRT chemotherapy and
`more frequent grade 3 or 4 neu -
`tropenia and neurotoxicity with
`FOLFOX chemotherapy. 10,u
`In the last decade, the introduc(cid:173)
`tion of targeted biological therapy
`has transformed the paradigm for
`treatment of mCRC. Antiangiogen-(cid:173)
`esis agents, such as bevacizumab, \2
`and epidermal growth factor receptor
`antagonists, such as cetuximah,n have
`been added to the standard combi-(cid:173)
`nation chemotherapy (FOLFOX or
`FOLFIRI), with improved survival
`outcomes reported in patients with
`mCRC. Angiogenesis, the process
`by which new blood and lymphatic
`vessels are formed, is required to
`support growth in the embryo and
`young animals, as well as to allow tis-(cid:173)
`sue repair and remodeling in adults.14
`For tumors, as with normal tissues,
`oxygen and nutrients are obtained
`and waste products are removed via
`the vasculature. Although tumors can
`grow in part by co-opting existing
`host vessels, 15 most tumors induce
`new vessel formation (neovascular-(cid:173)
`ization ), suggesting that angiogenesis
`is a hallmark of tumor growth and
`function throughout the tumor's
`life cycle. The predominant growth
`factor, or proangiogen ic factor, of
`the angiogenesis pathway is vascular
`endothelial growth factor (VEGF). 10,i 7
`Its continuous expression by the tu--
`
`mor makes VEGF a rational target for
`cancer therapy. i 7
`This article focuses on the
`clinical review of ziv-aflibercept
`(ziv" - a flib' er sept; Zaltrap, Regen-(cid:173)
`eron Pharmaceuticals and sanofi(cid:173)
`aventis ), a novel fully humanized
`monoclonal antibody with antian(cid:173)
`giogenic activity recently approved
`by the Food and Drug Administra(cid:173)
`tion (FDA) for use in combination
`with second-line FOLFIRI chemo(cid:173)
`therapy for patients with mCRC who
`have not responded to an oxaliplatin(cid:173)
`containing first--line regimen.
`
`18
`
`Pharmacology
`The mammalian VEGF family1 4
`•
`consists of six distinct glycoproteins,
`or growth factors: VECF-A, VEGF-B,
`VEGF-C, VEGF-D, VEGF-E, and pla(cid:173)
`cental growth factor (P1GF). These
`growth factors are ligands that
`bind to VEGF receptors that mediate
`tumor angiogenesis. Among these,
`VEGF-A (or simply VEGF) is con(cid:173)
`sidered the principal driving force in
`tumor angiogenesisY Each ligand has
`specific affinity for different receptors.
`There are three VEGF receptors:
`VEGFR 1, VEGFR-2, and VEGFR-3.
`All of these VEGF receptors are char(cid:173)
`acterized by seven immunoglobulin
`(Tg)-like domains in the extracellular
`region, a single transmembrane do(cid:173)
`main, and an intracellular tyrosine
`kinase domain. 19 These VEGF recep-(cid:173)
`tors are high-affinity (denoted by low
`dissociation constant) receptors, with
`tyrosine kinase activity expressed in
`normal and tumor vasculature (i.e.,
`
`Table 1.
`Key Differences in Biological Properties of Ziv-aflibercept
`and Bevadzumab2123
`·"
`
`Property
`
`Ziv-aflibercept
`
`Bevacizumab
`
`VEGF-t\ VEGF-B, PIGF
`
`Binding target(s)
`Equilibrium dissociation
`constant.b pM
`0.49
`Elimination half-life, days
`5-6
`avEGF = vascular endothelial growth factor, P!GF == piacentai growth factor.
`1;A measure of binding affinity! \N!th smal!er values mdicating stronger binding.
`
`VEGF-A
`
`58
`20
`
`1888
`
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`
`20 The ma-(cid:173)
`vascular endothelial cells). 18
`•
`jor receptor for VEGF-A is VEGFR-2
`(flkl/KDR). Although VEGF-A binds
`to VEGFR-1 with 10 times higher af(cid:173)
`finity than does VEGFR-2, the higher
`tyrosine kinase activity of VEGFR-2
`makes it the most important effector
`20 Of note, PlGF,
`in VEGF signaling.\8
`•
`which binds to VEGFR-1 but not
`VEGFR-2, also contributes to tumor
`angiogenesis. L
`9
`Ziv-aflibercept, a fully humanized
`soluble recombinant fusion protein,
`is created by fusing extracellular lg
`domain 2 of VEG FR-1 and extracel -
`lular lg domain 3 of VECFR-2 to
`the Fe (constant) region of human
`IgG 1, resulting in the formation of a
`more potent and high-affinity VEGF
`blocker than hevacizumab.i 9 This fu(cid:173)
`sion protein has been demonstrated
`to have pharmacologically improved
`activity over bevacizumab ( Table
`l ). 21
`1 Since this fusion protein
`-"
`blocks the angiogenesis pathway by
`binding to all isoforms of VEGF-A,
`VEGF-B, and PlGF, it is also known
`as a "VEGF trap" or a composite
`decoy receptor (due to the fusion
`of both VEGFR-1 and VECFR-2
`L By binding to these en(cid:173)
`to IgGl). 2
`dogenous ligands, ziv-atlibercept
`inhibits the binding and activation
`of their cognate receptors, resulting
`in inhibition of downstream signal(cid:173)
`ing events that mediate neovascu(cid:173)
`larization and vascular permeability.
`This process results in maintenance
`of a more fimctional and normal
`vasculature,rn· 19 inhibition of tumor
`growth and tumor metastasis, and
`potentially improved drug delivery
`( due to "normalization" of tumor
`vasculature that enables tumor cells
`to become more sensitive to cyto-(cid:173)
`toxic chemotherapy). 24
`
`Pharmacokinetics and
`pharmacodynamics
`Zi v-aflibercept binds l: l to en -
`dogenous VEGF to form stable
`inert complexes, which appear in
`the circulation at a maximum level
`within 24---48 hours of treatment. 25
`
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`

`These complexes are retained in
`the systemic circulation. Clearance
`occurs via a receptor-- or pinocyte(cid:173)
`mediated pathway that results in
`proteolysis.
`Pharmacokinetic studies of ziv(cid:173)
`aflibercept involved the measurement
`of plasma concentrations of free and
`VEGF-bound ziv-aflibercept.26
`' The
`2
`-
`level of VEGF-bound ziv-aflibercept
`indicates the amount of endogenous
`VEGF produced in normal and tumor
`tissues, whereas free ziv-aflibercept
`is available for binding with newly
`secreted VEGF. Free ziv-aflibercept
`concentrations exhibit linear kinetics
`at a dose range of 2--9 mg/kg, with
`steady-state concentrations of free
`ziv-aflibercept reached by the sec(cid:173)
`ond dose. J'viaximum VEGF-bound
`ziv-aflibercept levels are reached at
`doses of 2 mgikg i.v. or greater, in(cid:173)
`dicating complete blockade of the li(cid:173)
`gand. In pharmacokinetic studies, the
`half- life of ziv-aflibercept increased
`(from l.7 to 5.1 days) as doses were
`increased from 0.3 to 7.0 mg/kg i.v.
`Clearance was stable at doses in the
`range of 2---7 mg/kg. There was no
`accumulation of free ziv-aflibercept
`between treatment cycles.
`Some studies also demonstrated
`that the biological effects of ziv(cid:173)
`aflihercept correlated closely with
`free ziv--aflibercept levels in excess
`of VEGF-bound ziv-aflibercept lev(cid:173)
`els. 20·29 The mean maximum ob-(cid:173)
`served plasma concentration of free
`ziv-aflibercept, at doses ranging
`from 0.3 to 7.0 mg/kg (0.3 mg/kg
`is about a tenth of the biologically
`effective dose in humans), varied
`from 4 to 159 ~Lg/mL. 29 Following the
`administration of ziv-aflihercept at
`2- and 3-mg/kg doses, free drug con-(cid:173)
`centrations were similar to VEGF(cid:173)
`bound ziv-aflibercept concentrations.
`With doses of ?.:4 mg/kg, free ziv(cid:173)
`aflibercept concentrations were in
`excess of hound ziv-aflibercept con(cid:173)
`centrations throughout the dosing
`intervals in most patients. Thus, a
`4-mg/kg i.v. dose provides a suf.
`ficient ziv-aflibercept concentration
`
`to block endogenous production of
`VEGF.
`Van Cutsem and colleagues 26
`showed that clearance and concentra(cid:173)
`tions of free and bound ziv-aflibercept
`at steady state in patients treated with
`irinotecan-based combination che(cid:173)
`motherapy were comparable to those
`observed with ziv-aflibercept mono-(cid:173)
`therapy. No clinically significant phar(cid:173)
`macokinetic drug---drug interactions
`were found between ziv-aflibercept,
`irinotecan, and SN-38 the active me-(cid:173)
`tabolite of irinotecan).
`
`Clinical trials
`Phase I research. The safety and
`dose determination of single-agent
`ziv-aflibercept therapy were explored
`in a dose-escalation trial conducted
`by Lockhart and colleagues29 that in-(cid:173)
`eluded 7 patients with mCRC among
`a total of 47 patients with refractory
`solid tumors. Seven dose levels were
`evaluated (0.3, LO, 2.0, 3.0, 4.0, 5.0,
`and 7.0 mg/kg); 3, 7, 6, 7, 7, 4, and
`13 patients were treated at each re(cid:173)
`spective dose level. The investigators
`also evaluated the safety and maxi-(cid:173)
`mum tolerable dose (MTD) of ziv(cid:173)
`aflibercept at doses ranging from 0.3
`to 7.0 mg/kg i.v. every two weeks. The
`MTD was defined as the highest dose
`at which 2 of 3-6 treated patients
`experienced a dose- limiting toxicity
`(DIT): uncontrolled hypertension,
`grade 3 or 4 proteinuria, febrile neu-(cid:173)
`tropenia, grade 4 neutropenia, grade
`3 or 4 thrombocytopenia, and any
`toxicity of any grade that led to drug
`discontinuation. DLTs were evalu-(cid:173)
`ated during each dose-escalation
`phase. T1..1mor response was evalu -
`ated after every two cycles (or four
`treatments per eight-week interval)
`according to the RECIST (Response
`Evaluation Criteria In Solid Tumors,
`version 1.0) scheme. Patients could
`elect to continue treatment until dis-(cid:173)
`ease progression or intolerable toxic(cid:173)
`ity or until they chose to withdraw
`consent.
`Results showed that single--agent
`ziv-aflibercept was generally well tol-
`
`Ziv-aflibercept
`
`i!ll!I
`
`erated, with a rate of partial response
`of 6% and a rate of stable disease
`for greater than one year of 4%. The
`types of treatment-related toxicities
`observed ( e.g., fatigue, hypertension,
`proteinuria) were consistent with
`those reported in other trials evalu -
`ating antiangiogenic therapies. 10
`34
`·
`The median times to the onset of
`hypertension or proteinuria were 3.5
`days (range, 1--21 days) and 15 days
`(range, 14-16 days), respectively.
`These adverse events were reversible
`on drug discontinuation or initiation
`of supportive care. Based on these
`observations and observed increases
`in the frequency and severity of ad-(cid:173)
`verse events at doses of ;::_:4 mg/kg,
`single-agent ziv-aflibercept 4 mg/kg
`i.v. every two weeks was determined
`to be the recommended dosage for
`use in Phase IT trials.
`In another study, investigators
`evaluated the safety, efficacy, DIT
`profile, and recommended dose of
`ziv-aflibercept in combination with
`irinotecan-based chemotherapy for
`second-line treatment of Japanese
`patients with mCRC, 10 ( 63i1/o) of
`whom had received prior beva(cid:173)
`cizumab therapy. 28
`35 Ziv-aflibercept
`•
`was administered at two dosage
`levels (2 and 4 mg/kg i.v. every two
`weeks, administered to 3 and 13
`patients, respectively). The median
`numbers of cycles administered were
`6 (range, 3---9) and 10 (range, 1--23),
`and the total numbers of cycles of
`the 2- and 4-mg/kg doses were 18
`and 131, respectively. No DITs were
`observed at either dosing level. The
`response rate and PFS for patients
`receiving the 4- mg/kg i.v. dose were
`8% and 7.6 months, respectively. At
`both dosing levels, the most common
`adverse events ( occurring in ?.:40%
`of patients) included bone marrow
`suppression (e.g., neutropenia) and
`gastrointestinal symptoms ( e.g., nau-(cid:173)
`sea, vomiting, diarrhea, stomatitis,
`decreased appetite); these toxicities
`are known to he associated with
`FOLFIRI regimens. In addition, tox-(cid:173)
`icities known to be associated with
`
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`
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`

`

`the antiangiogenesis therapy, such as
`h)1Jertension and epistaxis, were also
`frequently observed ( rates of 2='.40%)
`with use of the 4-mgikg dose. The
`most common grade 3 or 4 adverse
`events were neutropenia and hyper(cid:173)
`tension. This study established the
`recommended dose and schedule of
`ziv-aflibercept (i.e., 4 mg/kg i. v. every
`nvo weeks) to be used in combination
`with irinotecan -based chemotherapy
`for mCRC.
`Of note, ziv-afiibercept has been
`evaluated extensively for the treat(cid:173)
`ment of patients with other advanced
`14 Most of the patients
`solid tumors. 30
`·
`involved had received prior chemo-(cid:173)
`therapy regimens, either as first- or
`higher-line therapies. Ziv-aflibercept
`was found to have very modest
`clinical activity as a monotherapy;
`however, when it was used as a com(cid:173)
`ponent of combination therapies,
`partial-response rates ranged from
`4% to 18%.
`Phase n research. Tang and col(cid:173)
`leagues36 conducted a multicenter
`open-label Phase TI trial in 75 heav(cid:173)
`ily treated mCRC patients with good
`performance status (i.e., Eastern Co(cid:173)
`operative Oncology Group [ECOG]
`performance status of 2 or less). Pa(cid:173)
`tients had received a median of two
`prior regimens and were stratified
`as having received ( n = 51) or not
`received (n '" 24) prior bevacizumab
`therapy. The primary endpoints were
`response rate and PFS. After a medi(cid:173)
`an of 4 treatment cycles (range, 1---16
`cycles) of single-agent ziv-aflibercept
`therapy (4 mg/kg i.v. every 2 weeks),
`median PFS was 2.4 months among
`patients who had received prior beva(cid:173)
`cizumah therapy and 2.0 months in
`the bevacizumab--naive group. The
`efficacy of ziv-aflibercept did not
`seem to be affected by prior bevaciz(cid:173)
`umah therapy (duration not speci(cid:173)
`fied). In the prior--bevacizumab co-(cid:173)
`hort, l patient had a partial response
`and 6 patients (12%) had stable
`disease for greater than 16 weeks.
`In the bevacizumab-naive cohort,
`the best response was stable disease
`
`for greater than 16 weeks in 5 of 24
`patients (21%). Overall, the most
`common adverse events of any grade
`were fatigue ( 68% ), hypertension
`(51%), proteinuria (49%), headache
`(42%), voice alteration (31%), an(cid:173)
`orexia (24%), and joint pain (18%).
`Single-agent ziv-aflibercept appeared
`to be tolerated and to have modest
`antitumor activity in pretreated pa(cid:173)
`tients with mCRC, including those
`who had received prior bevacizumah
`therapy.
`A notable limitation of the trial
`of Tang et al.5 6 was that the activity
`of ziv-aflibercept against mCRC has
`never been directly compared with
`that of bevacizumah. The best con(cid:173)
`clusion that one can draw from this
`study is that ziv-aflibercept appears
`to be neither dramatically better nor
`worse than bevacizumab; this under(cid:173)
`lines the need for more studies with
`different drug combinations and di(cid:173)
`rect comparisons with bevacizumab-(cid:173)
`based therapies.
`Phase III research. Because of
`the acceptable clinical activity of
`ziv-aflibercept when used in com-(cid:173)
`bination therapies,23 3u 5 a Phase III
`prospective, multinational, double(cid:173)
`blin d, parallel-arm trial (the
`VELOUR trial) was conducted in
`patients with mCRC who had ex(cid:173)
`perienced disease progression while
`receiving oxaliplatin-based chemo(cid:173)
`therapy (e.g., FOLFOX).37
`The primary study endpoint was
`OS, as determined by the planned
`subgroup analysis. Secondary end(cid:173)
`points were PFS and response rate.
`A total of 1226 patients with mCRC
`and an ECOG score of 2 or less were
`randomly assigned in a 1:1 fashion
`to receive ziv-aflibercept ( n = 612)
`or a placebo (n '" 614) followed by
`FOLFIRI chemotherapy every two
`weeks. Patients were stratified based
`on prior bevacizumab treatment
`and performance status (an ECOG
`score of O or l versus a score of 2).
`The study had a power of 90% to
`detect a 20% improvement in OS
`in the ziv-aflibercept group. Al] pa-
`
`tients had received prior oxaliplatin
`therapy.
`Ziv-aflibercept was given as a
`4-mg/kg i.v. infusion prior to FOLFlRl
`chemotherapy. The FOLFIRI regimen
`was administered according to the
`National Comprehensive Cancer Net(cid:173)
`work (NCCN) colon cancer guideline
`(irinotecan hydrochloride 180 mg/m2
`i.v. on day l of each nvo-week cycle,
`to be administered concurrently with
`leucovorin 400 mg/m2 i.v., followed by
`fiuorouracil 400 mg/m2 by i.v. bolus
`and then fluorouracil 2400 mg/m 2
`by continuous i.v. infusion over 46
`hours 38
`). The use of supportive care
`medications, including atropine (for
`prophylaxis of acute diarrhea due to
`irinotecan) and colony--stimulating
`factor (for prophylaxis of neutrope(cid:173)
`nia) was permitted. Disease response
`was evaluated radiologically every
`six weeks. Treatment continued until
`disease progression or intolerable
`toxicity. The study groups were well
`balanced in terms of performance
`status and prior bevacizumab therapy.
`Approximately 30% of patients ( l 86
`of 612) in the ziv-aflibercept group
`had received bevacizumab, compared
`with 31% of patients (187 of 614) in
`the placebo group. The overaJl me(cid:173)
`dian age was 61 years; the majority of
`patients (87°10) were white, 7% were
`Asians, and 3.5% were black.
`At a median follow-up of 22.3
`months, the two-year survival rates
`were 28.0% and 18.7% in the ziv(cid:173)
`aflibercept and control groups, re(cid:173)
`spectively. Relative to placebo users,
`patients treated with ziv-afiibercept
`had longer OS (13.5 months versus
`12.l months; hazard ratio, 0.817;
`95% confidence interval, 0.71-0.94
`months; p = 0.0032), a higher re(cid:173)
`sponse rate ( 19 .8% versus 11. l %, p <
`0.001), and longer PFS (6.9 months
`versus 4.7 months, p < 0.0001). Pa(cid:173)
`tients receiving antiangiogenic thera-(cid:173)
`pywere given a median of seven cycles
`of ziv-aflibercept ( the numbers of
`cycles of FOLFIRI and ziv-aflihercept
`varied among these patients); those in
`the control group received eight cycles
`
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`

`of placebo administration. Irinotecan
`and fluorouracil were administered
`for a median of 21 weeks in the ziv(cid:173)
`aflibercept group and 18.l weeks in
`the control group.
`Cycle delays and dose modifica(cid:173)
`tions were more common among
`patients receiving ziv-atlibercept.
`Dose intensity ( defined as the ratio
`of the delivered chemotherapy dose
`to the standard full dose, expressed
`as a percentage) was 83% in the
`ziv--aflibercept group versus 92%
`in the control group. No significant
`relationship was observed between
`treatment outcomes and prior beva(cid:173)
`cizumab exposure. In a subgroup
`analysis, a greater OS benefit related to
`ziv-aflibercept therapy was observed
`only in patients with liver metastasis
`as opposed to metastasis to other or-(cid:173)
`gans. The benefits in OS and PFS seen
`in the bevacizumab--pretreated group
`were consistent with those observed
`in the overall population.
`Adverse events among VELOUR
`trial participants included diarrhea,
`asthenia, stomatitis, ulceration, nau(cid:173)
`sea, and infections. These adverse
`events were primarily grade I or 2
`and were more common in patients
`treated with ziv-aflibercept.
`Overall, adverse events of all grades
`were similar in both study groups.
`
`Grade 3 or 4 adverse events related
`to antiangiogenesis therapy that
`occurred more frequently in the
`ziv-aflibercept group relative to the
`control group included hyperten-(cid:173)
`sion (19% versus 1.5%), hemor(cid:173)
`rhage (2.9% versus 1.7%), arterial
`thromhoembolic events ( l .8°10 versus
`0.5%), venous thromboembolic
`events (8% versus 6%!), and protein(cid:173)
`uria ( 8% versus l % ) . Surprisingly, a
`significant increase in chemotherapy(cid:173)
`induced grade 3 or 4 toxicities----(cid:173)
`particul arly diarrhea ( 19% versus 8%),
`asthenia (17% versus 11 %), stomatitis
`( 13% versus 5%), and infections
`( 12% versus 7% )------was also observed
`with antiangiogenesis therapy (Table
`2). This apparent increase in ziv(cid:173)
`aflibercept-associated toxicities was
`not in line with Phase III study results
`on bevacizumab use in patients with
`mCRC. 38 However, prior bevacizum -
`ab treatment did not seem to impact
`the safety profile of ziv-afiibercept.
`The most common adverse events
`that led to treatment discontinuation
`included asthenia, infections, diar(cid:173)
`rhea, and hypertension.
`Based on the results that demon(cid:173)
`strated statistically significant im(cid:173)
`provement in OS, PFS, and response
`rate in patients with mCRC who
`received ziv-aflibercept as a second-
`
`Ziv-aflibercept
`
`i!ll!I
`
`line therapy with or without prior
`bevacizumab therapy, FDA approved
`ziv-afiibercept for use in this patient
`population in 2012. 22
`
`Safety
`Overall, ziv-afiibercept appears
`to be tolerated, even in heavily pre(cid:173)
`treated mCRC populations. In the
`VELOUR trial, the most common
`adverse effects observed in patients
`receiving ziv-aflibercept in combina(cid:173)
`tion with the FOLFIRI regimen were
`leucopenia, neutropenia, throm(cid:173)
`bocytopenia, diarrhea, proteinuria,
`and h)1Jertension. 22
`37 These adverse
`•
`effects were mostly grade l or 2 and
`reversible. Of note, some of these
`common adverse effects (hyperten -
`sion and proteinuria) were among
`the most common DLTs identified
`29 and were
`in Phase I and II trials 26
`·
`consistent with the inhibition of
`the angiogenesis pathway. Other
`adverse effects occurring more
`commonly in ziv-aflibercept versus
`control groups ( e.g., increases in
`liver function enzymes, stomatitis,
`fatigue, decreased appetite) may
`not be related to ziv-atlibercept's
`antiangiogenic effect.
`Class-related adverse effects. Hy(cid:173)
`pertension, proteinuria, and throm-(cid:173)
`boembolism are recognized as the
`
`Table 2.
`Most Common Adverse Effects of Ziv-aflibercept in Phase ill Trial37·•
`
`Adverse Effect
`
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Hypertension
`............................................
`Diarrhea
`Stomatitis
`Proteinuria
`
`0/o Patients Affected
`FOLFIRI + Ziv-aflibercept
`(n "'611)
`Grade 3 or4
`
`All Grades
`78
`67
`48
`41
`69
`50
`62
`
`16
`37
`3
`19
`19
`13
`8
`
`FOLFIRI + Placebo
`{n c=605)
`
`Al! Grades
`72
`57
`35
`11
`57
`33
`41
`
`Grade 3 or4
`12
`30
`2
`2
`8
`5
`
`3
`62
`ALT eievation
`50
`3
`aFOLFIR: = !eucovorin, fluorourad!, and irinotec.an; .4ST = a.spartate transaminase; ALT= alanine transaminase.
`
`54
`39
`
`2
`2
`
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`-
`
`hallmark class-related adverse ef(cid:173)
`fects associated with antiangiogenic
`therapy. 39
`42 Hypertension associated
`with antiangiogenic therapy is often
`of low grade (l or 2). Even grade 3
`or 4 hypertension may still be re(cid:173)
`versible, and patients are managed
`with angiotensin-converting enzyme
`inhibitors, calcium channel blockers,
`or diuretics.43
`Proteinuria (all grades) was re(cid:173)
`ported in 49% of patients in the
`VELOUR trial.3 7 The frequency of
`grade 3 or 4 proteinuria was 7.8%;
`dose modification may be necessary
`for patients who develop this compli(cid:173)
`cation. The drug manufacturer rec-(cid:173)
`ommends monitoring for protein(cid:173)
`uria by urine dipstick ( or urinalysis)
`and determination of the urinary
`protein-to-creatinine ratio (UPCR)
`prior to each dose of ziv-aflibercept. 22
`For patients with a UPCR greater
`than 1, analysis of a 24-hour urine
`collection is recommended.
`In addition, inhibition of the
`VEGF signaling pathway leads to
`dysfunctional endothelial cells in
`the vascular endothelium, ca us-(cid:173)
`ing activation of tissue factor and
`an increased risk of thrombosis.
`Experience with bevacizumab dem(cid:173)
`onstrated that bevacizumab--VEGF
`complexes induced platelet aggrega(cid:173)
`tion and led to the thromboembolic
`events observed in clinical trials_n. 44
`Currently, it remains unclear whether
`the biologically inert ziv-aflibercept(cid:173)
`VEGF complex is associated with a
`lower frequency of thromboembolic
`events. In the VELOUR trial, grade
`3 or 4 thromboembolic complica(cid:173)
`tions occurred in less than 1 % of
`patients. 37 It is, however, important
`to note that cancer patients in general
`are at an increased risk for thrombo(cid:173)
`sis due to their procoagulant disease
`state and that antiangiogenic therapy
`marginally increases this risk. 44
`Black-box warning. Ziv(cid:173)
`aflibercept carries an FDA-mandated
`black-box warning on treatment(cid:173)
`related hemorrhage, gastrointesti-(cid:173)
`nal perforation, and compromised
`
`wound healing. 22 In clinical trials,
`the rate of bleeding and hemor(cid:173)
`rhage together was 37.8% in the ziv(cid:173)
`aflibercept groups versus 19% in the
`control groups 35
`; the occurrence
`37
`•
`of grade 3 or 4 hemorrhage, includ(cid:173)
`ing severe intracranial hemorrhage,
`was also slightly higher with ziv(cid:173)
`aflibercept use (3% versus 1.7%). 22
`Patients receiving ziv-aflibercept
`should be monitored for signs and
`symptoms of bleeding. Therapy
`should be discontinued in patients
`who develop severe hemorrhage.
`Although the rates of gastrointes(cid:173)
`tinal perforation were similar in
`both study groups in the VELOUR
`trial, patients receiving antiangio(cid:173)
`genic therapy should be monitored
`and treatment should be discon(cid:173)
`tinued if gastrointestinal perfora-(cid:173)
`tion develops.
`Pregnancy consideration. Ziv(cid:173)
`aflibercept is classified as a pregnancy
`category D agent. It should be used
`in pregnancy only if the potential
`benefit justifies the potential risk to
`the fetus.22 Both female and male
`patients of reproductive potential
`must use effective contraception dur(cid:173)
`ing treatment and for a minimum of
`three months after the last dose of
`ziv-aflibercept.
`Immunogenicity and hypersen(cid:173)
`sitivity. During clinical research, the
`frequency of development of anti(cid:173)
`bodies to ziv-aflibercept was 3. l %
`in patients receiving ziv-aflibercept
`versus 1.7% in patients receiving a
`placebo 22; among patients who test(cid:173)
`ed positive for anti-ziv-aflibercept
`antibody, neutralizing antibodies
`were detected in 17 of 48 patients
`administered ziv-aflibercept and in
`2 of 40 placebo users. The impact
`of neutralizing antibodies on treat(cid:173)
`ment efficacy and safety remains
`unclear. Since the antibody assay
`may be influenced by many factors,
`direct comparison of the frequency
`of anti-ziv-aflibercept antibody for(cid:173)
`mation with the corresponding rate
`for other protein-based medications
`may be misleading. Currently, it is
`
`not known if such antibody forma-(cid:173)
`tion is persistent enough to cause
`infusion -related reactions or re(cid:173)
`duced ziv-aflibercept exposure. No
`data are available on the usefulness
`of routine screening for positive
`antibody.
`In regard to the frequency of se(cid:173)
`vere (grade 3 or 4) hypersensitivity
`reactions, no difference was found
`in ziv-afiibercept versus control
`patients in the VELOUR trial (0.3%!
`versus 0.5%).37
`Other safety considerations. Ziv(cid:173)
`aflibercept, known simply as afliber(cid:173)
`cept in European and other countries,
`is specifically named with the prefix
`"ziv" ( derived from the brand name
`Zaltrap and the abbreviation i.v.)
`in the United States in accordance
`with the FDA requirement that drug
`manufacturers reduce the potential
`for confusion related to sound-alike
`and look-alike medication names.
`The World Health Organization's in(cid:173)
`ternational nonproprietary name for
`Zaltrap is aflibercept.
`FDA required that the U.S. ge(cid:173)
`neric name ziv--aflibercept be used
`to clearly differentiate the formula(cid:173)
`tion approved for use in managing
`mCRC from its ophthalmic counter(cid:173)
`part, aflibercept, which is marketed
`under the proprietary name Eylea
`(Regeneron Pharmaceuticals) in a
`different strength. 2
`' The scientific
`literature still uses aflibercept as the
`generic name for ziv-aflibercept. lt is
`recommended that ziv--aflibercept be
`stored, segregated, and labeled with a
`specific warning to help distinguish
`the product from the ophthalmic
`product.
`
`Dosage, preparation, and
`administration
`The recommended dosage of
`ziv-atlibercept is 4 mg/kg i.v. ad(cid:173)
`ministered every two weeks prior
`to FOLFIRI combination chemo(cid:173)
`therapy. Treatment is continued until
`disease progression or intolerable
`toxicity. Ziv-afiibercept is supplied
`as a ready-to-use single-dose vial
`
`1892
`
`Am J Hea!th-Syst Pharm-Vol 70 Nov 1, 2013
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 1455
`
`

`

`of either 200 or 100 mg ( solution
`concentration, 25 mg/mL). After the
`withdrawal of the calculated dose
`from the vial, the drug is further
`diluted in a vehicle of 0.9% sodium
`chloride injection or 5% dextrose in(cid:173)
`jection to yield a final ziv-aflibercept
`concentration of 0.6-8 mg/mL. Di(cid:173)
`luted solution must be refrigerated
`and used within four hours.22
`Ziv-aflibercept should be admin(cid:173)
`istered as an intermittent infusion
`over one hour through a 0.2--~Lm
`polyethersulfone filter. 22 An adminis(cid:173)
`tration set made of one of the follow(cid:173)
`ing materials may he used: polyvinyl
`chloride (PVC)-containing diethyl(cid:173)
`he),_11 phthalate (DEHP), DEHP-free
`PVC containing trioctyl trimelli(cid:173)
`tate, polypropylene, polyethylene(cid:173)
`lined PVC, and polyurethane. Ziv-(cid:173)
`aflibercept is administered alone
`prior to any component of FOLFIRI
`combination chemotherapy.
`Ziv-aflibercept has not been
`shown to have clinically significant
`interactions with irinotecan, SN--38,
`and fluorouracil.2 6
`37 The manufac(cid:173)
`'
`turer has not conducted dedicated
`drug-drug interaction studies. 22
`The dosage of ziv-aflibercept does
`not need to be adjusted for renal im(cid:173)
`pairment.22 The VELOUR trial data
`indicated that no dosage adjustment
`is needed for mild hepatic impair(cid:173)
`ment; however, no information is
`available on the potential need for
`dosage adjustments in severe hepatic
`impairment ( defined in the VELOUR
`trial as a total hilirubin level greater
`than three times the upper limit of
`normal).}7
`Ziv-aflibercept should be dis(cid:173)
`continued for any of the following
`toxicities: arterial thromboembolic
`events, fistula formation, gastrointes(cid:173)
`tinal perforation, severe hemorrhage,
`hypertensive crisis, hypertensive en(cid:173)
`cephalopathy, nephrotic syndrome,
`thrombotic microangiopathy, and
`reversible posterior leukoencepha(cid:173)
`lopathy syndrome,22
`4
`A
`Dosage modifications should
`be made for patients with severe
`
`or uncontrolled hypertension; ziv-(cid:173)
`aflibercept should be withheld until
`blood pressure is controlled, with
`the dose subsequently reduced to 2
`mg/kg. 22 For patient with substantial
`proteinuria (i.e., :?:2 g in 24 hours),
`ziv-aflibercept should be withheld
`and only administered when the pro(cid:173)
`tein level declines below that level.
`If proteinuria recurs, ziv-aflibercept
`must be discontinued until the urine
`protein level falls below 2 g in 24
`hours, with therapy resumed at a
`reduced dose of 2 mg/kg.
`Patients must be monitored for
`hematologic toxicity at baseline
`and prior to each cycle of ziv-(cid:173)
`aflibercept.2' Treatment with ziv(cid:173)
`aflibercept and FOLFIRI chemo(cid:173)
`therapy must be delayed until the
`neutrophil count is 21.5 x 109 cells/L.
`Furthermore, ziv-aflibercept has
`been shown to delay and compro(cid:173)
`mise wound healing. Treatment
`should be stopped at least four weeks
`prior to elective surgery and should
`not be resumed until at least four
`weeks after surgery or until the surgi(cid:173)
`cal wound is frilly healed.
`No dosage adjustment is neces(cid:173)
`sary for the elderly. Based on a pop(cid:173)
`ulation pharmacokinetic analysis,2 2
`race and sex did not have a clinically
`significant effect on exposure to free
`ziv--aflibercept Currently, there is no
`recommendation for ziv-aflibercept
`dosing in obese patients. In one
`of the Phase I studies summarized
`above, patients weighing more than
`l 00 kg had a 29% increase in sys(cid:173)
`temic exposure to ziv--aflibercept
`compared with patients weigh(cid:173)
`ing 50---100 kg. 35 Furthermore, no
`recommendation for a maximum
`total dose of zi v-aflibercept has
`been made. In the VELOUR trial, a
`maximum patient weight was not
`specified. 22
`37
`'
`The use of FOLFIRI combination
`chemotherapy requires the calcula(cid:173)
`tion of body surface area (BSA). 22 In
`the VELOUR trial, if a patient's BSA
`was greater than 2 m2, the amounts
`of irinotecan and fluorouracil used
`
`Ziv-aflibercept
`
`i!ll!I
`
`were adjusted downward to the doses
`corresponding to a BSA of 2 m' for
`safety purposes. 22
`37
`•
`
`Cost considerations
`The average wholesale acqms