Breast Cancer: Basic and Clinical Research
`
`R e v i e w
`
`Open Access
`Full open access to this and
`thousands of other papers at
`http://www.la-press.com.
`Safety and Efficacy of nab-Paclitaxel in the Treatment
`of Patients with Breast Cancer
`
`Prakash vishnu and vivek Roy
`Division of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USA. Corresponding author email: roy.vivek@mayo.edu
`
`Abstract: Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel
`­formulations­have­been­developed­to­improve­efficacy­and­decrease­toxicity­associated­with­these­cytotoxic­agents.­nab-paclitaxel is a
`solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®,­Abraxis­Bioscience),­which­was­developed­
`to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated
`higher­ response­ rates,­ better­ safety­ and­ side-effect­ profile­ compared­ to­ conventional­ paclitaxel,­ and­ improved­ survival­ in­ patients­
`­receiving­it­as­second­line­therapy.­Higher­doses­can­be­administered­over­a­shorter­infusion­time­without­the­need­for­special­infu-
`sion­sets­or­pre-medications.­It­is­now­approved­in­the­US­for­treatment­of­breast­cancer­after­failure­of­combination­chemotherapy­
`for­metastatic­disease­or­relapse­within­6­months­of­adjuvant­therapy,­where­prior­therapy­included­an­anthracycline.­Recently,­several­
`phase II studies have suggested a role for nab-paclitaxel­as­a­single­agent­and­in­combination­with­other­agents­for­first-line­treatment­
`of metastatic breast cancer.
`
`Keywords: nab-paclitaxel, nab-technology, paclitaxel, metastatic breast cancer, taxanes
`
`Breast Cancer: Basic and Clinical Research 2011:5 53–65
`
`doi: 10.4137/BCBCR.S5857
`
`This article is available from http://www.la-press.com.
`
`© the author(s), publisher and licensee Libertas Academica Ltd.
`
`This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
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`vishnu and Roy
`
`Introduction
`Taxanes (eg, paclitaxel, docetaxel) and anthracyclines
`(eg, doxorubicin, epirubicin) remain among the most
`active­and­widely­used­chemotherapy­agents­in­breast­
`cancer,­ both­ in­ adjuvant­ and­ metastatic­ settings.1–3
`A recent meta-analyses of 13 randomized clinical tri-
`als­showed­a­significant­improvement­of­disease-free­
`and­overall­survival­(OS)­rates­in­high-risk­early­stage­
`breast­cancer­with­chemotherapy­regimens­incorpo-
`rating combination of taxanes and anthracyclines.4
`However,­ approximately­ 25%–30%­ of­ early­ stage­
`breast­cancers­will­recur.­There­is­an­imperative­need­
`for agents that not only overcome resistance but also
`have­a­favorable­toxicity­profile.­The­solvents­used­
`for dissolving hydrophobic molecules, paclitaxel and
`docetaxel­are­known­to­be­associated­with­significant­
`risk­of­hypersensitivity­reactions­and­neuropathy­and­
`also impair drug delivery to the tumor, limiting their
`clinical effectiveness.5,6
`With the advent of nanotechnology, a novel for-
`mulation of solvent free 130-nanometer albumin-
`bound paclitaxel (nab-paclitaxel, Abraxane®, Abraxis
`Bioscience)­ was­ developed­ for­ use­ as­ a­ colloidal­
`suspension intravenously. Based on the pivotal
`phase III clinical trial results, nab-paclitaxel­ was­
`approved­in­the­United­States­by­US­Food­and­Drug­
`­Administration­(FDA)­in­January­2005­and­in­Europe­
`by­European­Medicines­Agency­(EMEA)­in­January­
`2008­for­use­in­patients­with­metastatic­breast­cancer­
`(MBC)­who­have­failed­combination­chemotherapy­
`or­relapse­within­6­months­of­adjuvant­therapy­where­
`prior therapy included an anthracycline.
`This­ article­ provides­ a­ review­ of­ pharmacology,­
`safety­ and­ efficacy­ profile­ of­ nab-paclitaxel, and
`evaluates­its­benefit­in­treatment­of­breast­cancer.
`Side-Effects and Drawbacks
`of Solvent-Based Taxanes
`Taxanes bind to the interior surface of β-microtubule
`chain and enhance tubulin polymerization, thereby sta-
`bilizing microtubules. This inhibits mitosis, motility
`and­intracellular­transport­within­(cancer)­cells,­lead-
`ing­to­apoptotic­cell­death.­Taxanes­also­block­anti-
`apoptotic­effects­of­BCL-2­gene­family,­induce­TP53­
`gene­activation­with­resultant­mitotic­arrest­leading­
`to cell death.7
`Paclitaxel­was­first­approved­in­1992­for­clinical­
`use. It is a naturally occurring diterpinoid product
`
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`
`extracted­from­bark­of­pacific­yew.­Docetaxel,­another­
`taxane,­ which­ was­ approved­ by­ FDA­ for­ clinical­
`use­ in­ 2004,­ is­ a­ semi-synthetic­ esterified­ product­
`of 10-deacetyl baccatin III extracted from needles
`of­European­yew.­Both­paclitaxel­and­docetaxel­are­
`highly­hydrophobic.­Cremaphor­EL­(CrEL),­a­non-
`ionic surfactant poly-oxy-ethylated castor oil mixed
`1:1­with­dehydrated­ethanol­was­recognized­to­be­the­
`most feasible option to solubilize paclitaxel for intra-
`venous­administration.­Likewise,­the­solvent­used­for­
`Docetaxel­is­another­poly-oxy-ethylated­surfactant,­
`polysorbate-80.6 Being biologically and pharmaco-
`logically­ active,­ these­ solvents­ are­ associated­ with­
`several­ major­ side­ effects­ such­ as­ hypersensitivity­
`reactions and neuropathies. They also impair tumor
`penetration, limiting the clinical effectiveness of
`solvent-based taxanes.5,6­ CrEL-paclitaxel­ formula-
`tion needs special infusion set to minimize exposure
`to­ di(2-ethylhexyl)phthalate­ (DHEP),­ which­ may­
`be leached from standard polyvinyl chloride sets.
`­Prolonged­ infusion­ times­ and­ premedications­ with­
`corticosteroids and antihistamine agents are required
`to­reduce­hypersensitivity­reactions.­­However,­minor­
`reactions­ still­ occur­ in­ about­ 40%­ of­ all­ patients­
`receiving­ solvent-based­ taxanes­ and­ nearly­ 3%­
`develop potentially life-threatening reactions.6­CrEL­
`is­ also­ shown­ to­ cause­ neutropenia­ and­ prolonged­
`peripheral neuropathy related to axonal degenera-
`tion.­Fluid­retention,­a­toxicity­commonly­seen­with­
`docetaxel has been attributed in part due to alteration
`of­membrane­fluidity­by­polysorbate-80.6,8­­Formation­
`of­ large­ polar­ micelles­ of­ CrEL-paclitaxel­ in­ the­
`plasma compartment can cause entrapment of the
`drug­ leading­ to­ non-linear­ pharmacokinetics.5 This
`alters the pharmaco-dymanic characteristics of the
`solubilized drug resulting in a substantial increase
`in­ systemic­ exposure­ with­ concomitantly­ reduced­
`systemic­clearance­placing­patients­at­risk­for­severe­
`systemic toxicities. This drug entrapment phenom-
`enon­which­decreases­the­duration­of­drug­exposure­
`partly­explains­why­the­attempts­to­improve­efficacy­
`of­CrEL-paclitaxel­by­utilizing­doses­higher­than­the­
`standard-of-care­dose­(175­mg/m2 over 3 hours every
`3­weeks)­have­been­unsuccessful.9­More­frequent­dos-
`ing­(such­as­weekly­administration)­which­may­lead­
`to increased duration of exposure, has demonstrated
`improved­efficacy­in­both­adjuvant/­neoadjuvant­and­
`metastatic settings.10
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`To address these limitations of solvent-based tax-
`anes and to improve their therapeutic index, various
`solvent-free formulations and delivery systems such
`as liposomal encapsulated paclitaxel, paclitaxel vita-
`min­E­emulsion­and­polymer­microsphere­formula-
`tion­of­paclitaxel­were­investigated­but­with­limited­
`success.6,8­ First­ successful­ attempt­ to­ formulate­ a­
`solvent-free taxane has been the development of
`nab-paclitaxel. The nano-particle protein platform
`utilizes the natural properties of albumin to increase
`drug delivery to the tumor and eliminates the need for
`solvents.
`Nanomedicine and nab-Technology
`Nanomedicine is the medical application of molecular
`nab-technology,­a­new­area­of­science­that­involves­
`working­with­small­scale­materials­and­devices­that­
`are at the nanometer level (10-9­of­a­meter).­A­few­
`examples of the development by this discipline include
`liposomes, dendrimers, super paramagnetic nanopar-
`ticles and polymer-based platforms.11 Albumin has a
`number­of­features­that­make­it­an­ideal­drug­delivery­
`system. It is a natural carrier of endogenous hydropho-
`bic molecules such as vitamins, hormones and other
`water-insoluble­plasma­substances­that­are­bound­in­
`a reversible non-covalent manner. Albumin plays an
`important role in endothelial transcytosis of protein-
`bound and unbound plasma constituents mainly by
`binding­to­a­cell-surface­60­kDa­glycoprotein­recep-
`tor­ (gp60)­ on­ the­ endothelial­ cell­ membrane.­ This­
`leads­to­activation­of­caveolin-1,­a­major­component­
`of membrane vesicles, resulting in receptor medi-
`ated internalization of the albumin-drug complex into
`caveolae (small invaginations of plasma membrane).
`Subsequently,­ caveolae­ transports­ the­ albumin-drug­
`conjugate­ to­ the­ extracellular­ space,­ including­ the­
`tumor­interstitium.­SPARC­(secreted protein, acidic
`and rich in cysteine),­which­is­believed­to­be­selec-
`tively secreted by the tumors, binds to albumin-drug
`complex­with­the­resultant­release­of­the­drug­in­the­
`vicinity of tumor cells.11,12
`Preclinical and Clinical Evaluation
`of nab-Paclitaxel
`Comparative intratumoral and antitumoral activity of
`nab-paclitaxel has been demonstrated to be greater
`than­CrEL-paclitaxel­and­docetaxel­in­­multiple­tumor­
`types using preclinical models.12,13­Desai­et­al13 using
`
`Breast Cancer: Basic and Clinical Research 2011:5
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`nab-paclitaxel in breast cancer: safety and efficacy
`
`radiolabeled­ paclitaxel­ in­ mice­ with­ xenografts,­
`showed­ that­ nab-paclitaxel­ was­ significantly­ less­
`toxic;­LD50­(lethal­dose,­50%)­values­and­maximum­
`tolerated­dose­(MTD)­for­nab-paclitaxel­and­CrEL-
`paclitaxel­ were­ 47­ and­ 30­ mg/kg/day,­ and­ 30­ and­
`13.4­mg/kg/day,­respectively.­At­equal­doses,­intratu-
`moral­paclitaxel­accumulation­was­found­to­be­33%­
`higher for nab-paclitaxel. In live human umbilical vas-
`cular­endothelial­cells­(HUVEC),­endothelial­binding­
`and transport across the endothelial cell monolayer
`was­significantly­higher­(9.9­fold­and­4.2­fold­respec-
`tively)­ with­ nab-paclitaxel­ and­ this­ difference­ was­
`abrogated by methyl β-cyclodextrin,­a­known­inhibi-
`tor­of­endothelial­gp60­receptor­and­­caveolar-mediated­
`transport.13 Zhou et al recently reported similar anti-
`tumoral­responses­with­­nab-paclitaxel in hepatocel-
`luar carcinoma (HCC) cell lines.14 In a panel of HCC
`cell lines studied, nab-paclitaxel­showed­an­effective­
`IC50­ dose­ at­ 15-fold­ lower­ than­ paclitaxel­ or­ doc-
`etaxel alone, and ∼450-fold­less­compared­to­doxo-
`rubicin.­SPARC,­a­type­of­caveolin-1­has­a­sequence­
`homology­with­gp60,­leads­to­its­binding­to­albumin.­
`It is over expressed in several tumor types includ-
`ing­ breast­ cancer.­This­ interaction­ between­ SPARC­
`and albumin has been suggested to be the reason for
`enhanced­uptake­and­intra-tumoral­accumulation,­and­
`also­a­possible­role­for­SPARC­as­a­bio-marker­for­
`nab-paclitaxel effectiveness.12 These data provided
`the preclinical evidence to advance the drug to clini-
`cal studies.
`Phase 1 and Pharmacokinetic Studies
`Three different dose schedules of nab-paclitaxel
`have­been­evaluated­in­Phase­I­and­pharmacokinetics­
` studies. In a study by Ibrahim et al,15­19­patients­with­
`advanced solid tumors received nab-paclitaxel as a
`30­minute­infusion­given­every­3­weeks­without­pre-
`medication­using­doses­from­135­to­375­mg/m2. No
`infusion­related­acute­hypersensitivity­reactions­were­
`noted during the drug administration. Hematological
`toxicity­was­mild­and­not­cumulative.­At­the­highest­
`dose­studied­(level­3,­375­mg/m2), dose-limiting tox-
`icity­occurred­in­3­of­6­patients­and­consisted­of­sen-
`sory­ neuropathy­ (3­ patients),­ stomatitis­ (2­ patients)­
`and­ superficial­ keratopathy­ (2­ patients).­ The­ MTD­
`was­determined­to­be­300­mg/m2, substantially higher
`than­ the­ typical­ dose­ used­ with­ CrEL-paclitaxel.­
`Pharmacokinetic­ analyses­ revealed­ whole­ blood­
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`vishnu and Roy
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`paclitaxel concentrations and area under the curve
`(AUC)­values­to­increase­linearly­over­the­dose­range­
`of­135–300­mg/m2­unlike­the­non-linear­kinetics­of­
`solvent-based paclitaxel.
`In another phase 1 trial reported by Nyman
`et al,16­39­patients­with­advanced­non-hematological­
`malignancies received nab-paclitaxel­ without­ pre-
`medication­ at­ a­ dose­ levels­ from­ 80­ to­ 200­ mg/m2
`as­ a­ 30-minute­ infusion­ once­ a­ week­ for­ 3­ weeks­
`in each monthly cycle. One third of patients
`received $6­ cycles.­ After­ enrollment­ of­ the­ first­
`cohort,­ patients­ were­ enrolled­ into­ 1­ of­ 2­ cohorts,­
`‘lightly’ and ‘heavily’ pretreated based on the extent
`of­prior­exposure­to­­chemotherapy.­MTDs­for­these­
`two­cohorts­were­150­mg/m2­and­100­mg/m2; dose-
`limiting­ toxicities­ were­ grade­ 3­ peripheral­ neu-
`ropathy and grade 4 neutropenia respectively. The
`pharmacokinetics­was­again­noted­to­be­linear­and­
`there­ were­ no­ dose-dependant­ changes­ in­ plasma­
`­clearance.­ Partial­ response­ (PR)­ was­ observed­ in­
`patients­previously­treated­with­CrEL-paclitaxel.
`A randomized cross over study comparing the phar-
`macokinetics­of­nab-paclitaxel­and­ CrEL-paclitaxel­
`was­reported­by­Gardner­et­al.17­Seventeen­patients­
`with­locally­advanced­or­metastatic­solid­tumors­that­
`were­ likely­ to­ be­ responsive­ to­ taxanes­ were­ ran-
`domized to receive nab-paclitaxel­(260­ mg/m2 as a
`30-minute­infusion)­or­CrEL-paclitaxel­(175­mg/m2
`as a 3 hour infusion). Patients crossed over to the
`alternate treatment after 1st cycle. Thereafter, patients
`received­treatments­with­260­mg/m2 of nab-paclitaxel
`every­3­weeks.­Pharmacokinetic­studies­were­carried­
`out­for­the­first­cycle­of­CrEL-paclitaxel­and­the­first­
`two­ cycles­ of­ nab-paclitaxel. The total drug expo-
`sure­was­comparable­between­the­two­formulations­
`and­ the­ mean­ fraction­ of­ unbound­ paclitaxel­ was­
`significantly­higher­with­nab-paclitaxel compared to
`CrEL-paclitaxel­ (0.063­ ±­ 0.021­ vs.­ 0.024­ ±­ 0.009;­
`P , 0.001). This study purports that systemic expo-
`sure­ to­ unbound­ paclitaxel­ would­ lead­ to­ increased­
`tumoral­ uptake­ thereby­ resulting­ in­ an­ augmented­
`anti-tumor­efficacy­compared­to­CrEL-paclitaxel.
`In a phase 1 study of three different schedules of
`nab-paclitaxel­ in­ combination­ with­ carboplatin,18
`41­ heavily­ pretreated­ patients­ with­ advanced­ solid­
`tumors received nab-paclitaxel­and­carboplatin­AUC­
`of­ 6­ on­ day­ 1.­ Group­A­ received­ nab-paclitaxel at
`doses­ranging­from­220­to­340­mg/m2 on day 1 every
`
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`
`21­days;­group­B­received­nab-paclitaxel at 100 or
`125­mg/m2­on­days­1,­8,­and­15­every­28­days;­and­
`group C received nab-paclitaxel­125­or­150­mg/m2 on
`days­1­and­8­every­21­days.­MTD­of­nab-paclitaxel
`in­ combination­ with­ carboplatin­ was­ 300,­ 100,­ and­
`125­mg/m2­in­groups­A,­B,­and­C,­respectively­with­
`myelosuppression­was­the­primary­dose­limiting­tox-
`icity in all the groups.
`In a recent phase 1 study reported by Chien et al,19
`vascular-priming­chemosensitization­with­2-day­pulse­
`of­high­dose­lapatinib­followed­by­weekly­infusion­
`of­100­mg/m2 nab-paclitaxel­treatment­was­investi-
`gated­in­25­patients­with­advanced­solid­tumors.­72%­
`of­ these­ patients­ were­ previously­ taxane-refractory.­
`Maximum­tolerated­dose­of­lapatinib­was­defined­as­
`5250­mg/day­in­divided­doses.­The­dose-limiting­tox-
`icities­were­grade­3­vomiting­and­grade­4­­neutropenia.­
`65%­ of­ evaluable­ patients­ had­ a­ partial­ or­ stable
`response on this therapy.
`Phase II Studies
`Based on the results of phase 1 study,15 Ibrahim et al
`investigated nab-paclitaxel in a multicenter phase II
`study to evaluate safety and antitumor activity in patients
`with­MBC.20­63­women­with­confirmed­and­measur-
`able­MBC­received­300­mg/m2 of nab-paclitaxel over
`30­minutes­every­3­weeks.­48­patients­had­received­
`prior­chemotherapy;­39­patients­had­received­no­prior­
`treatment­ for­ metastatic­ disease.­ Median­ number­ of­
`treatments­was­6­cycles.­Overall­response­rate­(ORR),­
`which­ was­ the­ primary­ end­ point­ of­ the­ study,­ was­
`48%­for­all­patients­and­64%­for­those­receiving­nab-
`paclitaxel­as­first­line­treatment.­Median­time­to­pro-
`gression­(TTP)­was­26.6­weeks­and­median­OS­was­
`63.6­weeks.­No­severe­hypersensitivity­reactions­were­
`reported­ despite­ lack­ of­ premedication.­ Toxicities­
`noted­ were­ typical­ of­ paclitaxel­ and­ included­ grade­
`4­neutropenia­(24%)­and­grade­3­sensory­neuropathy­
`(11%)­and­grade­4­febrile­neutropenia­(5%).
`Blum et al21­ reported­ the­ benefit­ of­ weekly­ nab-
`paclitaxel­ in­ patients­ with­ MBC­ whose­ disease­ had­
`failed conventional taxane treatment. Taxane failure
`was­defined­as­metastatic­disease­progression­during­
`taxane­therapy­or­relapse­within­12­months­of­adjuvant­
`taxane­therapy.­Patients­received­100­mg/m2 (n =­106)­
`or­125­mg/m2 (n =­75)­on­days­1,­8,­and­15­of­28­day­
`cycle.­ Response­ rates­ were­ 14%­ and­ 16%­ for­ the­
`100­mg/m2­and­125­mg/m2­cohorts,­respectively­with­
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`nab-paclitaxel in breast cancer: safety and efficacy
`
`Table 1. nab-PACLiTAXeL: AT A GLANCe37
`nab-PACLITAXEL: AT A GLANCE37
`Mechanism of action
`Antimicrotubule agent, promote microtubules assembly from tubulin dimers and stabilize microtubules to prevent
`depolymerization. This stability causes inhibition of the normal dynamic reorganization of the microtubules which is
`necessary for important interphase and mitotic functions in the cells
`Dosing and administration
`260 mg/m2
`intravenous infusion over 30 minutes once every 3 weeks
`Pharmacokinetics
`Distribution: extensive extra-vascular distribution and/or tissue binding; does not penetrate blood brain barrier
`Protein binding: 89% to 98%
`Metabolism: Hepatic; P450 (CYP2C8 and CYP3A4)
`excretion: Fecal (20%); renal (4%)
`elimination half life: 27 hours
`Side effects
`Common:
`Cardiovascular: abnormal eKG (60%), edema (10%)
`Dermatologic: alopecia (90%)
`Gastrointestinal: diarrhea (27%), nausea (30%), vomiting (18%)
`Hematologic: Anemia (33%), Neutropenia, (any grade, 80%)
`Hepatic: raised transaminases (39%), raised alkaline phosphatase (36%)
`Neurologic: asthenia/myalgia/fatigue (47%), sensory neuropathy (any grade, 71%)
`Ophthalmic: visual disturbance (13%)
`Renal: raised serum creatinine (11%)
`Respiratory: dyspnea (12%)
`Serious:
`Cardiovascular: cardiac arrest, cerebrovascular accident, supraventricular tachycardia, transient ischemic attack (3%)
`Hematologic: severe anemia (1%), bleeding (2%), febrile neutropenia (2%), neutropenia, grade 4 (9%),
`severe thrombocytopenia (,1% )
`Neurologic: severe sensory neuropathy (10%)
`Special precaution
`Paclitaxel has been shown to be clastogenic, teratogenic and fetotoxic and should not be used in pregnancy. Men should
`be advised not to father a child while receiving treatment. it is not known if paclitaxel is excreted in human milk; however,
`it is recommended that nursing should be discontinued during therapy
`Synonyms
`ABi-007, albumin-bound paclitaxel
`Trade name
`ABRAXANe (Abraxis Bioscience)
`
`an­additional­12%­and­21%­of­patients,­respectively,­
`having stable­ disease­ (SD)­ for­ $16­ weeks.­ Median­
`progression-free­ survival­ (PFS)­ (3­ vs.­ 3.5­ months)­
`and­median­survival­(9.2­vs.­9.1­months)­were­simi-
`lar­for­the­two­dose­cohorts;­Survival­was­similar­for­
`responding­ patients­ and­ those­ with­ SD.­ No­ severe­
`hypersensitivity­reactions­were­reported­and­grade­4­
`neutropenia­occurred­in­less­than­5%­of­patients.
`Mirtsching­et­al­recently­reported­the­efficacy­and­
`safety­of­weekly­nab-paclitaxel­as­a­first-line­therapy­
`of­MBC.22 nab-paclitaxel­(125­mg/m2)­was­adminis-
`tered­by­30-minute­intravenous­infusion­weekly­for­
`3­of­4­weeks.­Patients­whose­tumors­overexpressed­
`
`HER2­ also­ received­ trastuzumab.­ 72­ patients­ were­
`enrolled;­22­patients­had­HER2+ breast cancer. The
`ORR­was­42.2%;­5­patients­had­a­CR­and­22­patients­
`had­a­PR.­Additionally,­17­patients­experienced­SD,­
`providing­a­disease­control­rate­(CR­+­PR­+­SD)­of­
`68.8%.­Patients­with­HER2+­disease­had­an­ORR­of­
`52.4%;­the­ORR­was­38.1%­in­the­HER2-­population.­
`Median­PFS­was­14.5­months­and­survival­rates­at­
`1­year­and­2­years­were­69%­and­62%,­respectively.­
`The­ most­ commonly­ observed­ toxicities­ were­ pain­
`(64%),­ fatigue­ (58%),­ sensory­ neuropathy­ (54%),­
`infection­ (46%),­ nausea­ (38%),­ alopecia­ (33%),­
`and­anemia­(33%).­The­investigators­concluded­that­
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`vishnu and Roy
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`weekly­­nab-paclitaxel­had­a­favorable­safety­profile­
`and­ was­ well­ tolerated­ as­ a­ first-line­ treatment­ for­
`MBC­including­patients­with­HER2+ disease.
`Roy­et­al,23 reported a multicenter phase II study
`of­weekly­nab-paclitaxel­in­combination­with­gem-
`citabine­ in­ patients­ with­ MBC.­ In­ this­ open-label,­
`one-stage­trial,­50­patients­with­previously­untreated­
`MBC­were­treated­with­125­mg/m2 of nab-paclitaxel
`and­1000­mg/m2 of gemcitabine­on­days­1­and­8­of­
`a­21­day­cycle­until­disease­progression.­40­patients­
`(80%)­ had­ visceral­ involvement­ and­ 30­ patients­
`(60%)­ had­ $3­ sites­ of­ metastases.­ ORR­ was­ 50%­
`(4­ complete­ responses,­ 8%;­ 21­ partial­ responses,­
`42%).­Median­PFS­was­7.9­months.­PFS­and­OS­at­
`6­months­was­60%­and­92%­respectively.­Neutrope-
`nia­ was­ the­ most­ common­ toxicity­ (grade­ 3:­ 43%,­
`grade­4:­12%).­Grade­3–4­neuropathy­was­noted­in­
`only­4­patients­(8%).
`Gradishar­ et­ al24 reported a randomized multi-
`center phase II study comparing nab-paclitaxel­with­
`docetaxel­ as­ first­ line­ treatment­ in­ patients­ with­
`MBC.­300­previously­untreated­MBC­patients­were­
`randomized to 3 different nab-paclitaxel treatment
`­schedules—300­ mg/m2­ every­ 3­ weeks­ (n­ =­ 76),­
`150­mg/m2­weekly­(n­=­74)­and­100­mg/m2­weekly­
`(n =­76).­Docetaxel­dose­was­100­mg/m2 once every
`3­weeks­(n­=­74).­43%­of­patients­had­received­prior­
`adjuvant­ or­ neoadjuvant­ chemotherapy.­ 150­ mg/m2
`weekly­ nab-paclitaxel­ demonstrated­ significantly­
`longer­ PFS­ than­ docetaxel­ (12.5­ vs.­ 7.5­ months).­
`On­the­basis­of­independent­radiologist­review,­both­
`150­mg/m2­(49%)­and­100­mg/m2­(45%)­weekly­nab-
`paclitaxel­demonstrated­a­higher­ORR­than­docetaxel­
`(35%),­but­this­did­not­reach­statistical­significance.­
`This­ trend­ was­ supported­ by­ statistically­ significant­
`investigator­ ORR­ for­ both­ weekly­ nab-paclitaxel
`doses­versus­docetaxel.­Every­3­weekly­nab-paclitaxel
`versus­docetaxel­was­not­different­in­terms­of­ORR­or­
`PFS.­Grade­3/4­fatigue,­neutropenia­and­febrile­neutro-
`penia­were­less­frequent­in­all­nab-paclitaxel arms and
`the­frequency­and­grade­of­peripheral­neuropathy­was­
`similar in all treatment groups but this resolved more
`rapidly­after­treatment­withdrawal­with­nab-paclitaxel
`compared­with­patients­who­received­docetaxel.
`Robert­et­al­in­a­pilot­study­reported­the­safety­of­
`sequential­adjuvant­dose-dense­(every-2-week)­doxoru-
`bicin­(A)­plus­cyclophasphamide­(C)­­followed­by­dose-
`dense nab-paclitaxel for early-stage breast cancer.25
`
`58
`
`Women­ with­ high­ risk­ breast­ ­cancer­ (T1-3,­ N1-2,­
`or­ N0­ disease­ with­ tumors­ that­ were­ .2­ cm)­ were­
`enrolled and received four cycles of dose-dense A
`(60­mg/m2)­plus­C­(600­mg/m2)­with­peg-filgrastim,­
`followed­ by­ dose-dense­ nab-paclitaxel­(260­ mg/m2)
`with­peg-filgrastim­given­as­needed.­Endpoints­were­
`adverse­ events­ (AEs),­ including­ myelosuppression.­
`30 patients received four cycles of dose-dense AC
`with­ no­ unanticipated­AEs,­ one­ withdrew­ after­AC­
`therapy.­Of­29­women­who­began­nab-paclitaxel ther-
`apy,­27­received­all­4­doses­(mean­cumulative­dose,­
`959­mg/m2); one discontinued nab-paclitaxel­after­2­
`doses due to unacceptable­AEs.­4­patients­had­a­grade­
`3 nab-paclitaxel related neuropathy (no grade 4 event).
`Of­ 29­ patients,­ 34%­ received­ ­peg-filgrastim­ during­
`nab-paclitaxel­therapy­and­31%­had­a­ nab-paclitaxel
`treatment delay, mainly due to hematologic toxicity.
`Based­ on­ Kaplan–Meier­ probability­ estimates,­ the­
`percentage of patients having #1 grade neuropathy
`at­the­end­of­treatment,­2,­and­8­months­after­treat-
`ment­were­59,­79,­and­97%.­The­authors­concluded­
`that­administering­adjuvant­dose-dense­AC­followed­
`by­260­mg/m2­dose-dense­nab-paclitaxel­was­feasible­
`in­women­with­early-stage­BC,­with­manageable­AEs.­
`Most­patients­had­#1­grade­neuropathy­2­months­after­
`treatment completion.
`nab-paclitaxel­ administered­ sequentially­ with­
`anthracycline­has­also­been­evaluated­in­a­neoadjuvant­
`setting for locally advanced breast cancer (LABC)
`in­ a­ phase­ II­ study­ by­ Robidoux­ et­ al26­ 66­ patients­
`with­LABC­but­without­prior­treatment­and­regard-
`less­of­hormone­receptor­or­HER2­status­were­treated­
`with­ nab-paclitaxel­ weekly­ for­ 12­ weeks­ followed­
`by­­5-fluorouracil,­epirubicin­and­cyclophosphamide­
`(FEC)­ every­ 3­ weeks­ for­ 4­ cycles.­ ­Trastuzumab­
`was­ allowed­ in­ HER2-positive­ (HER2+) patients.
`­Sixty-three­patients­completed­4­cycles­of­albumin-
`bound­ paclitaxel­ following­ which­ 58­ completed­
`4­ cycles­ FEC.­ 17­ of­ 19­ HER2+ patients received
`­trastuzumab.­ Pathologic­ complete­ response­ (pCR),­
`the­primary­objective­of­the­study,­was­29%­(19­of­
`65).­For­the­HER2+­subset,­the­pCR­was­58%­(11­of­
`19).­Both­nab-paclitaxel­and­FEC­were­well­­tolerated.­
`The­most­significant­toxicities­were­grade­2/3­neurop-
`athy­(16%)­with­nab-paclitaxel­and­grade­3/4­febrile­
`neutropenia­(7%)­with­FEC.
`These studies suggest that nab-paclitaxel alone
`or­in­combination­with­other­therapeutic­agents­has­
`
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`

`a­ significant­ activity­ in­ patients­ with­ breast­ ­cancer,­
`including­ those­ previously­ treated­ with­ taxanes­
`and/or­anthracyclines,.­These­studies­are­summarized­
`in Table­2.­Because­of­its­efficacy,­ease­of­administra-
`tion­and­a­favorable­toxicity­profile,­nab-paclitaxel is
`currently­being­evaluated­in­combination­with­other­
`cytotoxic or targeted agents in breast cancer and other
`solid tumors (Table 3).
`Phase III Studies
`Based on the favorable phase I and phase II data,
` nab-paclitaxel’s­ antitumor­ efficacy­ and­ safety­
`was­ compared­ to­ CrEL-­ paclitaxel­ in­ a­ pivotal,­
` multi-national randomized phase III trial conducted
`at­70­sites­in­5­countries.27­Of­the­460­women­with­
`MBC­enrolled­in­the­study,­454­were­randomized­to­
`3-weekly­ cycles­ of­ either­ nab-paclitaxel at a dose
`of­ 260­ mg/m2­ intravenously­ over­ 30­ minutes­ with-
`out premeditation (n =­229)­or­CrEL-paclitaxel­at­a­
`dose­of­175­mg/m2­intravenously­over­3­hours­with­
`corticosteroid and antihistamine premedications
`(n =­225).­The­large­majority­of­patients­had­more­
`than­three­metastatic­lesions­(76%),­visceral­disease­
`(79%),­ prior­ chemotherapy­ (86%),­ and­ progression­
`after­first-line­therapy­for­metastatic­disease­(59%).­
`About half of the patients in each group received at
`least­6­cycles­of­treatment.­Actual­delivered­paclitaxel­
`dose-intensity­was­49%­higher­in­the­­nab-paclitaxel
`group­ than­ in­ the­ CrEL-paclitaxel­ group­ (85.13­ vs.­
`57.02­ mg/m2/week).­ nab-paclitaxel demonstrated
`significantly­ higher­ response­ rates­ compared­ with­
`CrEL-paclitaxel­(33%­vs.­19%,­P = 0.001). Patients
`who­received­nab-paclitaxel­as­first­line­and­second­
`line­ or­ greater­ treatment­ had­ an­ ORR­ of­ 42%­ and­
`
`nab-paclitaxel in breast cancer: safety and efficacy
`
`27%­compared­to­27%­and­13%­with­CrE-paclitaxel,­
`respectively.­TTP­was­also­significantly­longer­with­
`nab-paclitaxel­ for­ all­ patients­ (23­ vs.­ 16.9­ weeks;­
`hazard­ratio­[HR]­=­0.75;­P =­0.006)­and­among­those­
`receiving­ second­ line­ therapy­ or­ greater­ (20.9­ vs.­
`16.1­weeks;­HR­= 0.73; P =­0.02).­There­was­no­sig-
`nificant­difference­in­median­OS­among­all­patients­
`between­ the­ nab-paclitaxel­ and­
`­CrEL-paclitaxel­
`groups­(65­vs.­55.7­weeks;­P =­0.374);­however­in­the­
`patients­who­received­nab-paclitaxel as second-line or
`greater­therapy­had­a­significantly­longer­OS­(56.4­vs.­
`46.7­weeks;­HR­= 0.73; P =­0.024).­The­incidence­of­
`grade­4­neutropenia­was­lower­in­nab-paclitaxel group
`compared­ to­ CrEL-paclitaxel­ group­ (9%­ vs.­ 22%)­
`despite­a­49%­higher­paclitaxel­dose.­Febrile­neutro-
`penia­was­uncommon­(,2%),­and­the­incidence­did­
`not­differ­between­the­two­study­arms.­­Interestingly,­
`grade­ 3­ sensory­ ­neuropathy­ was­ more­ common­ in­
`nab-paclitaxel­arm­than­in­the­­CrEL-paclitaxel­arm­
`(10%­vs.­2%)­but­was­easily­managed­and­improved­
`rapidly­ to­ grade­ 1–2­ in­ a­ median­ of­ 22­ days.­ No­
`severe­hypersensitivity­reactions­occurred­with­nab-
`paclitaxel despite the absence of premedication and
`shorter administration time.
`Similar­results­were­reported­from­a­phase­III­trial­
`comparing nab-paclitaxel­with­CrEL-paclitaxel­in­210­
`Chinese­patients­with­MBC.28­Patients­were­equally­
`randomized to receive either nab-paclitaxel­260­mg/
`m2­over­30­min­every­3­weeks­with­no­premedica-
`tion­ or­ CrEL-paclitaxel­ 175­ mg/m2 over 3 hours
`every­ 3­ weeks­ with­ standard­ premedication.­ ORR­
`was­52%­in­the­nab-paclitaxel­group­and­27%­in­the­
`­CrEL-paclitaxel­group­(P ,­0.001).­Median­TTP­(7.6­
`months­ vs.­ 5.7­ months;­ p­ =­ 0.03)­ and­ median­ PFS­
`
`Table 2. Summary table of Phase ii Clinical trial results.
`Median PFS (months)
`Study
`n
`ORR
`Phase II studies assessing the activity of nab-paclitaxel in metastatic breast cancer
`ibrahim et al
`63
`48% (all patients)
`6.2*
`64% (first line treatment)
`14% (100 mg/m2)
`16% (125 mg/m2)
`50%
`45% (100 mg/m2/q week)
`49% (150 mg/m2/q week)
`37% (300 mg/m2/q 3 weeks)
`Notes: *Time to progression; **in combination with gemcitabine.
`Abbreviations: ORR, overall response rate; PFS, progression-free survival; NR, not reached.
`
`Blum et al
`
`Roy et al**
`Gradishar et al
`
`181
`
`50
`300
`
`3 (100 mg/m2)
`3.5 (125 mg/m2)
`7.9
`12.8 (100 mg/m2/q week)
`12.9 (150 mg/m2/q week)
`11 (300 mg/m2/q 3 weeks)
`
`Breast Cancer: Basic and Clinical Research 2011:5
`
`Median survival
`
`Ref
`
`14.6 months
`
`9.2 months
`
`NR
`NR
`
`20
`
`21
`
`23
`24
`
`59
`
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`

`

`Compliance and safety
`
`Sep-10
`
`Adjuvant
`
`Capectabine
`
`Abbreviations: pCR, pathologic complete response; PFS, progression free survival; pK, pharmacokinetics; ORR, overall response rate; IBC, inflammatory breast cancer.
`NCT01204437
`
`vishnu and Roy
`
`PFS
`pCR
`
`pCR
`Tumor response
`
`pCR
`
`Safety and efficacy
`
`pCR
`
`Safety and efficacy
`
`PFS
`
`ORR
`pCR
`PFS
`PFS
`Feasibility and toxicity
`
`PFS
`pCR
`pCR
`pCR
`
`pK and toxicity
`
`pCR
`
`Safety and efficacy
`
`PFS
`
`Safety and efficacy
`Toxicity and response
`pCR
`
`Sep-10
`Dec-09
`
`Jul-09
`Jul-07
`
`Mar-09
`
`Jan-09
`
`Oct-08
`
`Sep-08
`
`Aug-08
`
`Jul-08
`May-08
`Apr-08
`Apr-08
`Feb-08
`
`Feb-08
`Feb-08
`Feb-08
`Feb-08
`
`Feb-08
`
`May-07
`
`May-07
`
`May-07
`
`May-07
`Feb-08
`Nov-06
`
`First line
`Neoadjuvant
`
`Neoadjuvant
`First line
`
`Neoadjuvant
`
`Second line
`
`Neoadjuvant
`
`First line
`
`First line
`line
`First or second
`Neoadjuvant
`First line
`First line
`Adjuvant
`
`Neoadjuvant
`Neoadjuvant
`Neoadjuvant
`Neoadjuvant
`line
`First or second
`
`Neoadjuvant
`line
`First or second
`
`Second line
`
`Second line
`First line
`Neoadjuvant
`
`Primary endpoint
`
`Start date
`
`Sequence
`
`Carboplatin
`Panitumumab and carboplatin
`
`Trastuzumab
`everolimus (RAD001)
`doxorubicin, cyclophosphamide
`Carboplatin, bevacizumab,
`
`imiquimod
`doxorubicin, cyclophosphamide
`Carboplatin, bevacizumab,
`
`Azacitidine
`
`Bevacizumab, erlotinib
`
`Lapatinib
`Carboplatin and bevacizumab
`Gemcitabine, Bevacizumab
`Carboplatin, bevacizumab
`Cyclophosphamide
`or bevacizumab
`Carboplatin and trastuzumab
`Carboplatin, trastuzumab
`Carboplatin, trastuzumab
`Carboplatin, vorinostat
`
`Single agent nab-paclitaxel
`
`Trastuzumab, vinorelbine
`
`Carboplatin and bevacizumab
`
`Bevacizumab
`
`Pemetrexed
`Single agent nab-paclitaxel
`Capecitabine
`
`NCT00470548
`NCT00456846
`NCT00397761
`nab-Paclitaxel in breast cancer: active phase II trials36
`Study identifier
`Table 3. On-going Phase ii c