Nab-Paclitaxel as first-line therapy for metastatic breast cancer
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Community Translations Jame Abraham, MD, Section Editor
West Virginia University, Morgantown, WV
nab-Paclitaxel as first-line therapy
for metastatic breast cancer
Women with metastatic breast cancer (MBC) have a poor prognosis, with a median survival of approximately 2 years.
First-line chemotherapy for patients with MBC generally consists of treatment with an anthracycline and/or taxane. The
use of agents such as paclitaxel in combination regimens increases toxicity, however, which can limit dose escalation,
necessitate dose reductions, and negatively affect patient quality of life. Taxane use can result in myelosuppression,
peripheral neuropathy, alopecia, edema, and other toxicities. Moreover, the solvents required for solubilization of hy-
drophobic drugs such as paclitaxel (eg, Cremophor-EL) can cause severe hypersensitivity reactions (requiring prophy-
laxis with corticosteroids and antihistamines) and may exacerbate the myelosuppression and peripheral neuropathy
associated with paclitaxel administration. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel paclitaxel
formulation that does not require Cremophor for solubilization, thus significantly reducing solvent-related toxicity. nab-
Paclitaxel monotherapy has been shown to be effective for the treatment of MBC. An interim analysis of a randomized
phase II trial of various first-line nab-paclitaxel regimens revealed that doses of 100 or 150 mg/m² administered weekly
for 3 of every 4 weeks resulted in statistically superior objective response rates and progression-free survival compared
with docetaxel monotherapy. Treatment-related grade 3/4 toxicities, including neutropenia, febrile neutropenia, and
fatigue, were significantly less frequent with nab-paclitaxel than with docetaxel. These data, together with results from
a previous phase III trial, support the use of nab-paclitaxel as an effective and tolerable option for women with MBC.
B
reast cancer is the most (MBC) generally have a median sur- sponse, and the significant toxicity of
common cancer in women, vival of approximately 2 years. standard regimens for MBC have fo-
accounting for more than Many chemotherapy agents and cused attention on the development
26% of all new cancer cas- regimens have been evaluated for of novel agents that could improve
es. An estimated 184,000 new cases treatment of MBC, but currently outcomes and lessen the frequency
are projected in the United States for no standard of care exists. Response and/or severity of adverse effects.
2008, and over 1 million new cases rates with monotherapy in the first- The taxanes have served as a cor-
worldwide were estimated in 2002.1,2 line setting range from approximately nerstone of chemotherapy for the
In the United States alone, this year 20% to 60%. Several effective chemo- treatment of MBC. In chemothera-
more than 40,000 women will die therapeutics have been developed for py-naïve patients, response rates with
from breast cancer, making it the sec- first-line treatment of MBC, and an- first-line single-agent paclitaxel range
ond leading cause, after lung cancer, thracyclines and the taxanes (paclitax- from 30% to more than 60% and with
of cancer-related mortality in this el and docetaxel [Taxotere]) are usu- docetaxel monotherapy, from 40%
population. ally considered as first-line options, to 68%.5 In a randomized phase III
Patients diagnosed with early- particularly in chemotherapy-naïve trial, paclitaxel and docetaxel mono-
stage breast cancer have a more fa- patients.4 Combination chemothera- therapy were compared in patients
vorable outcome, but those with more py using such agents results in high- with advanced breast cancer that had
advanced disease face a poor prog- er response rates and a longer time to progressed after an anthracycline-
nosis. Approximately 10% of women progression than does monotherapy, containing chemotherapy regimen.6
have locally advanced or metastatic but these benefits are often accompa- Patients (n = 449) were randomized
disease at the time of presentation.3 nied by greater toxicity. Selection of to receive treatment with docetaxel
Furthermore, depending upon the chemotherapy for women with MBC (100 mg/m²) or paclitaxel (175 mg/
initial stage and tumor characteris- should be individualized based upon m²) on day 1, every 21 days, until tu-
tics, 20%–85% of patients with early- the patients’ tumor as well as such pa- mor progression, unacceptable toxic-
stage breast cancer will progress and tient characteristics as performance ity, or study withdrawal occurred. In
develop recurrent and/or metastatic status, comorbidities, and personal the intent-to-treat population, me-
disease.3 Although outcomes vary ac- considerations (eg, convenience, tox- dian overall survival (15.4 months
cording to subtype and the presence icities affecting normal functioning). Summary written by Larry J. Rosenberg, PhD;
and location of metastases, women The limited efficacy of many current reviewed by Jame Abraham, MD, West Vir-
who develop metastatic breast cancer regimens, the limited duration of re- ginia University, Morgantown, WV.
© 2008 Elsevier Inc. All rights reserved. Commun Oncol 2008;5(suppl 7):1–7
Volume 5/Number 6/Supplement 7 June 2008 ■ COMMUNITY ONCOLOGY 1Community Translations
toxicities, including prolonged and
What’s new, what’s important occasionally irreversible peripheral
nab-Paclitaxel is a novel formulation of paclitaxel approved by the US Food sensory neuropathy.14–17 Premedica-
and Drug Administration (FDA) for use in patients with metastatic breast can- tion with corticosteroids and antihis-
cer who failed to respond to previous combination chemotherapy or relapsed tamines—causing well-known side
within 6 months of adjuvant chemotherapy. Prior therapy should have included
effects—is commonly required for
an anthracycline unless clinically contraindicated. The FDA-approved dose and
regimen are 260 mg/m² every 3 weeks.
prophylaxis against hypersensitivity
Some of the recent phase II studies have shown that nab-paclitaxel is a highly reactions when using these taxanes.
active drug when given as a single agent on a weekly schedule (3 weeks on Due to their ability to leach plasti-
and 1 week off treatment). The doses used in these studies ranged from 100 cizers (especially Cremophor-EL),
mg/m² to 150 mg/m². special intravenous (IV) tubing is re-
Because Cremophor is not required for solubilization, the overall side-effect quired for taxane administration. In
profile is considerably better than that associated with conventional paclitaxel addition, Cremophor-EL can trap
formulations, and it is administered over 30 minutes without corticosteroid or coadministered drugs through micelle
antihistamine premedication. formation, altering their pharmacoki-
Weekly injections of nab-paclitaxel are a convenient, effective way of giving netics and bioavailability and increas-
chemotherapy to patients who have significant comorbidities and to those older
ing the risk of drug interactions.15,18,19
than 65 years of age.
— Jame Abraham, MD
The inherent toxicity of taxanes, as
well as adverse effects associated with
solvents such as Cremophor-EL, also
vs 12.7 months; hazard ratio [HR], Toxicity also is a significant prob- may limit dose escalation of paclitax-
1.41; 95% confidence interval [CI], lem with anthracyclines, which, like el and docetaxel. Several studies have
1.15–1.73; P = 0.03) and median time taxanes, are commonly used in che- evaluated whether a higher dose of
to disease progression (5.7 months vs motherapy for MBC. Among other these taxanes may improve outcomes
3.6 months; HR, 1.64; 95% CI, 1.33– adverse effects, use of anthracyclines in women with MBC.20–23 Although
2.02; P < 0.0001) for docetaxel were is limited by cumulative dose-relat- some studies have suggested a dose
significantly longer than for paclitaxel. ed cardiotoxicity, which has led to response, in all cases dose escalation
The overall response rate (ORR) was the recent trend toward reducing or is limited by increasing toxicity at
higher for docetaxel (32% vs 25%; P = eliminating their role in therapy.10,11 higher dose levels. The incidences of
0.10), but the improvement was not Trastuzumab (Herceptin) can also most hematologic and nonhemato-
statistically significant. Subsequent exacerbate cardiotoxicity,12,13 particu- logic toxicities were related to an in-
analyses indicated that the survival larly when combined with cytotoxic creasing taxane dose, with significant
benefit associated with docetaxel per- chemotherapy, resulting in a decrease grade 3/4 neutropenia and neurotox-
sisted through year 4 of follow-up.7 in left ventricular ejection fraction icity. These toxicities also limit the
Treatment-related hematologic and (LVEF) in more than 25% of patients. maximum dose of taxanes achievable
nonhematologic toxicities, however, The risk of cardiotoxicity with these in combination chemotherapy regi-
were higher with docetaxel therapy agents may result in dose reduction or mens for MBC.
than with paclitaxel treatment. discontinuation of therapy or prevent The toxicity, administration is-
Despite their clinical activity in their use in older patients and, con- sues, additional staff and expenses,
MBC, the use of taxanes is limited by sequently, has prompted a search for possible alteration of pharmacoki-
significant toxicity in many patients. less-cardiotoxic agents. netics, and inability of dose esca-
Common adverse effects include bone The solvents required for solubi- lation highlight the limitations of
marrow suppression (mainly neutro- lization and delivery of hydrophobic standard taxane therapy for first-
penia), peripheral neuropathy, hyper- taxanes also contribute to the toxicity line MBC therapy. These drawbacks
sensitivity, arthralgias and myalgias, of paclitaxel and docetaxel, particu- have prompted the development and
alopecia, stomatitis and mucositis, larly hypersensitivity. Paclitaxel must evaluation of new, active agents that
cutaneous reactions, and fluid reten- be administered in polyethylated cas- do not require such solvents, such as
tion with docetaxel (including edema, tor oil (Cremophor-EL), whereas albumin-bound paclitaxel.
ascites, and pleural effusions).8,9 The docetaxel is delivered in polysorbate
incidence and profile of these toxici- 80 plus ethanol. These solvents can nab-Paclitaxel
ties differ for paclitaxel and docetaxel cause severe anaphylaxis; acute and Nanoparticle albumin-bound pa-
and may be affected by the dose and possibly fatal hypersensitivity reac- clitaxel (nab-paclitaxel; Abraxane) is
schedule used. tions; myelosuppression; and other a novel paclitaxel formulation that
2 COMMUNITY ONCOLOGY ■ June 2008 www.CommunityOncology.netdoes not require Cremophor or poly- hypersensitivity reactions were noted phase III trial of nab-paclitaxel versus
sorbate 80 for solubilization, thus re- with nab-paclitaxel. standard paclitaxel.32 Treatment con-
ducing solvent-related toxicity and A phase II trial subsequently sisted of IV nab-paclitaxel 260 mg/
micelle formation.24,25 nab-Paclitaxel evaluated nab-paclitaxel at a dose of m² (without corticosteroid or antihis-
takes advantage of the role of albu- 300 mg/m² in 63 patients with histo- tamine premedication) or standard IV
min as a naturally occurring carrier of logically confirmed and measurable paclitaxel 175 mg/m² (with premedi-
hydrophobic molecules. The albumin MBC.31 The drug was administered cation). Of the 460 women in this tri-
moiety of nab-paclitaxel binds to the by IV infusion over 30 minutes every al, most (86%) had received prior che-
cell surface gp60 receptor, promoting 3 weeks without premedication. For- motherapy, 76% had more than three
receptor-mediated drug internaliza- ty-eight patients had received prior metastatic lesions, and 59% had pro-
tion into caveolae, with subsequent chemotherapy, and 39 had no prior gressed following first-line chemo-
transcytosis and delivery of drug to first-line treatment for metastatic therapy for metastatic disease. Results
tumor cells. The leaky junctions as- disease. For all patients, a 48% ORR of this study demonstrated a signifi-
sociated with tumor vasculature also was achieved. The ORR increased to cantly greater response rate with nab-
facilitate drug entry and tumor reten- 64% for those who received nab-pacl- paclitaxel compared with standard pa-
tion of paclitaxel. Interaction of albu- itaxel as first-line therapy, compared clitaxel (33% vs 19%; P < 0.0001). Of
min with SPARC (secreted protein, with 21% for patients who had re- note, responses with nab-paclitaxel
acidic and rich in cysteine; osteonec- ceived prior chemotherapy for MBC. also were superior in the first-line set-
tin), which is overexpressed in many Median time to disease progression ting (42% vs 27%; P = 0.029). Further,
breast cancers,26 may also promote (TTP) was 26.6 weeks overall, and median TTP was greater with nab-
uptake of nab-paclitaxel.27 In pre- median overall survival (OS) was paclitaxel than with standard pacli-
clinical breast cancer xenograft mod- 63.6 weeks. Toxicities were less fre- taxel for the overall population (23.0
els, nab-paclitaxel was found to have quent and less severe than expected vs 16.9 weeks; P = 0.006). The clinical
superior antitumor activity compared with standard paclitaxel at compara- benefit was equivalent for older and
with standard paclitaxel, with more ble doses. No severe hypersensitivity younger patients. Neutropenia (grade
tumor-free survivors and longer time reactions were seen, despite the ab- 3/4) and flushing (grades 2–4) were
to relapse.28,29 nab-Paclitaxel also re- sence of corticosteroid or antihista- significantly less with nab-paclitaxel,
sulted in significantly higher tumor mine premedication. Compared with whereas sensory neuropathy (grades
drug accumulation, with preferential other taxanes, there was a relatively 2–4) was higher with this agent.
drug accumulation in tumor versus low incidence of grade 4 neutrope-
normal tissue. The lack of Cremo- nia and grade 3 sensory neuropathy. Phase II trial of nab-paclitaxel
phor solvent, coupled with the novel These encouraging results, particu- in first-line MBC
mechanism of action for nab-pacli- larly in the first-line setting, provid- Given the first-line activity of
taxel, led to its clinical evaluation for ed the impetus for further evaluation nab-paclitaxel observed in this phase
treatment of MBC. of this agent for MBC. III trial, an open-label, randomized
Gradishar and colleagues con- phase II study (CA024) was conduct-
Clinical studies of nab- ducted an international, randomized ed to compare the efficacy and safe-
paclitaxel in MBC
nab-Paclitaxel has been evaluated
Arm A
in patients with MBC to determine nab-Paclitaxel 300 mg/m² q3w
Comparisons
its efficacy and safety relative to oth-
nab-Paclitaxel vs docetaxel R
er taxanes. An initial phase I trial30 (A, B, C vs D) A Arm B
N
found the maximum tolerated dose Weekly vs q3w D nab-Paclitaxel 100 mg/m² weekly q3/4w
(MTD) to be 300 mg/m², which dosing of nab-paclitaxel O
(B, C vs A) M
is approximately 70% higher than Arm C
I
Low- vs high-dose weekly Z nab-Paclitaxel 150 mg/m² weekly q3/4w
the recommended 175 mg/m² dose dosing of nab-paclitaxel E
of paclitaxel administered every 3 (B vs C)
Arm D
weeks. No severe adverse events were Docetaxel 100 mg/m² q3w
observed with nab-paclitaxel. Dose-
limiting toxicities included keratitis,
FIGURE 1 Schema for phase II randomized trial of nab-paclitaxel as first-line therapy of
blurred vision, sensory neuropathy, metastatic breast cancer. nab-Paclitaxel administered at the maximum tolerated dose in arms
stomatitis, and grade 4 neutropenia. A, C, and D. Abbreviations: q3w = every 3 weeks; q3/4w = every 3 of 4 weeks. Adapted
In contrast to standard paclitaxel, no from Gradishar et al.33
Volume 5/Number 6/Supplement 7 June 2008 ■ COMMUNITY ONCOLOGY 3Community Translations
TABLE 1
Efficacy results of phase II randomized trial of nab-paclitaxel vs docetaxel for first-line therapy of metastatic
breast cancer
Arm A Arm B Arm C Arm D
nab-Paclitaxel nab-Paclitaxel nab-Paclitaxel Docetaxel
300 mg/m² q3w 100 mg/m² weekly 150 mg/m² weekly 100 mg/m² q3w
Outcome measure (n = 76) q3/4w (n = 76) q3/4w (n = 74) (n = 74)
Overall response rate (complete responses 43% 62% 70% 38%
plus partial responses)*
P value < 0.016 (vs arm B) 0.002 (vs arm D) 0.003 (vs arm D) –
< 0.007 (vs arm C) – 0.2 (vs arm B) –
Number of patients (%) with progression- 23 (30%) 25 (33%) 19 (26%) 33 (45%)
free survival event
Median progression-free survival, months > 10.6 9.3 9.2 7.3
95% Confidence interval, months 7.3 to > 10.6 7.1 to > 10.6 8.1 to > 10.8 5.6 to 8.4
q3w = every 3 weeks; q3/4w = every 3 of 4 weeks
* Investigator-confirmed objective response rates
Adapted from Gradishar et al33
TABLE 2
Selected treatment-related adverse events in phase II randomized trial of nab-paclitaxel vs docetaxel for first-line
therapy of metastatic breast cancer
Arm A Arm B Arm C Arm D
nab-Paclitaxel nab-Paclitaxel nab-Paclitaxel Docetaxel
300 mg/m² q3w 100 mg/m² weekly 150 mg/m² weekly 100 mg/m² q3w
Adverse event (n = 76) q3/4w (n = 76) q3/4w (n = 74) (n = 74)
Hematologic toxicity
Neutropenia 44 25 43 94
Febrile neutropenia 1 1 1 8
Nonhematologic toxicity
Fatigue* 4 0 3 19
Arthralgia* 1 0 0 0
Peripheral neuropathy* 17 9 16 11
* Grade 3 only
Adapted from Gradishar et al33
ty of various first-line nab-paclitaxel mg/m² every 3 weeks (arm D). The Four interim analyses were prospec-
regimens. In this trial, nab-paclitaxel primary study endpoints were ORR tively planned to assist in planning
was administered weekly or every 3 and safety. Major inclusion criteria future trials of nab-paclitaxel.
weeks, and lower-dose nab-paclitax- were measurable stage IV breast can- Preliminary results from this trial,
el was compared with a higher-dose cer; no prior chemotherapy for meta- based upon the fourth planned in-
regimen. In addition, the activity and static disease; ≥ 3 weeks since cyto- terim analysis, were presented at the
tolerability of nab-paclitaxel were toxic chemotherapy; ≥ 4 weeks since 2007 Annual Meeting of the Amer-
compared with standard docetaxel radiotherapy, with full recovery; East- ican Society of Clinical Oncology.33
therapy.33 ern Cooperative Oncology Group Three hundred patients were accrued
Patients with MBC were random- performance status of 0–2; and nor- onto this study from November 2005
ized to receive treatment with one of mal hematologic and blood-chemis- through June 2006. Patient charac-
four regimens (Figure 1): nab-pacli- try profiles. Patients were excluded if teristics were well balanced among
taxel 300 mg/m² once every 3 weeks they had received a cumulative doxo- each of the four treatment arms. The
(arm A); nab-paclitaxel 100 mg/m² rubicin dose ≥ 360 mg/m², had pa- investigator-confirmed ORR (RE-
weekly for 3 of every 4 weeks (arm renchymal brain metastases, or were CIST [Response Evaluation Criteria
B); 150 mg/m² weekly for 3 of ev- receiving concurrent immunotherapy In Solid Tumors] criteria) was 43%,
ery 4 weeks (arm C); or docetaxel 100 or hormonal therapy for breast cancer. 62%, and 70% in the nab-paclitaxel
4 COMMUNITY ONCOLOGY ■ June 2008 www.CommunityOncology.netarms A, B, and C, respectively, and
Response rate (%)
38% in the docetaxel (arm D; Table
1); the ORR for weekly nab-paclitaxel 80
in both arms B and C was statistically Pearson correlation coefficient
superior to the ORR for docetaxel in (investigator vs IRR) = 0.507 Investigator
70% IRR
arm D (P = 0.002 and P = 0.003, re-
60
spectively). Progression-free survival
62%
(PFS; as assessed by the investigators)
with nab-paclitaxel therapy was sta-
tistically superior to the PFS achieved 40 47%
45%
with docetaxel, with a HR of 0.63 for 43%
arm A (P = 0.046) and 0.46 for arm 35%
38%
C (P = 0.002). There was no statisti-
cal difference in PFS when arm B was 20 28%
compared with the docetaxel arm.
Comparison of higher versus lower
doses of nab-paclitaxel revealed that
the 150 mg/m² weekly dose resulted 0
in a significantly longer PFS than the nab-Paclitaxel nab-Paclitaxel nab-Paclitaxel Docetaxel
100 mg/m² weekly dose (HR, 0.55; 300 mg/m² q3w 100 mg/m² qw3/4 150 mg/m² qw3/4 100 mg/m² q3w
(Arm A; n = 76) (Arm B; n = 76) (Arm C; n = 74) (Arm D; n = 74)
P = 0.009).
Data from 1,414 investigator re-
FIGURE 2 Progression-free survival in phase II randomized trial of nab-paclitaxel as first-line
sponse assessments were reviewed by therapy of metastatic breast cancer. Abbreviations: q3w = every 3 weeks; q3/4w = every 3
a blinded independent radiology re- of 4 weeks. IRR = independent radiology review. Adapted from Gradishar et al.33
view (IRR). Responses as determined
by the IRR were 35%, 45%, and 47% with all three nab-paclitaxel regimens adverse effects caused by taxane sol-
for nab-paclitaxel arms A, B, and C, were less than those observed with vents such as Cremophor, can severe-
respectively, and 28% for arm D (Fig- docetaxel. ly limit the use of these agents for the
ure 2). When investigator-assessed Peripheral neuropathy occurred treatment of MBC and other tumor
and IRR data were compared, there with both nab-paclitaxel and docetax- types. Dose escalation with standard
was good correlation (Pearson corre- el, as expected with taxane therapy, taxanes often is limited by unaccept-
lation coefficient, r) for both response and was predominantly of low grade. able toxicity, and dose reductions or
rates (r = 0.507) and PFS (r = 0.852). The frequency of peripheral neuropa- discontinuations often are indicated
Overall survival data from this trial thy (all grades) was not significantly in patients with severe toxicities. For
are not yet mature. increased with nab-paclitaxel (range, some patients, any survival benefit af-
Selected grade 3/4 treatment-re- 53%–72%) relative to the frequency forded by these therapies may be out-
lated toxicities observed in the four seen with docetaxel (62%). No grade weighed by acute, chronic, or late-
treatment arms are shown in Table 2. 4 peripheral neuropathy was noted in onset toxicities. This is particularly
Overall, there were significantly few- any of the four treatment arms. Medi- true for older women (> 65 years) and
er patients with treatment-related ad- an time to improvement of peripheral those with comorbidities or poor per-
verse events in the three nab-paclitax- neuropathy was significantly shorter formance status who cannot tolerate
el arms than in the docetaxel arm (P < with nab-paclitaxel (median, 16-23 these drugs. Alternative chemother-
0.001 for all comparisons to docetax- days) than with docetaxel (median, 41 apy options with equivalent efficacy
el). Treatment with nab-paclitaxel (all days; Figure 3). nab-Paclitaxel thera- but reduced risk of serious adverse ef-
regimens) resulted in a significantly py was thus well tolerated in this pa- fects are highly desirable for first-line
lower frequency of treatment-relat- tient population and exhibited an im- therapy of MBC.
ed adverse events than docetaxel for proved safety profile relative to that Preclinical and clinical studies
neutropenia (P < 0.001), fatigue (P < of docetaxel, with faster resolution of have demonstrated that nab-pacli-
0.02), and arthralgia (P < 0.02, except peripheral neuropathy. taxel is associated with an improved
for arm B [not significant]; Cochran- toxicity profile relative to standard
Mantel-Haenszel test). Similarly, the Conclusion paclitaxel, due to the lack of the Cre-
incidences of grade 3/4 neutrope- The toxicities associated with an- mophor-EL solvent. The improve-
nia, febrile neutropenia, and fatigue thracyclines and taxanes, plus the ment results in fewer side effects and
Volume 5/Number 6/Supplement 7 June 2008 ■ COMMUNITY ONCOLOGY 5Community Translations
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