1.Introduction
2.Efficacy and safety
3.
Expert opinion
Drug Safety Evaluation
Safety and efficacy evaluation of albumin-bound paclitaxel
Sara Cecco,Maria Aliberti,Paolo Baldo,Elisa Giacomin &Roberto Leone ?
?
“GB Rossi University Hospital”,Department of Public Health and Community Medicine,Verona,Italy
Introduction:Nanoparticle albumin-bound paclitaxel (nab-paclitaxel)is a novel solvent-free formulation of paclitaxel,which was developed to avoid toxicities associated with Cremophor EL òvehicle used in solvent-based pacli-taxel.It is approved as monotherapy for treatment of metastatic breast cancer (MBC)in Europe and the US;in combination therapy for non-small-cell lung cancer (NSCLC)and for first-line treatment of advanced pancreatic cancer (PC)only in the US.The European Medicines Agency has recently released only a positive opinion for use of nab -paclitaxel in PC.
Areas covered:This review reports the clinical findings and the safety data of nab-paclitaxel for MBC,NSCLC and PC.
Expert opinion:In MBC,nab-paclitaxel has demonstrated a good safety and an efficacy profile compared with other taxanes,but no strong data on over-all survival are available.Considering the role of markers or predictive factors for nab-paclitaxel effectiveness in the metastatic setting would be useful.In PC,nab-paclitaxel and gemcitabine represent a new therapeutic choice with significant improvement in survival.In a Phase III study with NSCLC patients,nab-paclitaxel showed better results in a subgroup of patients with squamous histology,for whom results with conventional therapies are still poor and improved therapeutic options are needed.
Keywords:adverse drug reaction,albumin-bound paclitaxel,metastatic breast cancer,pancreatic cancer,squamous lung cancer
Expert Opin.Drug Saf.(2014)13(4):511-520
1.
Introduction
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel)(Box 1)is a novel formula-tion of paclitaxel in which the insoluble drug is bound to albumin to form a stable,water-soluble,negatively charged nanoparticle.The use of solubilising agents has been associated with toxic response,including hypersensitivity reactions and pro-longed sensory neuropathy,as well as with a negative impact on the therapeutic index of paclitaxel.
Based on the confirmation of the efficacy and manageable toxicity in the meta-static setting,nab-paclitaxel is actually licensed by the European Medicines Agency (EMA)and FDA as monotherapy for the treatment of metastatic breast cancer (MBC);furthermore,FDA has approved nab-paclitaxel in advanced non-small-cell lung cancer (NSCLC)and pancreatic cancer (PC).According to recent data,EMA released a positive opinion for the therapeutic use in PC at the end of November 2013.
In this review,we focus on the safety,efficacy and clinical utility of nab-paclitaxel in different types of tumours.
10.1517/14740338.2014.893293?2014Informa UK,Ltd.ISSN 1474-0338,e-ISSN 1744-764X
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2.
Efficacy and safety
2.1
Development of nab -paclitaxel
The active substance in nab-paclitaxel formulation is pacli-taxel,a mitotic inhibitor that acts via microtubule stabilisa-tion.Paclitaxel was initially isolated from the bark of the Pacific yew tree,Taxus brevifolia [1].More recently,a semi-synthetic process has been developed and paclitaxel is now directly extracted from plant cell cultures,then purified by chromatography and isolated by crystallisation.
Since paclitaxel is highly insoluble in water,in order to allow intravenous administration the formulation of this agent requires emulsification with polyoxyethylated castor oil (Cremophor EL ò:CrEL)and ethanol.The solvents used in paclitaxel formulation are biologically and pharmacologi-cally active,which makes the choice of materials for intrave-nous infusion complicated on one hand,and induces specific adverse response on the other.As a matter of fact,CrEL solubilises phthalates such as a plasticizer bis (2-ethyl-hexyl)phthalate (DEHP),which is released from standard intravenous tubing sets containing polyvinyl chloride (PVC).In order to avoid leached DEHP,which stimulates histamine release and results in hypersensitivity reaction,PVC --DEHP-free medical devices are necessary when pacli-taxel is administered.In addition,paclitaxel safety profile
includes peripheral,sensory and motor neuropathies associ-ated with the excipient used [2,3].
Many efforts have been made to develop a new formula-tion,in order to avoid the above-mentioned disadvantages derived from solvent-based taxanes.Protein-bound paclitaxel is an injectable formulation of paclitaxel.Albumin plays an important role in the delivery of hydrophobic molecules to target tissue,such as vitamins and hormones [4,5].
This albumin-bound drug is preferentially taken up by tumour tissue,primarily because it can pass more easily through the leaky capillary junctions in the tumour bed than through the normal vessels in healthy tissue [6].
2.2
Mechanisms of action
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation.This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network,which is essential for the vital interphase and mitotic cellular functions.This blocks progres-sion of mitosis,and prolongs the activation of the mitotic checkpoint that triggers apoptosis or reversion to the G-phase of the cell cycle without cell division [7,8].In addition,pacli-taxel induces abnormal arrays or ‘bundles’of microtubules
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throughout the cell cycle and multiple asters of microtubules during mitosis.
Nab-paclitaxel is prepared by high-pressure homogenisa-tion of paclitaxel in the presence of serum albumin,resulting in a colloidal suspension comprising nanoparticles with an average size of 130nm,that prevent the risk of capillary blockage after intravenous infusion [9,10].
Upon intravenous administration,the nanoparticles dissociate rapidly into soluble,albumin-bound paclitaxel complexes of approximately 10nm in size.Albumin is known to mediate endothelial caveolar transcytosis of plasma constit-uents,and in vitro studies demonstrated that the presence of albumin in nab-paclitaxel enhances the transport of paclitaxel across endothelial cells.The enhanced transendothelial caveo-lar transport is probably mediated by the gp-60albumin receptor,with an augmented accumulation of paclitaxel in the area of tumour due to the albumin-binding protein,secreted protein acidic rich in cysteine (SPARC)[11].
2.3
Pharmacokinetics
Paclitaxel delivered as nab-paclitaxel shows a linear pharmaco-kinetics:plasma levels of paclitaxel decline in a biphasic man-ner after intravenous administration of nab-paclitaxel,with a rapid first phase representing distribution to the peripheral tissue and a second slower phase of drug elimination.In a direct comparison of the pharmacokinetics of the formula-tions of paclitaxel at dose schedules commonly used in the clinic,the maximum concentration of paclitaxel was 6.5-fold higher for nab-paclitaxel than for CrEL-paclitaxel but the AUC was not significantly different for the two formulations notwithstanding the differences in administration dose,resulting in similar half-life elimination for paclitaxel in both groups of treatment [10,12].Presumably,this was because the total body clearance of the drug from plasma and the apparent volume of distribution were both approximately 50%higher for nab-paclitaxel than for CrEL-paclitaxel.The large volume of distribution for nab-paclitaxel suggests exten-sive extravascular distribution and/or tissue binding of paclitaxel.This seems to confirm the hypothesis that cremo-phor prevents the escape of paclitaxel from the vascular compartment and the distribution to tissues.2.4
Clinical application 2.4.1Efficacy in MBC
Breast cancer has the highest incidence and the second-highest mortality rate of any cancer in women worldwide.Only lung cancer kills more women every year [13].Although breast can-cer mortality has declined over the last two decades [13,14],approximately 30%of women initially diagnosed with an ear-lier stage of breast cancer will develop metastatic disease,which remains essentially incurable [15].Because of this,the medical community continues searching for novel agents that may lead to improvements in survival in patients with MBC.
Taxanes have been widely demonstrated to be among the most active cytotoxic drugs for the treatment of breast cancer and,since their advent,provided a novel chemotherapy option in the treatment of patients with MBC.
In the pivotal multinational Phase III trial that led to nab-paclitaxel approval in patients with MBC,460patients (454evaluable)were randomised to receive single agent nab-paclitaxel (260mg/m 2every 3weeks)or CrEL-paclitaxel (175mg/m 2every 3weeks)[16].Nab-paclitaxel was adminis-tered without premedication over 30min and CrEL-paclitaxel was administered over 3h with corticosteroid and antihista-mine premedication.However,8%of the nab-paclitaxel-treated patients received premedication for toxicity other than hypersensitivity.Treatment compliance of both groups was equally high with 96(nab-paclitaxel)or 94%(CrEL-paclitaxel)of patients receiving 90%of the protocol-specified dose despite a higher dose intensity of paclitaxel in the nab-paclitaxel group than in CrEL-paclitaxel group.Treatment discontinuation,dose reduction and dose delay due to adverse events were also infrequent in both treatment groups.
The large majority of patients had >3metastatic lesions (76%),visceral disease (79%),prior chemotherapy (86%)and progression after first-line therapy for metastatic disease (59%).
The overall response rates (ORR)for patients treated with nab-paclitaxel group and CrEL-paclitaxel group were 33and 19%(p <0.001),respectively,and in patients receiving first-line treatment the response rates were 42and 27%(p =0.029).Time to progression (TTP)was also significantly longer with nab-paclitaxel for all patients (23vs 16.9weeks;hazard ratio [HR]=0.75;p =0.006)and among those receiv-ing the drug as second-line or greater therapy (20.9vs 16.1weeks;HR =0.73;p =0.02).There was no significant difference in median overall survival (OS)among all patients between the two groups of treatment.
2.4.2
Efficacy in PC
In September 2013,the US FDA approved nab-paclitaxel in combination with gemcitabine as first-line treatment of patients with metastatic adenocarcinoma of pancreas.Over the years,a large number of cytotoxic and target therapies were evaluated in combination with gemcitabine in clinical trials,but almost all failed to further improve the survival in this patients setting.The advent of FOLFIRINOX regime represented a successful option but,because of related toxic-ities,it’s being used selectively [17].
The Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT)study was a multinational Phase III trial launched following the encouraging results of a Phase I/II trial of nab-paclitaxel plus gemcitabine in advanced PC.In the pivotal trial,842patients with metastatic PC and Karnofsky performance scores of 70or higher were randomised to receive nab-paclitaxel,125mg/m 2followed by gemcitabine,1000mg/m 2on days 1,8and 15every 28days or
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gemcitabine,1000mg/m 2weekly for 7weeks followed by 1week of rest,and then on days 1,8and 15every 4weeks thereafter.
Of the patients,43%had head of pancreas tumour,85%had liver metastasis,7%had undergone a previous Whipple procedure and 17%had biliary stent at enrollment.Patients who received nab-paclitaxel-gemcitabine did much better than those in the gemcitabine-only arm,with median survival of 8.5versus 6.7months (HR:0.72;p <0.001),1-year sur-vival of 35versus 22%,2-year survival of 9versus 4%and objective response rate of 23versus 7%,respectively.The median progression-free survival (PFS)was 5.5months in the nab-paclitaxel-gemcitabine group,as compared with 3.7months in the gemcitabine group (HR for disease progression or death,0.69;p <0.001)[18,19].
2.4.3
Efficacy in NSCLC
FDA has already approved the use of nab-paclitaxel in combination with carboplatin as first-line treatment in patients with locally advanced or metastatic NSCLC,who are not candidates for curative surgery or radiation therapy.In a multicenter,randomised,open-label trial,nab-paclitaxel was administered as an intravenous infusion over 30min at a dose of 100mg/m 2on days 1,8and 15of each 21-day cycle.CrEL-paclitaxel injection was administered as an intravenous infusion over 3h at a dose of 200mg/m 2,fol-lowing premedication [20].In both treatment arms,carbopla-tin at a dose of AUC =6mg min/ml was administered intravenously on day 1of each 21-days cycle after completion of nab-paclitaxel/paclitaxel infusion.
On the basis of independent assessment,nab-paclitaxel demonstrated a significantly higher ORR than paclitaxel (33vs 25%;p <0.005)and in patients with squamous histol-ogy (41vs 24%;p <0.001).Nab-paclitaxel was as effective as CrEL-paclitaxel in patients with nonsquamous histology (ORR,26vs 25%;p <0.808).There was a slight but not significant improvement in median OS (12.1vs 11.2months;p <0.271)and PFS (6.3vs 5.8months;p <0.214).2.5
Safety evaluation 2.5.1Preclinical data
Comparative intratumoural and antitumoural activity of nab-paclitaxel has been demonstrated to be greater than CrEL-paclitaxel and docetaxel in multiple tumour types using preclinical models [21,9].Desai et al .[21]using radiolabelled paclitaxel in mice with xenografts showed that nab-paclitaxel was significantly less toxic;LD50(lethal dose,50%)values and maximum tolerated dose (MTD)for nab-paclitaxel and CrEL-paclitaxel were 47and 30mg/kg/day and 30and 13.4mg/kg/day,respectively.At equal doses,intratumoural paclitaxel accumulation was found to be 33%higher for nab-paclitaxel.In live human umbilical vascular endothelial cells,endothelial binding and transport across the endothelial cell monolayer was significantly higher with nab-paclitaxel (9.9-and 4.2-fold,respectively)and this difference was
abrogated by methyl b -cyclodextrin,a known inhibitor of endothelial gp-60receptor and caveolar-mediated transport [9].These data provided the preclinical evidence to advance the drug to clinical studies.
2.5.2
Monotherapy
In an early Phase I study,pretreated patients with a variety of solid tumours were given nab-paclitaxel at 3-week intervals using doses from 135to 375mg/m 2.No infusion-related acute hypersensitivity reactions were noted during the drug administration.Haematological toxicity was mild and not cumulative.At the highest dose studied (level 3,375mg/m 2),dose-limiting toxicity occurred in three of six patients and consisted of sensory neuropathy,stomatitis and superficial keratopathy.However,only one patient experienced any grade 3or higher toxicity among those treated with <375mg/m 2.The investigators concluded that the MTD was 300mg/m 2[10].
Since weekly CrEL-paclitaxel has been demonstrated to be more effective than 3-week administration and is commonly used in practice,nab-paclitaxel was administered as a 30-min infusion to 39patients with advanced nonhaemato-logical malignancies,without premedication,at a dose levels from 80to 200mg/m 2once a week for 3weeks in each monthly cycle.After enrolment of the first cohort,patients were enrolled into ‘lightly’and ‘heavily’pretreated based on the extent of prior exposure to chemotherapy.MTDs for these two cohorts were 150and 100mg/m 2,respectively;dose-limiting toxicities were grade 3peripheral neuropathy and grade 4neutropenia,respectively.Myelosuppression,gas-trointestinal symptoms and fatigue were generally mild and not more frequent than in the 3-weekly schedule.Neuropa-thies were primarily sensory,and three of the five patients with grade 3neuropathy continued to receive nab-paclitaxel at a lower dose [22].
In the pivotal multinational Phase III trial,the safety profile of nab-paclitaxel was comparable with CrEL-paclitaxel,although there were some differences between the two groups.Consistent with safety data,no differences in quality of life (QOL)were observed between the two groups.The incidence of grade 4neutropenia was lower in nab-paclitaxel group compared to CrEL-paclitaxel group (9vs 22%)despite an almost 50%higher dose of paclitaxel.Febrile neutropenia was uncommon (<2%),and the incidence did not differ between the two study arms,as was severe anaemia and thrombocytopenia.Interestingly,grade 3sensory neuropathy was more common in nab-paclitaxel arm than in CrER-paclitaxel arm (10vs 2%)but was easily managed and improved rapidly to grade 1--2in a median of 22days.Four weeks after the first appearance,4of 28patients on nab-paclitaxel and 4of 5patients on CrEL-paclitaxel had per-sistent grade 3neuropathy.No severe hypersensitivity reac-tion occurred with nab-paclitaxel despite the absence of premedication and shorter administration time.Except for hyperglycaemia that occurred more frequently in patients on
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CrER-paclitaxel and in particular on patients aged 65years or over (0and 19%of patients on nab-paclitaxel and CrER-paclitaxel group,respectively),the frequency of other adverse events was not significantly different among patients on the two arm of the trial.Overall,gastrointestinal toxicity (nausea,vomiting and diarrhoea)was more frequent among patients on nab-paclitaxel [16].
In Table 1results of nab-paclitaxel monotherapy in patients with MBC are provided.
2.5.3
Combination therapy
After the encouraging results in clinical studies with nab-paclitaxel in monotherapy,the question is whether nab-paclitaxel should replace other taxanes in combination regimens not only for MBC.
In Phase III clinical trial in patients with NSCLC,adverse reactions were assessed in 514nab-paclitaxel/carboplatin-treated patients and 524paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB)or metastatic (IV)NSCLC [20].The differences in paclitaxel dose and schedule between the two arms limit a direct comparison of dose-and schedule-dependent adverse reactions.Among patients evaluable for adverse reactions,the median age was 60years,49%had ade-nocarcinoma,43%had squamous cell lung cancer and 76%were ECOG performance status 1.Patients in both treatment arms received a median of six cycles of treatment.
Of all treated patients,46%in the nab-paclitaxel arm and 23%in the paclitaxel arm had a taxane dose reduction,pre-dominantly because of neutropenia (29and 10%),thrombo-cytopenia (13and 4%),anaemia (6and <1%)and sensory neuropathy (2and 6%).Dose delays were more common in the nab-paclitaxel arm (82%)compared with the paclitaxel arm (54%).The frequency of carboplatin dose reductions,dose interruptions and dose delays was similar to that of taxanes.
Significantly less grade ?3sensory neuropathy (3vs 12%),neutropenia (47vs 58%),arthralgia (0vs 2%)and myalgia (<1vs 2%)occurred in the nab-paclitaxel arm,but less thrombocytopenia (18vs 9%)and anaemia (27vs 7%)occurred in the paclitaxel arm.Median time to improvement in grade ?3sensory neuropathy to grade 1was 38days in the nab-paclitaxel arm and 104days in the comparative arm.Sensory neuropathy (all grades)was significantly less with nab-paclitaxel (46%)compared with paclitaxel (62%;p <0.001).Conversely,the percentage of patients who did not develop neuropathy was higher with nab-paclitaxel (54%)versus paclitaxel (38%;p <0.001).Two treatment-related deaths occurred,one in each arm.
The nab-paclitaxel-gemcitabine combination was well tolerated as first-line treatment of PC.In MPACT study [18],patients in the combination arm received 71and 63%of planned nab-paclitaxel and gemcitabine doses,respectively,and the gemcitabine-only arm received 79%of the planned gemcitabine dose.The added toxicity risks from the addition
Table 1.Nab-paclitaxel monotherapy in metastatic breast cancer.
Study Regimen
N Response
Most frequent grade events Gradishar et al .(2005)Phase III [16]Paclitaxel 175mg/m 2i.v.d1q21d
Nab-paclitaxel 300mg/m 2i.v.d1q21d
225229ORR 19%,CR -,SD -,TTP months 16.9
ORR 33%p =0.001,CR -,SD -,TTP months 23.0
Neutropenia 46%,FN <2%,leucopenia 7%,neuropathy 2%Neutropenia 30%,FN <2%,leucopenia 6%,neuropathy 10%Blum et al .(2007)
Phase II [36]
Nab-paclitaxel 125mg/m 2d1,8,15q28d
Nab-paclitaxel 100mg/m 2d1,8,15q28d
75106
ORR 16%,PFS months 3.5,OS months 9.1
ORR 14%,PFS months 3.0,OS months 9.2
Neutropenia 34%,leucopenia 36%,fatigue 12%,sensory neuropathy 19%,nausea 3%,vomiting 1%,diarrhoea 5%
Neutropenia 18%,leucopenia 19%,fatigue 5%,sensory neuropathy 8%,nausea 4%,vomiting 3%,diarrhoea <1%
Ibrahim et al .(2005)
Phase II [37]Nab -paclitaxel 300mg/m 2q3w
63ORR 48%,TTP weeks 26.6
Neutropenia 24%,sensory neuropathy 11%,FN 5%
Gradishar et al .(2009)Phase II [26]and
Update OS (2012)[27]
Docetaxel 100mg/m 2i.v.d1q21d
Nab-paclitaxel 300mg/m 2i.v.d1q21d
Nab-paclitaxel 150mg/m 2i.v.d1q21d
Nab-paclitaxel 100mg/m 2i.v.d1q21d
74767476
CR 0,PR 35%,SD 23%,OS months 26.6,PFS months 7.5
CR 1%,PR 36%,SD 32%,OS months 27.7,PFS months 11.0
CR 0,PR 49%,SD 31%,OS months 33.8,PFS months 12.9
CR 0,PR 45%,SD 30%,OS months 22.2,PFS months 12.8
Neutropenia 94%,FN 8%,fatigue 19%,neuropathy 12%Neutropenia 44%,FN 1%,fatigue 5%Neutropenia 44%,FN 1%,fatigue 3%,Neuropathy 14%Neutropenia 25%,FN 1%,alopecia
3%,neuropathy 8%
-:Data not available;CR:Complete response;FN:Febrile neutropenia;ORR:Overall response rate;OS:Overall survival;PR:Partial response;PFS:Progression-free survival;SD:Stable disease;TTP:Time to progression.
Albumin-bound paclitaxel
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of nab-paclitaxel were acceptable and manageable,and grade 3or worse adverse events included neutropenia,febrile neu-tropenia,thrombocytopenia and fatigue.Grade 3or worse peripheral neuropathy occurred in 17%of patients in the nab-paclitaxel-containing arm and improved to grade 1or better in a median of 29days;in addition,44%resumed nab-paclitaxel following improvement of the peripheral neu-ropathy.In this Phase III study,the addition of nab-paclitaxel to gemcitabine did achieve a statistical and clinically meaning-ful survival improvement for patients with metastatic PC,and the added toxicity risk was acceptable and manageable including neutropenia and neuropathy.The more favourable toxicity profile makes nab-paclitaxel plus gemcitabine a very attractive backbone for developing novel agents [18,19].
In MBC,other nab-paclitaxel combinations have been investigated:the most frequently assessed combination is with bevacizumab;other combinations included trastuzumab,lapatinib,capecitabine,gemcitabine and carboplatin [23].Seidman et al.[24]conducted an open-label Phase II study randomis patients into one of three groups:arm A (nab-paclitaxel at 260mg/m 2d1q21d with bevacizumab 15mg/kg d1q21d,);arm B (nab-paclitaxel 260mg/m 2d1q14d with bevacizumab 10mg/kg d1q14d)or arm C (nab-paclitaxel 130mg/m 2weekly uninterrupted with beva-cizumab 10mg/kg d1q14d).
No significant differences in ORR were noted (A:45%,B:41%,C:46%),but TTP was numerically greater in arm C (9.0months)versus arms A (8.0months)and B (5.8months).As per protocol,arm B was closed early due to safety concerns,with significantly more grade 3/4fatigue (B:35%,A:17%,C:19%,p =0.015)and grade 2/3bone pain (B:21%,A:11%,C:4%,p =0.002).Febrile neutrope-nia was acceptable (<2%)for all treatment schedules but grade 2--4neuropathy was high at 50%in all arms.The authors suggested that weekly (three out of four)nab-paclitaxel was the most tolerable regimen with bevacizumab.The same combination schedule was evaluated in a Phase II study with 49patients enrolled (27evaluable):efficacy results were similar to those previously exposed but with reduced sensory neuropathy (12%);grade 3/4neutropenia was 46%[25].
A summary of combination therapy trials is reported in Table 2.
3.
Expert opinion
Since CrEL-paclitaxel and nab-paclitaxel differ only in their formulation,the question is if nab-paclitaxel can be used now in any setting where paclitaxel was previously used and in any https://www.doczj.com/doc/41603151.html,parison of nab-paclitaxel and CrEL-paclitaxel in all these settings would be very costly,would require many years of research and a substantial num-ber of patients enrolled in trials addressing relatively minor questions.
According to the data obtained from Phase III pivotal study [16],nab-paclitaxel seems to be a promising agent in the treatment of MBC.Nab-paclitaxel prolonged OS signifi-cantly in second or higher therapy lines.No significant differ-ence in OS was observed between the arms in patients receiving first-line therapy.In terms of safety profile,nab-paclitaxel was generally less toxic despite the higher adminis-tration dose:lower rate of grade 4neutropenia (9vs 22%)and a shorter median time to improve in grade 3sensory neuropathy to grade <2(22vs 79days).
In a Phase IIb trial in first-line treatment of patients with MBC [26,27],all doses of nab-paclitaxel produced higher ORRs compared with docetaxel.Final survival results revealed that the 150mg/m 2dose of nab-paclitaxel resulted in a 33.8-month median OS compared with 26.6months in the docetaxel arm [27].
In a metastatic setting,it would be useful to consider the role of SPARC as a potential predictive marker of efficacy when administering nab-paclitaxel for the treatment of MBC.SPARC is known to be overexpressed in several tumour types including breast cancer and may be associated with a poor prognosis [28].In preclinical breast cancer mod-els [21]and recently in a retrospective analysis of a clinical study of nab-paclitaxel in head and neck cancer [11],SPARC expression and its interaction with albumin has been sug-gested to be the reason for enhanced uptake and intratumou-ral accumulation indicating a possible role for SPARC as a biomarker for nab-paclitaxel effectiveness.
O’Shaughnessy et al.[29]showed a significantly higher ORR in patients with visceral-dominant metastases treated with nab-paclitaxel in comparison with CrEL-paclitaxel or docetaxel.Thus,visceral-dominant metastases may be a predictive factor for nab-paclitaxel.
In patients with metastatic pancreatic adenocarcinoma,nab-paclitaxel and gemcitabine represents a new therapeutic choice with significant improvement in survival.Interestingly,the combination of CrEL-paclitaxel and gemcitabine had never been systematically evaluated in treatment of naive advanced PC except for a Phase I study of this combination with radiation [30].Over the years,a large number of cytotoxic and target therapies were evaluated in combination with gem-citabine in clinical trials,but almost all failed to improve OS.The success,in 2010,of FOLFIRINOX,an intense cytotoxic regimen,extended the survival of patients with metastatic can-cer by 4.3months compared with gemcitabine alone [17].However,toxicities related to FOLFIRINOX are significant and it is being used selectively in clinical practice.Nab-pacli-taxel has a more favourable toxicity profile and in the near future,could be the most frequent choice in this patients set-ting.QOL will influence recommendation on which regimen to initiate in a newly diagnosed metastatic patient.Unlike the PRODIGE 4/ACCORD 11trial [31],formal QOL assessment was not part of the MPACT trial.However,the relative toler-ability of nab-paclitaxel-gemcitabine can be inferred from the fact that patients treated with nab-paclitaxel-gemcitabine
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Table 2.Nab-paclitaxel combination therapy in metastatic breast cancer.
Study
Regimen
N Response Most frequent grade events Mirtsching et al .(2011)
Phase II [38]
Nab-paclitaxel 125mg/m 2i.v.d1,8,15q28d
Trastuzumab initial dose of 4mg/kg (as a 90-min i.v.infusion)and then at 2mg/kg infused over 30min on a weekly schedule
72
ORR 42.2%,CR 5/72,PR 22/72,SD 17/72
Pain 64%,fatigue 58%,sensory neuropathy 54%
Infection 46%,nausea 38%,alopecia 33%,anaemia 33%
Link et al .(2007)
Phase III [39]
Nab-paclitaxel 80--125mg/m 2i.v.d1,8,15q28d
Bevacizumab 10mg/kg i.v.d1q14d versus
Nab-paclitaxel 170--220mg/m 2i.v.d1,15q28d
Bevacizumab 10mg/kg i.v.d1q14d 19
14CR 11%,PR 47%,SD 16%CR 7%,PR 29%,SD 16%Pain/bone pain 8%,anaemia 5%,neuropathy 3%,FN -not reported Pain/bone pain 8%,anaemia 5%,neuropathy 3%,FN -not reported Seidman et al .(2013)
Phase II [24]
Arm A:nab-paclitaxel 260mg/m 2i.v.d1q21d
bevacizumab 15mg/kg i.v.d1q21d Arm B:nab-paclitaxel 260mg/m 2i.v.d1q14d
filgrastim (dosing not available)
bevacizumab 10mg/kg i.v.d1q14d Arm C:nab-paclitaxel 130mg/m 2i.v.d1q7d
bevacizumab 10mg/kg i.v.d1q14d
75
54
79
ORR 45%,TTP months 8.0ORR 41%,TTP months 5.8
ORR 46%,TTP months 9.0Neutropenia 16%,FN 3%,neuropathy 33%,fatigue 17%,
Arthralgia 5%,skin rash 3%,nausea 4%,hypertension 4%
Neutropenia 6%,anaemia 4%,FN 2%,neuropathy 56%
Fatigue 35%,arthralgia 2%,skin rash 2%,nausea 7%,
Diarrhoea 6%,hypertension 2%Neutropenia 33%,anaemia 8%,neuropathy 46%
Fatigue 19%,skin rash 1%,nausea 3%,diarrhoea 8%,hypertension 5%Danso et al .(2008)
Phase II [25]Nab-paclitaxel 125mg/m 2i.v.d1,8,15q28d
Bevacizumab 10mg/kg i.v.d1q14d 49CR 0%,PR 30%,SD 22%Neutropenia 46%,neuropathy 12%,anaemia 11%,FN -not reported Colin et al .(2010)
Phase II [40]Nab-paclitaxel 100mg/m 2i.v.d1,8,15q28d
Carboplatin AUC 2i.v.d1,8,15q28d Trastuzumab 4mg/kg then 2mg/kg i.v.weekly
32
CR 7%,PR 53%,SD 19%
Neutropenia 50%,FN 3%,leucopenia 47%,fatigue 16%
Schwartzberg (2012)
Phase II [41]Capecitabine 825mg/m 2p.o.-b.i.d on days 1--15
Nab-paclitaxel 125mg/m 2i.v.d1,8q21d
50
ORR 61%,CR 4%,PR 57%,SD 22%PFS months 10.6
Hand --foot syndrome 18%,neutropenia 13%,pain 5%
Roy et al .(2009)
Phase II [42]Nab-paclitaxel 125mg/m 2i.v.d1,8q21d
Gemcitabine 1000mg/m 2i.v.d1,8q21d
50
CR 8%,PR 42%,SD -Neutropenia 54%,FN 2%,fatigue 29%,anaemia 14%
Lobo et al .(2010)
Phase II [43]
Nab-paclitaxel 150mg/m 2i.v.d1,15q28d
Gemcitabine 1500mg/m 2i.v.d1,15q28d
Bevacizumab 10mg/kg i.v.d1,15q28d
30
PFS months 10.4,CR 27.6%,PR 48.3%
Leucopenia 3.4%,thrombocytopenia 3.4%,neuropathy 3.4%
PorthaCATH infection 6.9%,abscess 3.4%,FN 3.4%
Hamilton et al .(2013)
Phase II [44]Nab-paclitaxel 100mg/m 2i.v.d1,8,15q28d
Carboplatin AUC 2i.v.d1,8,15q28d Bevacizumab 10mg/kg i.v.d1q15d 34
PFS months 9.2,CBR 94%,ORR 85%
Neutropenia 53%,thrombocytopenia 18%
Yardley et al .(2012)
Phase II [45]
Nab-paclitaxel 125mg/m 2i.v.d1,8,15q28d
Lapatinib 1250mg orally once daily on a continuous basis
60
CR 4%,PR 28%,SD 10%
Neutropenia 22%,fatigue 10%,diarrhoea 22%
CBR:Clinical beast response;CR:Complete response;FN:Febrile neutropenia;ORR:Overall response rate;PFS:Progression-free survival;PR:Partial response;SD:Stable disease;TTP:Time to progression.
Albumin-bound paclitaxel
Expert Opin.Drug Saf.(2014)13(4)
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E x p e r t O p i n . D r u g S a f . D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y C e l g e n e C o r p o n 07/07/15
F o r p e r s o n a l u s e o n l y .
maintained comparable dose intensity as the gemcitabine-alone arm.
In patients with advanced NSCLC,the combination nab-paclitaxel plus carboplatin met the primary end point of ORR,demonstrating significantly improved antitumour activity compared with CrEL-paclitaxel (31%improvement)and was well tolerated.Overall responses are consistent with the results from a Phase III trial in patients with advanced NSCLC treated with CrEL-paclitaxel plus carboplatin.Patients with squamous cell histology responded remarkably well to treatment with nab-paclitaxel,with a 68%improve-ment compared with that in the CrEL-paclitaxel arm,which is the highest reported in a Phase III study in this patient pop-ulation.This is particularly intriguing because improved ther-apeutic options for the subset of patients with squamous histology are needed.In general,survival in this study was comparable with historic results from trials in patients with advanced NSCLC [32-35].In the intention to treat population,nab-paclitaxel was noninferior to CrEL-paclitaxel,with an approximately 10%improvement for PFS and OS favouring the nab-paclitaxel arm.The nab-paclitaxel regimen produced less severe neuropathy,neutropenia,myalgia and arthralgia compared with CrEL-paclitaxel.The increased risk of throm-bocytopenia and anaemia in the nab-paclitaxel regimen was readily manageable.As first-line therapy for all patients with NSCLC the nab-paclitaxel regimen has altogether a more favourable risk-benefit profile than CrEL-paclitaxel one.In a new era when relevant economic resources are invested to develop new target therapies,nab-paclitaxel has demon-strated how a traditional cytotoxic drug can reach enhanced therapeutic results when improving drug delivery and phar-macokinetics with nab-technology.
Declaration of interest
The authors have no competing interests to declare and have received no funding in preparation of the manuscript.
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Affiliation
Sara Cecco 1,Maria Aliberti 2ScB,
Paolo Baldo 3BPharm,Elisa Giacomin 1&Roberto Leone ?4ScB ?
Author for correspondence 1
Degree in Pharmaceutical Chemistry and Technology,Pharmacist,
CRO Aviano National Cancer Institute,Hospital Pharmacy,Via F.Gallini,2,33081,Aviano,Italy 2
Research fellow,
CRO Aviano National Cancer Institute,Hospital Pharmacy,Pharmacovigilance Unit,Via F.Gallini,2,33081,Aviano,Italy 3
Pharmacist,
CRO Aviano National Cancer Institute,Hospital Pharmacy,Pharmacovigilance Unit,Via F.Gallini,2,33081,Aviano,Italy 4
Professor of Pharmacology,
“GB Rossi University Hospital”,Department of Public Health and Community Medicine,p.le LA Scuro 10,37134Verona,Italy Tel:+390458027612;Fax:+390458124876;
E-mail:roberto.leone@univr.it
S.Cecco et al .
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Expert Opin.Drug Saf.(2014)13(4)
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F o r p e r s o n a l u s e o n l y .