abi 007 an advance on paclitaxel in metastatic breast cancer

Inpharma 1423 - 7 Feb 2004

ABI 007 an advance on paclitaxel in metastatic breast cancer– Karen McRae –

ABI 007 [Abraxane], a nanoparticle albumin-bound (nab) formulation of paclitaxel, demonstrated efficacysuperior to that of standard solvent-based paclitaxel [Taxol] in patients with metastatic breast cancer in a head-to-head comparative study. Data from this study were presented in a late-breaker session at the 26th SanAntonio Breast Cancer Symposium (SABCS) [San Antonio, US; December 2003] by Dr Joyce O’Shaughnessy fromthe Baylor-Charles A. Sammons Cancer Center, US Oncology, Dallas, US. The study results showed that overallresponse rates and time to tumour progression were significantly increased in patients treated with ABI 007,compared with paclitaxel recipients. Importantly, although they did not receive routine concomitantcorticosteroids for hypersensitivity prophylaxis, patients treated with ABI 007 experienced significantly lesshypersensitivity and flushing than paclitaxel recipients who did receive concomitant corticosteroids.

status of 0 or 1.1,2* ABI 007 (n = 229) and paclitaxel wereWhy cut cremophor?administered intravenously over 30 min and 3 hours,Paclitaxel is an important drug in the fight againstrespectively, every 3 weeks for a planned 6 courses; thebreast cancer. However, as it is a highly water-insolubleABI 007 and paclitaxel doses were 260 mg/m2 andagent, a solvent (e.g. cremophor) has been required175 mg/m2, respectively. Overall, patients in bothbefore it can be administered intravenously. However,treatment groups received 98% of the planned dose ofmany of the adverse effects associated with paclitaxelstudy drug with the mean total paclitaxel dosage perare not caused by the drug itself, but rather by thepatient being 1459 mg/m2 in the ABI 007 group, andsolvent. Cremophor is responsible for paclitaxel-909 mg/m2 in the paclitaxel group. Only paclitaxelassociated hypersensitivity reactions in patients and isrecipients received standard premedication withthe reason concomitant corticosteroid therapy isdexamethasone and antihistamines [see table 1].required. Furthermore, the use of cremophor limits

The median ages of patients receiving ABI 007 andtumour penetration, as it entraps paclitaxel in micelles.paclitaxel were 53 years and 52 years, respectively. TheABI 007 is produced using a proprietary process thatprimary site of measurable disease was the liver in acombines human albumin with paclitaxel to form stablemean of 42% of patients, and the lung in 34%, while 37%nanoparticles that are 1% of the size of red blood cells.of patients had bone involvement. The majority ofWhen administered in this way, paclitaxel is amorphouspatients had previously received chemotherapy forand has rapid bioavailability, avoiding the need for ametastatic disease; 42% of patients had received onesolvent.prior regimen and 17–18% had been given ≥ 2 priorIn vitro studies in athymic mice with human MX-1regimens. Patients who had previously received taxanestumours have shown that ABI 007 is more effective thanfor metastatic disease were excluded from the study.cremophor paclitaxel in reducing tumour volume, andPatients were stratified according to prior anthracyclinehas significantly greater tumour penetration. Phase IIexposure; anthracycline therapy had been administeredstudies of ABI 007 in patients with metastatic breastas an adjuvant and/or for metastatic disease to 77% ofcancer have shown objective overall confirmedpatients, while 54% had received anthracycline forresponse rates of between 40% (175 mg/m2 everymetastatic disease only.3 weeks) and 48% (300 mg/m2 every 3 weeks).

Importantly, no hypersensitivity reactions wereTable 2. Overall response rate, according toobserved, despite the absence of concomitanttherapycorticosteroids. The increased antitumour activity with

higher doses of ABI 007 suggests "a possible dose All patients First-line therapyresponse relationship not seen with paclitaxel", said

ABI 007 Paclitaxel ABI 007 PaclitaxelDr O’Shaughnessy. (n = 229)a (n = 225)b (n = 97) (n = 89)

Overall response ratec [% of patients (95% CI)]:Table 1. Concomitant medications in patients

Investigator- 33* 19 42** 27treated with ABI 007 or paclitaxel [Taxol] assessed (27–39) (14–24) (32–52) (18–36)ABI 007 Paclitaxel Independent 21† 10 29** 14 (6–21)

(1293 cycles) (1174 cycles) radiology review (16–27) (6–14) (20–38)

Concomitant medication (% of cycles): * p < 0.001 vs paclitaxel** p < 0.05 vs paclitaxelCorticosteroids 8 98† p < 0.01 vs paclitaxelCorticosteroids for 2 95

hypersensitivity prophylaxisa a n = 215 for independent radiology reviewb n = 214 for independent radiology reviewNon-serotonin3 receptor 2 2

antagonists c complete + partial response rateSerotonin3 receptor antagonists 16 14Colony-stimulating factors < 1 3

Superior efficacy. . .a Initiated on or before the day of study drug administration Overall response rates, whether assessed by the

investigators or by an independent radiology review,were significantly higher among ABI 007, comparedHead-to-head studywith paclitaxel, recipients [see table 2]. Furthermore, theThe efficacy and tolerability of ABI 007 and standardsecondary endpoint of time to tumour progression wascremophor paclitaxel were compared in a randomised,significantly longer for ABI 007 recipients than paclitaxelphase III study involving 454 women with measurablerecipients (21.9 weeks vs 16.1 weeks; p = 0.029). At themetastatic breast cancer and an ECOG performance

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Single Article

ABI 007 an advance on paclitaxel in metastatic breast cancer –continued

time of the analysis, the median overall survival duration paclitaxel groups with respect to the incidences ofhad not been reached. fatigue, myalgias, and oedema. No septic deaths

When the overall response rates were assessed by the occurred during the study.investigators according to the dominant visceral disease Neuropathy resolves more rapidlysite, they were significantly higher among recipients of

The incidence of peripheral neuropathy was greater inABI 007, compared with paclitaxel, for disease in theABI 007 recipients compared with paclitaxel recipients;liver (26% vs 13%; p = 0.03) and the lungs (43% vs 25%;this was not unexpected given the higher dose ofp = 0.035).paclitaxel in the ABI 007 treatment group. However,

. . .with reduced toxicity recovery from neuropathy was more rapid amongABI 007 demonstrated a markedly improved ABI 007 recipients than paclitaxel-treated patients.

tolerability profile, compared with cremophor paclitaxel. When ABI 007 was withheld until grade 3 neuropathyPatients treated with ABI 007 were receiving larger resolved to grade 1 or 2 (a median of 22 days ofdoses of active drug than those treated with paclitaxel. treatment interruption) followed by a dose reduction toDespite this, ABI 007 recipients had significantly less 220 mg/m2, the neuropathy resolved. In contrast, theneutropenia, compared with paclitaxel-treated patients median time to recovery from neuropathy was 79 days[see table 3]. for patients treated with paclitaxel (p = 0.028 vs

ABI 007).The increased time to recovery from sensoryTable 3. Incidences of adverse events, according to

neuropathy among patients treated with paclitaxel,therapycompared with ABI 007, may be due to cremophor

ABI 007 Paclitaxel solvent, which may be causing structural nerve fibre (n = 229) (n = 225)damage; this type of neuropathy is prolonged, whereas

Neutropenia* that associated only with paclitaxel has a rapidgrade 3 25 31 resolution.grade 4 9 22

Weekly schedule possible?HypersensitivityWith respect to the treatment of metastatic breastgrade 2 < 1 0

cancer, ABI 007 has a number of advantages overgrade 3 0 1paclitaxel. Dr O’Shaughnessy highlighted the "shorter

Flushing* infusion schedule, no prophylactic steroidgrade 2 < 1 5 premedication, superior overall response rate, longer

Sensory Neuropathy** time to tumor progression, less neutropenia despitegrade 2 20 10 higher dose, and manageable peripheral neuropathy"grade 3 10 2 with ABI 007.grade 4 0 0 Following the presentation of this study at SABCS,

Vomiting† questions were raised regarding the effects of a weeklygrade 2 4 4 schedule for ABI 007, and the implications of such agrade 3 3 1 schedule on sensory neuropathy. Dr O’Shaughnessygrade 4 < 1 0 noted that in 25 patients (4 responders), a weekly

schedule of ABI 007 at a dosage of 125 mg/m2 for* p < 0.001 favouring ABI 007 (all grades)3 weeks with the fourth week off resulted in virtually no** p < 0.001 favouring paclitaxel (all grades)toxicity. The results of a study using a weekly schedule† p < 0.05 favouring paclitaxel (all grades)will be awaited with interest.* A total of 460 patients were randomised; 454 patients receivedAlthough ABI 007 recipients did not routinely receive≥ 1 dose of the study medication.corticosteroids, they had a similar incidence of

hypersensitivity reactions to paclitaxel recipients; 1. O’Shaughnessy J, et al. ABI-007 (ABRAXANE TM), a nanoparticle albumin-bound paclitaxel demonstrates superior efficacy vs Taxol in MBC: a phase IIIgrade 3 hypersensitivity reactions occurred in 1% oftrials. 26th Annual San Antonio Breast Cancer Symposium : (plus oralpaclitaxel recipients, whereas < 1% of patients treated presentation) abstr. 44, 3 Dec 2003. Available from: URL: http://www.sabcs.org.

2. American Pharmaceutical Partners Inc. Detailed Positive ABRAXANE(TM)with ABI 007 developed grade 2 hypersensitivity.Phase III Data Released at San Antonio Breast Cancer Symposium: PatientsFurthermore, the incidence of flushing, itself indicativeWith Metastatic Breast Cancer Treated With ABRAXANE(TM) Achieve

of hypsersensitivity, was significantly lower among Almost Double the Tumor Response Rate and Longer Time to TumorProgression Compared With TAXOL(R). Media Release : 5 Dec 2003.ABI 007, compared with paclitaxel recipients (< 1% vsAvailable from: URL: http://www.appdrugs.com.5%; all grade 2).

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The incidences of grade 3 and grade 4» Editorial comment: ABI 007 [American BioScience,thrombocytopenia, anaemia, and febrile neutropeniaAmerican Pharmaceutical Partners] is awaiting registration forwere low, with no significant differences between thethe treatment of metastatic breast cancer in the US; the US FDAtwo treatment groups. Furthermore, there were nohas granted fast track status for this indication.significant differences between the ABI 007 and

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