Inpharma 1571 - 20 Jan 2007

Abraxane the best taxane for metastatic breast cancer?– Samantha Crofskey –

When administered weekly at doses of 100 or 150 mg/m2, the nanoparticle albumin-bound formulation ofpaclitaxel [Abraxane] may be more active, and associated with less toxicity, than the US FDA approved dose ofdocetaxel [Taxotere] given every 3 weeks in the first-line treatment of metastatic breast cancer, according to datapresented at the 29th Annual San Antonio Breast Cancer Symposium (SABCS) [San Antonio, Texas, US; December2006]. Interim results of the head-to-head phase II trial demonstrated that first-line treatment with weeklypaclitaxel significantly increased objective response rates by more than 60%, compared with docetaxel therapy.Both weekly dosing regimens of paclitaxel were also associated with a significant increase in objective responserate, compared with a third paclitaxel treatment arm which received a 300 mg/m2 dose of paclitaxel every3 weeks. Compared with docetaxel, all three paclitaxel arms demonstrated a more favourable tolerabilityprofile, with significantly lower incidences of grade IV neutropenia, febrile neutropenia, and grade I or IIstomatitis/mucositis; there were no significant between-treatment differences for peripheral neuropathy. In thisstudy, paclitaxel 100 mg/m2, administered weekly, demonstrated the most favourable balance between efficacyand tolerability, and is the selected dosing regimen for a proposed worldwide phase III registration trial ofAbraxane.

Paclitaxel powder for injectable suspension is Study designproduced using a proprietary process that combines Patients with stage IV adenocarcinoma of the breasthuman albumin with paclitaxel to form stable who had not received prior chemotherapy for metastaticnanoparticles that are 1% of the size of red blood cells. disease were eligible for inclusion in the study. A total ofWhen administered in this way, paclitaxel is amorphous 300 patients were randomised to one of four treatmentand has rapid bioavailability, avoiding the need for a regimens:solvent. • paclitaxel 300 mg/m2, administered every 3 weeks

(300 mg/m2 q3w; n = 76);Study rationale• paclitaxel 100 mg/m2, administered weekly onCompared with standard solvent-based paclitaxel

days 1, 8 and 15, every 28 days (100 mg/m2 qw; 76);[Taxol] in two prior phase III studies in patients with• paclitaxel 150 mg/m2, administered weekly onmetastatic breast cancer, docetaxel demonstrated

days 1, 8 and 15, every 28 days (150 mg/m2 qw; 74);significantly improved overall survival and time toordisease progression, but greater toxicity, whereas

• docetaxel 100 mg/m2, administered every 3 weeksnanoparticle albumin-bound paclitaxel was shown to(100 mg/m2 q3w; 74).provide a significantly greater overall response rate and

The primary endpoints of the study were the objectivetime to disease progression, combined with less toxicity.response rate, evaluated every 8 weeks regardless ofIn these studies, the incidences of grade III or IVtreatment regimen, and tolerability; secondaryneutropenia and febrile neutropenia were 93% and 15%,endpoints included progression-free survival.respectively, among docetaxel recipients, compared

with 30% and < 2% in patients treated with nanoparticle Abraxane the better taxanealbumin-bound paclitaxel. A cross trial analysis of these First-line treatment with paclitaxel 100 or 150 mg/m2,studies suggested that the antitumour activity of administered weekly, provided significant increases innanoparticle albumin-bound paclitaxel may be objective response rates of 61% and 72%, respectively,comparable to docetaxel, whilst providing a more compared with docetaxel; the corresponding objectivefavourable tolerability profile. response rates were 58%, 62% and 36% [see table 1]. A

In other phase III studies in patients with metastatic blinded, independent radiological review of thebreast cancer, weekly dosing of solvent-based paclitaxel response data is currently in progress, and the finalwas associated with a significantly higher response rate, analysis of this data will be available later in 2007.significantly longer time to tumour progression and ahigher incidence of peripheral neuropathy, when

Table 1. Objective response ratescompared with a dosing regimen administered everyDocetaxel Paclitaxel3 weeks; another study comparing solvent-based

paclitaxel at doses of 175, 210 and 250 mg/m2, given 100 mg/m2 300 mg/m2 100 mg/m2 150 mg/m2

every 3 weeks, demonstrated that there were no q3w q3w qw qw(n = 74) (n = 76) (n = 76) (n = 74)significant differences between the dose groups for

response rate, progression-free survival or overall Objective response rate (% of patients):survival. Confirmed 36 33 58* 62*

A randomised, head-to-head phase II study was* p < 0.005 vs docetaxel; p < 0.001 vs paclitaxelconducted to compare the efficacy and tolerability of300 mg/m2 q3wnanoparticle albumin-bound paclitaxel with docetaxel in

the first-line treatment of metastatic breast cancer; theAlthough progression-free survival data are notcomparative efficacy and tolerability of weekly versus

mature, with only 33% of potential events havingevery-3-weeks dosing of nanoparticle albumin-boundoccurred at the time of the analysis, all three paclitaxelpaclitaxel, as well as a 150 mg/m2 versus 100 mg/m2

treatment arms showed longer progression-free survivaldose of weekly nanoparticle albumin-bound paclitaxel,durations when compared with the docetaxel group.were also investigated; data from the third interim

Compared with docetaxel, all three paclitaxel dosinganalysis of this study were presented at the SABCSregimens were associated with significantly lowermeeting.1,2

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Abraxane the best taxane? – continuedincidences of grade IV neutropenia, febrile neutropenia, regimen.and grade I or II mucositis/stomatitis [see table 2]. There Compared with the 300 mg/m2 q3w and 150 mg/m2

were no significant differences between paclitaxel and qw dosing regimens of paclitaxel, paclitaxel 100 mg/m2

docetaxel with respect to peripheral neuropathy, and no qw was associated with significantly fewer incidences ofgrade IV peripheral neuropathy was observed in any of peripheral neuropathy (51% and 47% of patients vs 37%the four treatment groups. of patients, respectively; both p ≤ 0.05), arthralgias (33%

and 35% vs 16%; both p < 0.005), and fatigue (33% and39% vs 21%; both p < 0.05).Table 2. Incidences of selected adverse events

The incidence of fatigue was significantly lower in theDocetaxel Paclitaxel paclitaxel 100 mg/m2 weekly arm, compared with the100 mg/m2 300 mg/m2 100 mg/m2 150 mg/m2 docetaxel group (21% vs 46% of patients, respectively;

q3w q3w qw qw p < 0.001). Although the 300 mg/m2 q3w andIncidence of adverse events (% of patients): 150 mg/m2 qw dosing regimens of paclitaxel resulted in

significantly higher incidences of arthralgia, comparedGrade IV 74 4* 3* 7*neutropenia with docetaxel (33% and 35% of patients vs 16% of

Febrile 7 1* 1* 1* patients, respectively; p < 0.05), the incidences ofneutropenia arthralgia in the weekly paclitaxel 100 mg/m2 and

Grade I or II 20 3* 1* 0* docetaxel groups were comparable.mucositis/ Based on results from this interim analysis, Abraxisstomatitis

BioScience intends to initiate a worldwide, head-to-head* p < 0.001 vs docetaxel phase III registration trial comparing the 100 mg/m2

weekly regimen of nanoparticle albumin-boundpaclitaxel with docetaxel 100 mg/m2, administeredWeekly dosing defeats q3wevery 3 weeks, in the first-line treatment of metastaticBoth weekly dosing regimens of paclitaxel were breast cancer; the trial is expected to begin in the firstassociated with a significant increase in objective half of 2007, at various centres in Canada, Europe, theresponse rate, when compared with paclitaxel given US, and the Asia-Pacific region.every 3 weeks; the objective response rate in the1. Gradishar W, et al. A randomized phase 2 trial of qw or q3w ABI-007 vs. q3Wpaclitaxel q3w treatment arm was 33% [see table 1,

solvent-based docetaxel as first-line therapy in metastatic breast cancer. Breastprevious page]. Cancer Research and Treatment 100 (Suppl. 1): 21 (plus oral presentation) abstr.46, Dec 2006.Weekly paclitaxel 100 mg/m2 the winner? 2. Abraxis BioScience Inc. Interim Data from a Randomized, Head-to-Head PhaseII Study Shows Weekly ABRAXANE Increased Tumor Response Rate byAlthough no dose-dependent increase in objectiveGreater than 60 Percent Versus Taxotere in First-Line Treatment of Metastaticresponse rate was observed by increasing the weekly Breast Cancer. Media Release : 17 Dec 2006. Available from: URL: http://

paclitaxel dose by 50%, weekly paclitaxel 100 mg/m2 www.abraxisbio.com.801069180demonstrated a better therapeutic index than the other

two dosing regimens of paclitaxel and the docetaxel

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