A Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel With or Without Trastuzumab in Metastatic Breast Cancer

Original Study

A Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel With or Without Trastuzumab in Metastatic Breast Cancer Barry Mirtsching,1 Thomas Cosgriff,2 Graydon Harker,3 Mark Keaton,4 Tarek Chidiac,5 Myo Min6 Abstract Introduction: Weekly administration of nanoparticle albumin-bound (nab) paclitaxel as a first-line treatment for metastatic breast cancer (MBC) has not been fully investigated. The addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is less understood. This phase II study evaluated the efficacy and safety of weekly nab paclitaxel in the first-line MBC setting. Patients whose tumors overexpressed HER2 also received trastuzumab. Patients and Methods: Patients with locally advanced or metastatic breast cancer received nab paclitaxel (125 mg/m2) by 30-minute intravenous infusion weekly for 3 of 4 weeks. Patients who were HER2-positive received concurrent trastuzumab. Results: Seventy-two patients were enrolled; HER2 expression was detected in 22 patients. The overall response rate (ORR) was 42.2% (95% CI, 30%–55%); 5 patients had a complete response (CR) and 22 patients had a partial response (PR). Additionally, 17 patients experienced stable disease (SD), providing an overall benefit (CR ⫹ PR ⫹ SD) of 68.8%. Patients with HER2-positive tumors had an ORR of 52.4%; the ORR was 38.1% in the HER2-negative population (P ⫽ .3). Median progression-free survival was 14.5 months (range, 1– 49.3 months) and survival rates at 1 year and 2 years were 69% and 62%, respectively. The most commonly observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%). Conclusion: Our findings demonstrate that weekly nab paclitaxel has a favorable safety profile and is well tolerated as a first-line treatment for MBC. An ORR of 42% and an overall benefit of 69% is extremely encouraging, particularly in the HER2-positive population where 52% of patients responded. Clinical Breast Cancer, Vol. 11, No. 2, 121-8 © 2011 Published by Elsevier Inc. Keywords: Nab paclitaxel, HER2, Sensory neuropathy, SPARC, Veeda Oncology Network

Introduction 1

An estimated 40,000 people will die of breast cancer in 2010. For those patients with metastatic breast cancer (MBC), solvent-based taxanes (paclitaxel and docetaxel) are considered standard treatment.2,3 Alternative therapies are essential for this patient populaPresented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; May 30 –June 3, 2008; and at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14 –17, 2006. 1

Center for Oncology Research and Treatment, PA, Dallas, TX Hematology and Oncology Specialists, Metairie, LA 3 Utah Cancer Specialists, Salt Lake City, UT 4 Augusta Oncology Associates, Augusta GA 5 Mid Ohio Oncology/Hematology, Columbus, OH 6 Maryland Hematology Oncology Associates, PA, Baltimore 2

Submitted: Jul 13, 2010; Revised: Oct 21, 2010; Accepted: Oct 26, 2010 Address for correspondence: Barry Mirtsching, MD, Center for Oncology Research and Treatment, PA, 7777 Forrest Ln, Ste B242, Dallas, TX 75230 Fax: 972-5665587; e-mail contact: [email protected]

1526-8209/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clbc.2011.03.007

tion, as median survival is 2–3 years4 and the 5-year survival rate is approximately 20%.5 Although paclitaxel and docetaxel have significant efficacy in breast tumors, their hydrophobic nature necessitates the use of synthetic solvents; polyoxyethylated castor oil (Cremophor® EL) for paclitaxel and polysorbate 80 for docetaxel.6,7 These solvents directly contribute to many of the toxicities observed in treated patients, most notably hypersensitivity reactions and peripheral neuropathy.8,9 Such toxicities limit the dose and duration of drug treatment and the opportunity to combine taxanes with other agents that have overlapping toxicity profiles.8 Tumor penetration and drug activity may also be compromised by solvent-associated entrapment of active drug in micelles formed in the plasma compartment, thus altering the taxane pharmacokinetics.10 Moreover, both drugs require the use of premedications and in the case of paclitaxel, special tubing and in-line filters are necessary because of leeching of DEHP (di-[2-ethylhexyl]phthalate) caused by Cremophor® EL.9

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Weekly Nab-Paclitaxel With or Without Trastuzumab in MBC Nanoparticle (or nab) paclitaxel (ABI-007, Abraxane®, Abraxis BioScience, Los Angeles, CA), an albumin-bound 130-nm particle form of paclitaxel, was developed in response to these toxicity and drug delivery concerns. The absence of synthetic solvents allows for easier administration of nab-paclitaxel, including a shorter infusion schedule and no need for special infusion kits. Hypersensitivity reactions are rare and premedication is not required.11 Both the absence of solvents and the presence of albumin allow higher doses of paclitaxel to be delivered via nab paclitaxel than with solvent-based paclitaxel. Indeed, drug transport into tumors is enhanced by albumin receptor (gp60)-mediated transcytosis across endothelial cells in preclinical models12 and by the association with the albumin-binding protein SPARC (osteonectin; secreted protein, acidic and rich in cysteine).13 In preclinical12 and clinical11,14 –16 studies, the equitoxic paclitaxel dose of nab paclitaxel was approximately 50%–70% higher than that of solvent-based paclitaxel. These higher doses afforded by nab paclitaxel appear to translate into increased drug efficacy without an increase in toxicity. Patients with MBC receiving nab paclitaxel every 3 weeks (300 mg/m2) experienced an overall response rate (ORR) of 48%, with a response rate of 64% in those patients receiving nab paclitaxel as first-line treatment for MBC.14 A phase III randomized study comparing 3-week cycles of nab paclitaxel (260 mg/m2) and solvent-based paclitaxel (175 mg/m2) reported ORRs of 33% and 19% for each treatment group, respectively. Those patients receiving nab paclitaxel as first-line treatment for MBC had a response rate of 42%, compared with 27% for patients receiving solvent-based paclitaxel.15 Randomized studies that established the advantages of a weekly taxane schedule compared with an every-3-week schedule17–20 prompted the examination of a weekly nab paclitaxel schedule. In a direct comparison between weekly (100 mg/m2 or 150 mg/m2) and every-3-week nab paclitaxel (300 mg/m2) and docetaxel (100 mg/m2), either dose of weekly nab paclitaxel was superior as a first-line treatment for MBC.21 Additional studies have further demonstrated that weekly administration of nab paclitaxel is both safe and efficacious,16,22 even in taxane-refractory patients.23 Regardless of dose or schedule, nab paclitaxel had a favorable safety profile when compared with docetaxel. These studies have demonstrated an increased efficacy of nab paclitaxel without a concurrent increase in toxicity when given weekly versus every 3 weeks. Despite the lack of premedications, severe hypersensitivity reactions were not observed.11,14 –16,23 To date, few studies have investigated the effect of weekly nab paclitaxel in the first-line MBC setting.21,22,24 Less information is available regarding nab paclitaxel when used in combination with trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The addition of trastuzumab to standard chemotherapy (an anthracycline plus cyclophosphamide or paclitaxel alone)25 or docetaxel26 has a significant clinical benefit in this patient population. A recent study investigating the combination of weekly nab-paclitaxel, carboplatin, and trastuzumab showed this regimen to be both well tolerated and efficacious with an ORR of 62.5% in patients with previously untreated HER2-positive MBC.22 The current phase II study sought to evaluate the safety, efficacy, and tolerability of nab paclitaxel given weekly as a first-line treatment of

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MBC for both HER2-positive and HER2-negative breast tumors. The addition of trastuzumab was also examined in those patients whose tumors overexpressed HER2.

Patients and Methods Patient Selection This open-label multicenter phase II trial was conducted in the community-based Veeda Oncology Network (formally the International Oncology Network) practices. The protocol was approved by a central institutional review board (IRB) with jurisdiction over sites that registered patients on study. Local IRB approval was obtained by individual sites where required. All patients signed an informed consent form before admission into the study. From March 2005 to September 2006, the Network enrolled patients with histologically or pathologically confirmed diagnosis of locally advanced or metastatic breast cancer. Patients must have had measurable disease, but were permitted to have either HER2-positive or HER2-negative breast cancer. Additional eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, age 18 years or older, estimated life expectancy of at least 12 weeks, absolute neutrophil count ⱖ 1500/ ␮L, platelets ⱖ 100,000/␮L, hemoglobin ⱖ9 g/dL, creatinine ⱕ 2 mg/dL or calculated creatinine clearance ⬎ 40 mL/min, and bilirubin ⱕ upper limit of normal (ULN). For patients with no liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must have been ⱕ 1.5 ⫻ ULN. For patients with liver metastases, AST and ALT must have been ⱕ 2.5 ⫻ ULN. Patients were not eligible if they had previously received nab paclitaxel or any previous chemotherapy for their metastatic disease. However, previous adjuvant chemotherapy, including taxane-containing regimens, was permitted provided that it was completed ⱖ 12 months before enrollment. Previous hormonal, aromatase inhibitor therapy, or immunotherapy for metastatic or locally advanced breast cancer was permitted but must have been terminated before enrollment. Previous radiation therapy was also permitted provided that ⬍ 25% of the bone marrow had been treated, the patient recovered from the acute toxic effects of treatment before trial enrollment, and treatment was completed ⱖ 4 weeks before enrollment. In addition, patients with serious intercurrent medical or psychiatric illness, a second primary malignancy (except carcinoma in situ of the cervix or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated ⬎ 5 years previously and with no evidence of recurrence), parenchymal or leptomeningeal brain metastases, or a history of hypersensitivity to taxanes or any of the components in taxanes or nab paclitaxel were not eligible. Female patients could not be pregnant or lactating.

Treatment and Procedures Patients received single-agent nab paclitaxel 125 mg/m2 as a 30minute intravenous (I.V.) infusion once a week for 3 weeks; a dose chosen based on data previously presented.27,28 A cycle was defined as 4 weeks and nab paclitaxel was not given on week 4. Trastuzumab was given concurrently to patients who were HER2 positive at an initial dose of 4 mg/kg (as a 90-minute I.V. infusion) and then at 2 mg/kg infused over 30 minutes on a weekly schedule. Patients continued to receive treatment until progressive disease (PD) or unacceptable toxicity. Patients who discontinued nab paclitaxel for rea-

Barry Mirtsching et al sons other than PD were permitted to receive single-agent trastuzumab until disease progression. Patients were removed from the study if they experienced a treatment delay ⬎ 2 weeks. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria (NCI-CTC) version 3.0. Dose adjustments for nab paclitaxel (to 100 mg/m2 and then to 80 mg/m2) were made based on hematologic and nonhematologic toxicities when appropriate. Pretreatment evaluations consisted of medical history; physical examination with assessment of ECOG PS and peripheral neuropathy; laboratory studies including complete blood count, serum chemistry profile (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total and direct bilirubin, alkaline phosphatase, AST and/or ALT, potassium, magnesium, chloride, sodium, and total calcium); and radiologic evaluation (computed tomography [CT] or magnetic resonance imaging [MRI]). Serum pregnancy tests were required for women of childbearing potential. HER2-positive patients who received trastuzumab were required to have a baseline left ventricular ejection fraction (LVEF) within 90 days of study entry (measured by either echocardiogram or multiple gated acquisition [MUGA] scan) ⱖ the lower limits of normal for the radiology facility. During treatment, patients underwent weekly blood counts and a toxicity assessment. Serum chemistries and a physical examination, with assessment of ECOG PS and peripheral neuropathy, were performed before each cycle. A radiologic evaluation was performed every 8 weeks. HER2-positive patients who received trastuzumab were required to undergo cardiac monitoring and LVEF assessment via echocardiogram or MUGA scan every 16 weeks.

Response Criteria Response was assessed every 8 weeks by radiologic evaluation, using Response Evaluation Criteria in Solid Tumors (RECIST).29 All objective responses were confirmed by a follow-up scan at least 4 weeks following documentation of the response.

Statistical Analysis The endpoints of this study were the ORR, progression-free survival (PFS), 1- and 2-year survival rates, and the safety profile of patients with locally advanced or metastatic breast cancer, who were administered nab paclitaxel weekly as first-line treatment. All analyses were completed with MedCalc software, version 11.0. The sample size of 72 patients was based on an STPlan’s exact method of binomial distribution to detect an increase in response rate from 21% to 35%, based on a significance level of 0.05 and a power of 80%. An average of 4 patients per month were recruited over a 17month period. All 72 patients recruited for this trial received study drug and were considered in the intent-to-treat (ITT) population. Only patients who had received at least 2 courses of chemotherapy were considered evaluable for response. A patient was considered a responder if a complete response (CR) or partial response (PR) was found at least once during the course of the study and confirmed 4 weeks later. The overall benefit rate was calculated as the proportion of CR ⫹ PR ⫹ stable disease (SD) responses. Those who died during therapy and before progression were counted as PD as of the date of death. The distribution of response classifications (CR, PR, SD, and PD) was examined. The ORR was analyzed as the proportion of

patients showing a CR or PR while on study. Its 95% CI is presented. A subanalysis was run comparing the responses of those patients who were HER2-positive versus HER2-negative. Progression-free survival was estimated using the Kaplan-Meier method30 and summarized by the median and 95% CI. Progressionfree survival was measured from the date of first treatment to either the date the patient was first recorded to have disease progression or the date of death if the patient died from any cause before progression. Patients who were lost to follow-up were censored as of the last date of contact. Patients who had not progressed or who died were censored at the date of last follow-up. Death was assumed from any cause and measured as the time from the start of treatment to the date of death or the last date the patient was known to be alive. Using the Kaplan-Meier method,30 the proportion of patients surviving at 1 and 2 years was estimated, and the median survival duration and its 95% CI were recorded. Patients who received 1 dose of study drug were included in the safety analysis. Adverse events were coded using the NCI-CTC, version 3.0. These were summarized by frequencies and percents. Chemotherapy administered was described in terms of the total number of cycles administered, the median (range) of cycles/doses administered, and reasons for dose modifications.

Results Patients Seventy-two patients were enrolled in this study. Patient characteristics are presented in Table 1 Patients had an ECOG PS of 0 or 1, though 1 patient with an ECOG PS of 2 was allowed to enroll in the study and was later found to be evaluable. A majority of patients had received previous adjuvant treatment, chemotherapy being the most common. Specifically, 15 patients previously received taxanes and 2 patients received previous trastuzumab. HER2 expression was detected in 22 patients (30.6%). For unknown reasons, testing was not performed in 2 patients.

Treatment Administration and Safety Seventy-two patients were treated with study drug and evaluated for safety. Patients received a median of 6 cycles (range, 1–22 cycles) and a median of 5.9 months of treatment (range, 6 days to 25.1 months). The median dose intensity was 100% of the planned dose intensity. The median dose of nab paclitaxel received by patients was 125 mg/m2/week, with a minimum dose of 94 mg/m2/week and a maximum dose of 130 mg/m2/week. Dose modifications because of toxicity occurred in 14 patients (19.4%). Nine patients (12.5%) experienced a dose modification because of other causes. Twenty patients whose tumors were HER2-positive received trastuzumab. At least 1 adverse event was experienced by 65 patients (90.3%), though the vast majority of adverse events were grade 1 or grade 2 (Table 2). The most frequently observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%). Of the 46 patients who complained of pain, 8 patients had arthralgia, 6 had back pain, and 5 had headaches. The remaining instances of pain were comprised of varied pain, including extremity pain, myalgia, tumor pain, and bone pain. Adverse events that occurred in ⱖ 10% of patients are presented in Table 2 There were 3 instances of a grade 4 event; 1 case each of arrhythmia, colitis, and cerebrovascular ischemia. A total of 9

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Weekly Nab-Paclitaxel With or Without Trastuzumab in MBC Table 1 Patient Characteristics (N ⴝ 72) Characteristic, n (%)

Table 2 Adverse Events Experienced by > 10% of Patients Value

Adverse Event Preferred Term

Sex Male

2 (2.8)

Female Median Age, Years Range

70 (97.2) 63.5 41–90

Race Black Hispanic Caucasian Asian

G1

G2

G3

G4

Total (%)a

Pain

19

16

11

0

46 (64)

Fatigue

17

20

5

0

42 (58)

Sensory Neuropathy

19

14

6

0

39 (54)

Infection

2

22

9

0

33 (46)

Nausea

22

4

1

0

27 (38)

9 (12.5)

Alopecia

5

19

0

0

24 (33)

4 (5.6)

Anemia

11

12

1

0

24 (33)

58 (80.6)

Diarrhea

15

6

0

0

21 (29)

Nail Changes

11

5

3

0

19 (26)

Edema

11

6

1

0

18 (25)

1 (1.4)

ECOG Performance Status 0

43 (59.7)

Constipation

10

3

1

0

14 (19)

1

28 (38.9)

Dyspnea

3

7

4

0

14 (19)

2

1 (1.4)

Vomiting

10

2

2

0

14 (19)

Desquamation

6

6

1

0

13 (18)

Previous Adjuvant Treatment No

18 (25)

Fever

11

1

1

0

13 (18)

Yesa

54 (75)

Anorexia

5

6

0

0

11 (15)

10 (14)

Neutropenia

1

1

8

0

10 (14)

2 (2.7)

Cardiac event

5

3

0

1

9 (13)

Chemotherapy

49 (68)

Allergic Rhinitis

7

2

0

0

9 (13)

Taxane

15 (20.8)

Cough

6

3

0

0

9 (13)

Biologic Trastuzumab

Hormonal

14 (19)

Hemorrhage

8

1

0

0

9 (13)

Radiation

17 (24)

Muscle Weakness

4

3

2

0

9 (13)

Surgery

4 (6)

Blurred Vision

5

3

0

0

8 (11)

Heartburn

6

2

0

0

8 (11)

HER2 Status Positive

22 (30.6)

Leucopenia

6

1

1

0

8 (11)

Negative

48 (66.7)

Tearing

6

2

0

0

8 (11)

Unknown

2 (2.8)

Chills

5

2

0

0

7 (10)

Dizziness

6

1

0

0

7 (10)

Dysgeusia

5

2

0

0

7 (10)

Insomnia

5

2

0

0

7 (10)

Mood Alteration

2

5

0

0

7 (10)

Pulmonary, Other

5

2

0

0

7 (10)

Abbreviations: ECOG ⫽ Eastern Cooperative Oncology Group; HER2 ⫽ Human Epidermal growth factor Receptor 2. a Patients could have more than 1 type of adjuvant treatment.

patients experienced cardiac problems, of whom 5 had received trastuzumab. Of these 5 patients, there were 3 grade 1 events (1 case each of tachycardia, arrhythmia, and left ventricular diastolic dysfunction); 1 grade 2 tachycardia event; and 1 grade 4 arrhythmia event. During the study, 25% (n ⫽ 18) of the patients recorded a total of 30 serious adverse events (SAEs); most events were due to pain, infection, or gastrointestinal or pulmonary symptoms. Of the 30 SAEs, 25 were considered related to drug treatment. The majority of events (n ⫽ 22) resolved, though 3 events were continuing, 4 resolved with sequelae, and 1 event was fatal caused by PD. All 72 patients eventually stopped treatment for various reasons, including disease progression (33.3%), adverse events (26.4%), physician decision (16.7%), withdrawal of consent (12.5%), treatment delay ⬎ 2 consecutive weeks (9.7%), and noncompliance (1.4%). Adverse events responsible for treatment discontinuation spanned several body systems. The most frequent responsible events were

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Number of Patients (N ⴝ 72)

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a

Percent of adverse events is based on the number of patients who received at least 1 dose of study drug (N ⫽ 72).

neuropathy, nail changes, enteritis, and allergic rhinitis. Thirteen patients died on study; 12 of PD and 1 of an unknown cause.

Objective Tumor Response The ORR (the rate of CR ⫹ the rate of PR) in the evaluable population was 42.2% (95% CI, 30%–55%). Five patients experienced a CR and 22 patients a PR. In addition, 17 patients experienced SD, providing an overall benefit (CR ⫹ PR ⫹ SD) of 68.8% (Table 3). An ORR of 52.4% (3 CRs and 8 PRs) was achieved in patients with HER2-positive tumors, while the ORR was 38.1% (2 CRs and 14 PRs) in the HER2-negative population, though these

Barry Mirtsching et al Table 3 Best Response to Treatment Evaluable Population (N ⴝ 64)

Evaluable Population HER2-Positive (n ⴝ 21)

Evaluable Population HER2-Negative (n ⴝ 42)

Evaluable Population HER2-Unknown (n ⴝ 1)

CR

5

3

2

-

PR

22

8

14

-

SD

17

4

12

1

PD

20

6

14

-

ORR (CR ⴙ PR)

27 (42.2%)

11 (52.4%)

16 (38.1%)

0

95% CI for ORR

30%–55%

30%–75%

24%–54%

-

Overall Benefita (CR ⴙ PR ⴙ SD)

44 (68.8%)

15 (71.4%)

28 (66.7%)

0

Treatment Response

Abbreviations: CR ⫽ complete response; HER2 ⫽ human epidermal growth factor receptor 2; ORR ⫽ overall response rate; PD ⫽ progressive disease; PR ⫽ partial response; SD ⫽ stable disease. The overall benefit rate was defined as the number of CR ⫹ PR ⫹ all SD (with no minimum time period on SD).

a

differences were not statistically significant (P ⫽ .3). The overall benefits in the HER2-positive and HER2-negative populations were 71.4% and 66.7%, respectively. The ORR in patients whose tumors were HER2-positive and who received trastuzumab was 57.9%. However, this value was not statistically different from those patients who did not receive trastuzumab (35.6%; P ⫽ .17). Moreover, among the 15 patients who received previous taxanes, the ORR was 38.5%; a value not statistically different from those patients not previously treated with taxanes (43.1%; P ⫽ 1.0). Eight patients were not assessable for response because of withdrawal of consent (n ⫽ 1), noncompliance (n ⫽ 2), disease progression before completing 2 cycles of treatment (n ⫽ 2), and unacceptable toxicities (1 case each of grade 4 cerebral ischemia, grade 3 desquamation, and grade 3 neuropathy).

Survival At the time of analysis, 59 patients (82%) had PD or died. Progression-free survival for the ITT population is shown in Figure 1. The median PFS for the ITT population was 14.5 months (range, 1– 49.3 months). At 48 months, 8% of patients remain progressionfree. Progression-free survival at 12, 24, and 36 months was 59%, 24%, and 15%, respectively. Further analysis for each HER2 subgroup revealed that median PFS was higher for the HER2-positive subset (18.7 months) compared with the HER2-negative subset (12.8 months). However, this difference was not statistically significant. Overall survival for the ITT population is presented in Figure 2. At the time of analysis, 41 patients (56.9%) had died, while 31 patients (43.1%) were alive. Overall survival rates for the ITT population at 12, 24, 36, and 48 months were 69%, 62%, 41%, and 14%, respectively. Median survival was 29 months (range, 1– 49.3 months). Median survival time for the HER2-positive subset was higher (36.8 months) than the HER2-negative subset (27.3 months). This difference did not reach statistical significance. The median follow-up time was 17.0 months (range, 3 weeks to 44.6 months).

Discussion This multicenter phase II study evaluated the efficacy and safety of weekly nab paclitaxel, given with or without trastuzumab, as a firstline treatment for MBC. We report an ORR of 42.2%, overall benefit of 68.8%, median PFS of 14.5 months, and a median OS of 29

months. The dose and weekly schedule of nab paclitaxel were well tolerated and most adverse events were manageable. Our results show that weekly nab paclitaxel is a promising first-line treatment for patients with HER2-negative and HER2-positive MBC. The addition of trastuzumab was very beneficial, as demonstrated by an ORR of 57.9% in patients who received this combination. The absence of synthetic solvents in nab paclitaxel provides many advantages over the solvent-based taxanes, including ease of administration and the ability to deliver higher doses of paclitaxel without a concurrent increase in drug toxicity.11,14 –16 Moreover, nab paclitaxel exhibits limited, but encouraging, efficacy in patients who are refractory to taxane treatment23 or who have received previous anthracycline treatment.14,15 Previous studies directly comparing docetaxel or paclitaxel to nab paclitaxel report higher response rates and longer durations of PFS and OS in patients treated with the latter.15,21 Indeed, the most encouraging results were observed in those patients treated on a weekly schedule rather than an every-3-week schedule.21 This is not surprising considering the strong evidence affirming the benefits of paclitaxel given on a weekly rather than an every-3-week schedule.17 CALGB 9840 and Anglo-Celtic IV, both phase III trials, established the superiority of weekly paclitaxel in terms of improved response rate,18,20 thus providing more evidence that weekly paclitaxel be the standard treatment schedule in MBC. Indeed, this regimen is also superior in the adjuvant setting, as reported by the ECOG 1199 trial.19 Few studies have investigated the effect of weekly single-agent nab paclitaxel in the first-line treatment setting of MBC.21,22,24 Patients who received 100 mg/m2/week or 150 mg/m2/week of nab paclitaxel experienced response rates of 45% and 49%, respectively, according to the independent radiologist assessment and 63% and 74%, respectively, according to investigator assessment.21 Continuous, uninterrupted weekly nab paclitaxel (130 mg/m2) in combination with bevacizumab was associated with an ORR of 46%.24 A recent study that investigated the combination of weekly nab paclitaxel, carboplatin, and trastuzumab in 32 patients with HER2-positive MBC reported an ORR of 62.5%.22 Our reported ORR of 42%, which was attained in a multicenter, nonacademic setting, is consistent with these data. Additionally, patients who were HER2-positive and who received trastuzumab experienced an ORR of 57.9%. Not surprisingly, pain, fatigue, and nausea were common, though most events

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Weekly Nab-Paclitaxel With or Without Trastuzumab in MBC

100 90 80 70 60 50 40 30 20 10 0 0

12

24

36

48

Time, Months

were grades 1 or 2. These rates are consistent with other studies of weekly nab paclitaxel.21–23 More than half of the patients in our population experienced sensory neuropathy, though only 6% of patients had a grade 3 event and there were no grade 4 events. These findings concur with other studies using a similar nab paclitaxel dose and schedule, and patient population. Only 3% of patients with first-line MBC who received weekly nab paclitaxel (100 mg/m2) in combination with carboplatin and trastuzumab experienced grade 3 sensory neuropathy.22 Likewise, single-agent weekly nab paclitaxel was associated with 8% of patients experiencing grade 3 neuropathy at a 100 mg/m2 dose and 14% at a 150 mg/m2 dose.21 Interestingly, a schedule of uninterrupted weekly nab paclitaxel (130 mg/m2) coincided with much higher rates of grade 3 (38%) and grade 4 neuropathy (1%),24 suggesting that a 3-week-on/1-week-off schedule is preferred. Moreover, patients who were heavily pretreated appeared to experience somewhat higher rates of sensory neuropathy (19% with the 125 mg/m2 dose).23 In contrast to other studies of weekly nab paclitaxel,21,22 we observed a lower incidence of neutropenia. The reasons for this difference are unclear, but may be caused by the addition of carboplatin to the treatment regimen22 or differences in the patient populations. Approximately 25%–30% of breast cancers overexpress the HER2 gene.31 This overexpression is associated with a poorer prognosis when compared with patients whose tumors are HER2-negative, as shown by shorter PFS and OS.31,32 Trastuzumab inhibits tumor growth when used alone, but additive and synergistic effects have been observed when combined with docetaxel and paclitaxel, respectively.33,34 The addition of trastuzumab to other chemotherapy agents, including docetaxel, vinorelbine, doxorubicin, cyclophosphamide, and paclitaxel, has a significant clinical benefit in patients with untreated MBC.25,26,35 Further, trastuzumab was active and well tolerated when used as a single agent in patients who preferred not to receive chemotherapy for their metastatic disease.36 Though the advantages of trastuzumab have been thoroughly reported, only 1 other study has investigated the combination of trastuzumab and nab paclitaxel.22 We report a beneficial effect of trastuzumab in our HER2-positive patient population as shown by an ORR of 57.9%, though there was no statistical difference in terms of ORR between

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Figure 2 Kaplan-Meier Analysis of Overall Survival in the Intent-to-Treat Population

Overall Survival, %

Progression-Free Survival, %

Figure 1 Kaplan-Meier Analysis of Progression-Free Survival in the Intent-to-Treat Population

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100 90 80 70 60 50 40 30 20 10 0 0

12

24

36

48

Time, Months

those who received trastuzumab and those who did not. Moreover, a subgroup analysis revealed that both median PFS and OS were higher in the HER2-positive group compared with the HER2-negative group; however, these differences were not statistically significant. Notwithstanding, we believe that these survival data are clinically significant, even in the absence of statistical significance. The failure to show statistical significance may be caused by our sample distribution as there was only half the number of HER2-positive patients compared with the HER2-negative patients. Nevertheless, cardiac toxicity is a concern with trastuzumab administration.25 However, more recent studies suggest that this side effect is manageable and within the expected range for this type of therapy.26 In the current study, 5 patients who received trastuzumab experienced cardiac problems. All events were grade 1 or grade 2, with the exception of 1 grade 4 arrhythmia event. Though the efficacy parameters reported in the current study are very encouraging, the response rate and duration of survival is still limited in this metastatic setting. At 48 months of follow-up, only 14% of our patients were still alive and less than half of our patients responded to treatment. The use of predictive biomarkers may be one way to improve drug response by customizing treatment. SPARC may be one such predictive marker.13 This albumin-binding protein is overexpressed in ⬎ 50% of breast cancers.37 Implicated in tumor progression and angiogenesis, SPARC upregulation is typically associated with a worse prognosis.38 However, SPARC overexpression may account for preferential accumulation of nab paclitaxel, and other albumin-bound agents, at the tumor site.12 In a retrospective study of patients with head and neck cancer, response to nab paclitaxel was higher for those patients with SPARC-positive tumors.39 Likewise, in terms of which patients respond to trastuzumab therapy, evidence suggests that deficiencies in PTEN (phosphatase and tensin homolog) protein levels may be predictive.40 Our study enrolled patients before these developments; thus the expression of SPARC and PTEN in our population is unknown. Other areas of research have focused on combining nab paclitaxel with other chemotherapy agents, including gemcitabine41 or bevacizumab,24,42,43 or all 3 agents.44 The addition of a platinum agent, like carboplatin, to a paclitaxel/trastuzumab regimen is very benefi-

Barry Mirtsching et al cial in the MBC setting.17,45 Replacing paclitaxel with nab paclitaxel further translated into increased efficacy when given in conjunction with carboplatin and trastuzumab.22 The use of sequential neoadjuvant therapy consisting of weekly nab paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide has also been shown to be beneficial in patients with locally advanced breast cancer.46 Finally, preclinical data suggest that the addition of nab paclitaxel to radiation therapy produced supra-additive effects when given before radiation.47 These studies and others will perhaps clarify the best treatment options for this patient population.

Conclusion The current study provides “real-world” data regarding the use of weekly nab paclitaxel in a multicenter nonacademic setting. Encouraging efficacy data and a well-tolerated safety profile further establish weekly nab paclitaxel as a promising treatment regimen in the firstline metastatic setting, suggesting that it could be a favorable alternative to weekly treatment with solvent-based taxanes. Moreover, the addition of trastuzumab was beneficial to those patients whose tumors overexpressed HER2.

Acknowledgments The authors thank the enrolled patients and clinicians who contributed to their care, and the Veeda Oncology Network for project support. In addition, we are grateful to Jennifer Newcomb-Fernandez, PhD, for editorial assistance and Des Ilegbodu, DrPH, for statistical assistance. This study was supported by Abraxis BioScience Inc.

Disclosures Mark Keaton has served on a Speaker’s Bureau for Abraxis BioScience Inc. All other authors report to have no relevant relationships to disclose.

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