- Email: [email protected]
Randomized Phase II Trial of Weekly vs. Every 2 Weeks vs. Every 3 Weeks Nanoparticle Albumin-Bound Paclitaxel With Bevacizumab as First-Line Chemotherapy for Metastatic Breast Cancer
Original Study
Randomized Phase II Trial of Weekly vs. Every 2 Weeks vs. Every 3 Weeks Nanoparticle AlbuminBound Paclitaxel With Bevacizumab as First-Line Chemotherapy for Metastatic Breast Cancer Andrew D. Seidman,1 Alison K. Conlin,2 Ariadne Bach,1 Mary Ellen Moynahan,1 Diana Lake,1 Andres Forero,3 Gail Shaw Wright,4 Mary Helen Hackney,5 Alicia Clawson,6 Larry Norton,1 Clifford A. Hudis1 Abstract This randomized phase II trial tested nanoparticle albumin-bound paclitaxel (nab-P) in 3 different schedules: weekly, every 2 weeks (q2W), and every 3 weeks (q3W). Because bevacizumab prolonged progression-free survival in earlier trials with taxanes in metastatic breast cancer (MBC), all the patients received this agent. Weekly nanoparticle albumin-bound paclitaxel (nab-P) appeared to have the highest therapeutic index, but treatment was limited by sensory neuropathy. Background: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC. Patients and Methods: This open-label phase II study randomized patients to nab-P 260 mg/m2 q3w (arm A) vs. 260 mg/m2 q2w with filgrastim (arm B) vs. 130 mg/m2 weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints. Results: Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P ¼ .105). Conclusions: Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored. Clinical Breast Cancer, Vol. 13, No. 4, 239-46 ª 2013 Elsevier Inc. All rights reserved. Keywords: Nanoparticle albumin-bound paclitaxel, Taxanes, Combination therapy, Neuropathy, Human epidermal growth factor receptor 2 negative
Introduction The efficacy and safety profiles of nanoparticle albumin-bound paclitaxel (nab-P) were established in a phase III trial of patients This article contains original material that was presented at the 34th San Antonio Breast Cancer Symposium Meeting, December 2011, and the American Society of Clinical Oncology Meeting, June 2009, Chicago, Illinois
with metastatic breast cancer (MBC).1 Compared with solvent-based paclitaxel 175 mg/m2 every 3 weeks (q3w), nab-P 260 mg/m2 q3w demonstrated a significantly higher overall response rate (ORR) (the 5
Virginia Commonwealth University, Richmond, VA Celgene Corporation, Summit, NJ
6
Submitted: Nov 27, 2012; Accepted: Feb 26, 2013 1
Memorial Sloan-Kettering Cancer Center, Department of Medicine, Division of Solid Tumor Oncology, New York, NY 2 Providence Cancer Center, Department of Medicine, Portland, OR 3 University of Alabama at Birmingham, Department of Medicine, Birmingham, AL 4 Florida Cancer Specialists, New Port Richey, FL
1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.02.008
Address for correspondence: Andrew D. Seidman, MD, Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY 10065 Fax: (646) 888-4555; e-mail contact: [email protected]
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Figure 1 Consort Diagram
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; nab-P ¼ nanoparticle albumin-bound paclitaxel.
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primary endpoint, 33% vs. 19%; P ¼ .001) and a significantly longer time to tumor progression (TTP) (23.0 vs. 16.9 weeks, hazard ratio [HR], 0.75; P ¼ .006). Although a 49% higher dose of paclitaxel was achieved with nab-P compared with solvent-based paclitaxel, the incidence of treatment-related grade 4 neutropenia was significantly lower for patients who received nab-P vs. solventbased paclitaxel (9% vs. 22%, respectively; P < .001). Efforts to optimize clinical outcomes with nab-P for MBC have focused on different schedules and doses.2-4 In a phase II trial of patients with MBC who previously had been heavily treated with taxanes for MBC (N ¼ 181), nab-P on a first 3 of 4 weeks (qw 3/4) schedule produced similar median overall survival (OS) durations when given at a dose of 100 or 125 mg/m2 qw 3/4 (9.2 and 9.1 months, respectively).5 The ORRs of 14% and 16%, respectively, demonstrated the activity of nab-P in taxane-resistant MBC. More recently, a second randomized phase II trial compared different schedules and doses of nab-P vs. docetaxel as first-line treatment for patients with MBC.4 Results of this trial suggested that, at least at the maximum tolerated doses for q3w and qw 3/4, the qw 3/4 schedule of nab-P had greater efficacy than the q3w nab-P schedule.4,6 However, 47% of patients in the qw 3/4 treatment arm
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required 1 dose reduction due to adverse events (AEs), which alluded to the need for yet further research on optimal dosing.6 Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor.7 A total of 5 phase III trials demonstrated varying advantages for the combination of bevacizumab with chemotherapy with respect to progression-free survival (PFS), but none of these trials revealed a significant difference in terms of median OS.8-12 Although the US Food and Drug Administration (FDA) approval for bevacizumab was rescinded,7 taxanes were routinely administered with this antiangiogenic agent both on and off study when the present trial was designed. Every 2 weeks (q2w) solvent-based paclitaxel as a component of dose-dense adjuvant chemotherapy improved relapse-free survival and median OS compared with q3w solvent-based paclitaxel.13 Dose-dense therapy with nab-P as part of a sequential chemotherapy treatment regimen has been demonstrated to be feasible in early breast cancer trials.11,14,15 Preclinical models show unique antiangiogenic synergy for nab-P and bevacizumab,16 and a recent trial demonstrated a reasonable tolerability profile for patients with early-stage breast cancer treated with concurrent dose-dense nab-P and bevacizumab.14,15 Motivated by these observations, we
Andrew D. Seidman et al
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Figure 2 Trial Design: Bevacizumab Is Administered at 10 mg/kg in Weekly and Every 2 Weeks (q2W) Arms and 15 mg/kg in Every 3 Weeks (q3W) Arm
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HER2 ¼ human epidermal growth factor receptor 2 negative; MBC ¼ metastatic breast cancer; nab-P ¼ nanoparticle albumin-bound paclitaxel; qw ¼ weekly; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
performed a randomized phase II trial that compared q3w, q2w, and continuous weekly nab-P, all with bevacizumab, as first-line chemotherapy for MBC, with the aim of optimizing this doublet for future randomized phase III comparison in the metastatic setting and possibly the adjuvant setting.
This study was performed in compliance with the Declaration of Helsinki, and the study protocol was approved by the responsible institutional review boards or ethics committees of participating centers. All patients gave voluntary written institutional review board-approved, protocol-specific informed consent.
Patients and Methods
Study Design
Patients
Patients were randomly assigned to receive nab-P 260 mg/m2 q3w with bevacizumab 15 mg/kg q3w (arm A), nab-P 260 mg/m2 q2w with bevacizumab 10 mg/kg q2w with prophylactic filgrastim or pegfilgrastim (arm B), or nab-P 130 mg/m2 weekly uninterrupted with bevacizumab 10 mg/kg q2w (arm C) (Figure 2). Both nab-P and bevacizumab were to be continued until disease progression or limiting toxicity. All patients who received 1 dose of treatment were evaluable for response and toxicity. In the absence of progression, patients continued in the study unless they developed prohibitive toxicity. Progressive disease or unacceptable toxicities were the criteria for treatment failure and discontinuation from the study. Baseline imaging studies were performed within 30 days of registration, and an electrocardiogram was performed within 42 days. Complete blood cell counts were obtained q3w. Prophylactic filgrastim was not generally used in arms A or C but could be used as required for treatment-limiting neutropenia. A 21-day cycle of therapy could be initiated in patients in the weekly nab-P group provided the absolute neutrophil count (ANC) was 1000/mL; for q2w and q3w nab-P, the ANC had to be 1500/mL. Platelets had to be 100 109/L for all schedules on day 1 of each cycle. No steroid or antihistamine premedication was planned. The protocol was amended on November 1, 2007, to remove arm B, based on an interim analysis that showed excessive toxicity and the recommendation of the Independent Data Safety Monitoring Committee.
The study population consisted of women with measurable histologically confirmed MBC. Up to one line of prior chemotherapy (adjuvant or neoadjuvant) for early-stage breast cancer was allowed. Bone-only metastases, lymphangitic pulmonary metastases, and previously irradiated tumors without subsequent progression were considered nonmeasurable. Prior adjuvant taxane-containing therapy was allowed, provided that 1 year had transpired from its completion to protocol entry. For a nonetaxane-based adjuvant regimen, 6 months had to have elapsed from treatment to relapse. Adequate renal, hepatic, and hematologic function was required. Patients were not eligible for inclusion in this study if they had parenchymal brain metastases, including leptomeningeal involvement; uncontrolled hypertension (defined as blood pressure of > 150/100 mm Hg) or New York Heart Association grade 2 congestive heart failure; or a history of coagulopathy, thromboembolism, bleeding diathesis, or therapeutic anticoagulation (including chronic use of aspirin or nonsteroidal anti-inflammatory drugs). Low-dose warfarin for anticoagulation of venous access device or low-dose low-molecular-weight heparin for deep venous thrombosis prophylaxis was permitted. Patients with preexisting sensory neuropathy of grade > 1 were excluded. The urine proteincreatinine ratio had to be < 1.0 at screening. Women of childbearing potential required a negative serum behuman chorionic gonadotropin test.
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Table 1 Baseline Demographic and Patient Characteristics Characteristic
Arm A, nab-P 260 mg/m2 q3w D Bevacizumab (n [ 75)
Arm B, nab-P 260 mg/m2 q2w D Bevacizumab (n [ 54)
Arm C, nab-P 130 mg/m2 Weekly D Bevacizumab (n [ 79)
59 (29-80)
56 (36-79)
56 (32-85)
Median age (range), y Age, n (%) < 65 y
53 (71)
41 (76)
63 (80)
65 y
22 (29)
13 (24)
16 (20)
ECOG performance status, no. (%) 0
43 (57)
33 (61)
48 (61)
1
29 (39)
17 (31)
27 (34)
2
3 (4)
4 (7)
4 (5)
70 (89)
Visceral-dominant disease, no. (%) Yes
65 (87)
51 (94)
No
9 (12)
2 (4)
9 (11)
Unknown
1 (1)
1 (2)
0
Premenopausal, no. (%) Yes
11 (15)
11 (20)
16 (20)
No
64 (85)
43 (80)
63 (80)
Prior chemotherapy, no. (%)
46 (61)
35 (65)
48 (61)
Prior neoadjuvant or adjuvant taxane, no. (%)
27 (36)
21 (39)
31 (39)
Solvent-based paclitaxel
18 (24)
14 (26)
18 (23)
9 (12)
7 (13)
13 (16)
38 (54)
28 (52)
41 (52)
35 (47)
23 (43)
38 (48)
3 (4)
5 (9)
3 (4)
33 (44)
28 (52)
36 (46)
Docetaxel Prior neoadjuvant or adjuvant anthracycline, no. (%) Doxorubicin Epirubicin Disease-free interval < 2 y, no. (%)
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; nab-P ¼ nanoparticle albumin-bound paclitaxel; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
Dose Modifications nab-P could be given at the start of each cycle provided the ANC returned to the level specified below and the platelet count returned to > 100 109/L. For each subsequent dose of nab-P within a cycle, the patients had to have an ANC as specified below and platelets > 75 109/L. The q3w schedule. Treatment should be delayed for a patient with ANC < 1500/mL on the day of the next dose until ANC rises to 1500/mL. Filgrastim or pegfilgrastim would be administered on subsequent cycles. The q2w schedule. Treatment should be delayed for a patient with ANC < 1500/mL on the day of the next dose until ANC rises to 1500/mL (prophylactic filgrastim or pegfilgrastim is already part of this schedule). Dose should then be reduced by 1 dose level for subsequent cycles.
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Weekly schedule. For a patient with ANC < 1000/mL on the day of any weekly dose, filgrastim should be administered on days 2 to 5, 24 hours after dosing. For a second ANC < 1000/mL (despite filgrastim on days 2-5), nab-P should be reduced by 1 dose level for subsequent treatments.
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In the event of grade 3 or nonhematologic toxicity, nab-P was to be held until resolution to grade 2. The dose of nab-P could be reduced by approximately 15% of the starting dose level and subsequently by 18% of the previous dose level (Supplementary Table 1). Doses were not to be re-escalated.
Statistical Methods The primary efficacy endpoint was the percentage of patients who achieved an objective confirmed complete or partial overall lesion response based on the Response Evaluation Criteria in Solid Tumors.17 Treatment group differences for the ORR were tested by using the Cochran-Mantel-Haenszel test stratified by study center. Secondary efficacy endpoints included the percentage of patients with stable disease for 16 weeks, time to disease progression, duration of response, and patient survival. The safety and/or tolerability endpoints were the incidence of treatmentemergent AEs and serious AEs, nadir of myelosuppression, and the incidence of patients who experienced dose modifications, dose interruptions, and/or premature discontinuation of the study drug. In exploratory analyses, these endpoints also were evaluated among patients with a disease-free interval (DFI) of < 2 years, defined as
Andrew D. Seidman et al Figure 4 Overall Survival
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Figure 3 Time to Tumor Progression
Abbreviations: nab-P ¼ nanoparticle albumin-bound paclitaxel; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks; TTP ¼ time to tumor progression.
the length of time from completion of (neo)adjuvant therapy to the diagnosis of MBC, and among patients with visceral dominant metastases. Survival was measured from the date of the first dose of the study drug until the date of death due to any cause. Surviving patients were censored at the date last known to be alive. TTP was measured from the date of the first dose until the date of first disease progression. Surviving patients without disease progression were censored at the date last known to be progression free. Patient survival and TTP were analyzed by using Kaplan-Meier methods. Because all the regimens were expected to result in responses in > 30% of patients, there was no early stopping rule for efficacy; however, interim safety analyses were conducted separately for each treatment group when 20, 40, and 60 patients had completed 4 cycles of therapy. If 7 of 20 patients, 12 of 40 patients, or 16 of 60 patients in a treatment group experienced grade 3 to 4 nonhematologic toxicity or grade 3 to 4 febrile neutropenia, accrual would be stopped in that group and the dosage and schedule would be re-evaluated. If all regimens met the criterion for continuation, the patients were to continue to be randomly assigned to the treatment arms until the trial was completed. In this case, “the winner” would be chosen based on an aggregate of efficacy and toxicity. If all 3 regimens had similar apparent efficacy, the least toxic regimen would be taken forward. If all 3 regimens had similar toxicity, the most-effective regimen would be taken forward. As per the protocol-specified stopping rule, arm B was closed early because of the unacceptable safety profile of interim safety analyses. Therefore, the group comparisons of efficacy and safety were performed between arms A and C only. However, descriptive statistics are presented for arm B.
Results Patient Characteristics Of the 212 patients randomized, 208 patients were treated (Figure 1). Demographic and clinical characteristics for the 208 patients treated with nab-P and bevacizumab are shown in Table 1. Arms A, B, and C were well balanced for prior adjuvant anthracycline and taxane exposure. The patients had a preponderance of
Abbreviations: nab-P ¼ nanoparticle albumin-bound paclitaxel; OS ¼ overall survival; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
visceral-dominant disease. Approximately one-fourth of patients were aged > 65 years.
Treatment Exposure Dose delay and/or dose reduction impacted the relative dose intensity (delivered and/or planned dose in mg/m2/wk). The median delivered dose intensity of nab-P was higher in arm B (117.04 mg/m2/wk) than in arm A (82.11 mg/m2/wk) and in arm C (95.42 mg/m2/wk). The median cumulative dose for nab-P during the study in arm A (1740 mg/m2) was higher than that in arm B (1570 mg/m2) and was similar to that in arm C (1700 mg/ m2). Dose reductions occurred more frequently in arms B (61%) and C (67%) than in arm A (47%). More patients in arm C required dose delays (86%) compared with the other treatment arms (arm A, 53%; arm B, 52%).
Efficacy The response proportions for arms A, B, and C were 45%, 41%, and 46%, respectively (P ¼ .664 for arm A vs. arm C). There was no statistically significant differences among the arms. As shown in Figure 3, the median TTP for arms A, B, and C were 8.0, 5.8, and 9.0 months, respectively (P ¼ .494 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.7, 5.8, and 8.8 months, respectively (P ¼ .537 for arm A vs. arm C). The median OS for arms A, B, and C was 21.3, 19, and 23.7 months, respectively (P ¼ .650 for arm A vs. arm C) (Figure 4).
Subset Analyses Among patients with a DFI of < 2 years, response rates were 33%, 50%, and 44% (P ¼ .275 for arm A vs. arm C) in arms A (n ¼ 33), B (n ¼ 28), and C (n ¼ 36), respectively. The median TTP for arms A, B, and C was 7.0, 5.8, and 8.8 months, respectively (P ¼ .200 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.3, 5.8, and 8.8 months, respectively (P ¼ .177 for arm A vs. arm C), and the median OS was 19.1, 21.9, and 22.3 months, respectively (P ¼ .592 for arm A vs. arm C).
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Table 2 Toxicity by Treatment Arm Arm A, 260 mg/m2 q3w, no. (%) (n [ 75)
Arm B, 260 mg/m2 q2w, no. (%) (n [ 54)
Grade 1-2
Grade 1-2
Grade 3-4
Grade 3-4
Arm C, 130 mg/m2 Weekly, no. (%) (n [ 79) Grade 1-2
Grade 3-4
P Value (arm A vs. arm C)a
Hematologicb Thrombocytopeniac Neutropenia Anemiac
4 (5) 6 (8) 17 (23)
Febrile neutropenia
0
0 12 (16) 0 2 (3)
2 (4)
0
6 (11)
3 (6)
7 (9)
26 (33)
.044
21 (39)
2 (4)
28 (35)
6 (8)
.019
0
.149
0
1 (2)
3 (4)
0
0
.829
Nonhematologic Neuropathy c
41 (55)
25 (33)
18 (33)
30 (56)
30 (38)
36 (46)
.407
Arthralgia
19 (25)
4 (5)
20 (37)
1 (2)
11 (14)
Fatigue
43 (57)
13 (17)
29 (54)
19 (35)
51 (65)
15 (19)
Skin rashc
20 (27)
2 (3)
17 (31)
1 (2)
35 (44)
1 (1)
.053
Diarrheac
24 (32)
0
21 (39)
3 (6)
40 (51)
6 (8)
.001
Nauseac
34 (45)
3 (4)
32 (59)
4 (7)
38 (48)
2 (3)
.983
Nail changesc
13 (17)
0
13 (24)
3 (6)
29 (37)
7 (9)
<.001
Epistaxisc
32 (43)
1 (1)
23 (43)
0
43 (54)
1 (1)
.209
Hypertensionc
20 (27)
3 (4)
9 (17)
8 (10)
4 (5)
.070
1 (2)
0
.002 .134
Abbreviations: q2w ¼ every 2 weeks; q3w ¼ every 3 weeks. a P values are based on a Cochran-Mantel-Haenszel test for all grades. b Hematologic toxicities are based on investigator-reported events. c No grade 4 toxicity was reported.
Among patients with visceral-dominant metastases, response rates were 45%, 39%, and 46% in arms A (n ¼ 65), B (n ¼ 51), and C (n ¼ 70), respectively (P ¼ .465 for arm A vs. arm C). The median TTP for arms A, B, and C was 7.7, 5.8, and 9.0 months, respectively (P ¼ .146 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.6, 5.8, and 9.0 months, respectively (P ¼ .166 for arm A vs. arm C), and the median OS was 19.8, 18.9, and 24.6 months, respectively (P ¼ .335 for arm A vs. arm C).
Safety AE data are presented in Table 2. Peripheral neuropathy was common and treatment limiting, which resulted in protocol withdrawal in 19%, 43%, and 27% of patients in arms A, B, and C, respectively. As per prior reports,1,4 encountered neurotoxicity was primarily sensory and commonly readily reversible upon treatment delay and dose reduction; 34 of 36 patients who experienced grade 3 or 4 peripheral neuropathy with weekly nab-P dosing improved to grade 2 after a median of 15 days. The most common grade 3 or 4 AEs experienced by patients with a DFI < 2 years or those with visceral-dominant metastases were sensory neuropathy (44% in both groups), fatigue (24% in both groups), and neutropenia (22% and 19%, respectively). The majority of patients discontinued treatment due to disease progression (36%) or unacceptable toxicity (40%). No new or unique safety signals were associated with the use of bevacizumab.
Discussion
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Regardless of administration schedule, nab-P with bevacizumab is an active regimen as first-line therapy in human epidermal growth factor receptor 2enegative MBC. Although there were no statistically significant differences in response rates (the primary endpoint)
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or TTP between arm A and arm C, statistically nonsignificant trends in these endpoints appear to favor weekly dosing, a finding consistent with prior published experience with nab-P and solventbased paclitaxel.4,6,18,19 Shorter DFI and visceral-dominant metastases typically predict less favorable efficacy outcomes in patients with MBC.20-22 These 2 patient subsets were examined among the 3 treatment arms in this trial to determine whether patients with poor prognostic factors would experience the same clinical efficacy from nab-P plus bevacizumab compared with the intent-to-treat population. The results of these exploratory analyses revealed that both subsets of patients experienced similar efficacy and AEs as those of the intent-to-treat population. Of particular note, these patients did not demonstrate higher rates of grade 3 or 4 AEs in arm B, which was closed early due to toxicity. Thus, a DFI < 2 years or the presence of visceraldominant metastases should not preclude patients who would otherwise be eligible from receiving nab-P plus bevacizumab. The administration of nab-P 260 mg/m2 q2w caused clinically unacceptable cumulative toxicity, which resulted in the early closure of that arm. Peripheral neuropathy was the limiting toxicity in general and resulted in frequent dose reductions and delays in the weekly arm in particular. However, the grade 3 neurotoxicity encountered in the present trial, as per previous reports,1,4,5 was commonly and readily reversible upon treatment interruption. Taken together with prior published clinical experience for weekly nab-P, the use of a qw 3/4 schedule, with or without bevacizumab, may be preferable to uninterrupted weekly dosing to mitigate treatment-limiting neuropathy.4,5,23,24 Furthermore, weekly nab-P has served as a feasible foundation on which gemcitabine or capecitabine could be added for patients deemed appropriate for combination chemotherapy for MBC.25,26
Andrew D. Seidman et al Although the intermittent weekly schedule was not directly tested in our trial, nab-P on a qw 3/4 schedule has been studied in other phase II trials in MBC.4-6,23,24 The doses studied included 100, 125, and 150 mg/m2. The higher 150 mg/m2 qw 3/4 dose was selected for a phase III comparison with solvent-based paclitaxel 90 mg/m2 qw 3/4, both in combination with bevacizumab 10 mg/ kg q2w in the Cancer and Leukemia Group B (CALGB) 40502 trial that was reported at the 2012 annual meeting of the American Society for Clinical Oncology.27 Although a protocol amendment made the use of bevacizumab optional in March 2011, after the withdrawal of US Food and Drug Administration approval of bevacizumab, 98% of patients did receive the drug. The median PFS, the primary endpoint, was not statistically different between the nab-P (n ¼ 271) and solvent-based paclitaxel (n ¼ 283) arms (9.2 and 10.6 months, respectively; HR, 1.19 [95% CI, 0.96-1.49]; P ¼ .12). Median OS durations also were similar between the 2 groups (27 and 26 months, respectively; HR, 1.02 [95% CI, 0.75-1.38]; P ¼ .92). The nab-P arm was associated with higher rates of grade 3 hematologic (51% vs. 21%; P < .0001) and nonhematologic (60% vs. 44%; P ¼ .0002) toxicities and a higher rate of dose reductions by cycle 3 (45% vs. 15%). A high percentage of patients (67% in the continuous nab-P 130 mg/m2 weekly arm) in the current trial also underwent dose reductions; however, the continuous schedule set this trial apart from the CALGB study just described. Complete published results of CALGB 40502 are eagerly awaited. Although the 260 mg/m2 q2w arm B was closed early due to excessive cumulative toxicity, it is noteworthy that this dose can be safely incorporated into dose-dense sequential adjuvant chemotherapy regimens, as has been demonstrated in 2 pilot studies.11,15 Notably, these trials also used prophylactic filgrastim support, and the number of nab-P cycles was limited to 4. Indeed, many of the grade 3 events in our arm B emerged later in patients who continued beyond 4 cycles in the absence of disease progression.
Conclusion nab-P q3w or weekly with bevacizumab is active, with manageable toxicity. Future clinical studies might compare weekly uninterrupted nab-P with a qw 3/4 schedule because peripheral neuropathy, although generally quickly reversible, is dose limiting on an uninterrupted schedule. Optimizing treatment with nab-P by modifying dose, schedule, and combination partners will remain a key objective in tailoring therapy for patients with MBC.
Clinical Practice Points Weekly dosing of nab-P has been shown to result in a higher ORR
and longer PFS vs. a q3w schedule All 3 regimens tested in this first-line trial in MBC demonstrated significant clinical activity. 2 nab-P 260 mg/m plus bevacizumab 10 mg/kg q2w dosing did not appear feasible for patients with MBC due to the high rate of toxicity. Grade 3/4 sensory neuropathy appeared to be treatment limiting, which led to protocol withdrawal in 19%, 43%, and 27% of patients in arms A, B, and C, respectively; however, sensory neuropathy was reversible in the vast majority of the patients. Future trials to examine the effectiveness of continuous weekly dosing of nab-P vs. a qw 3/4 schedule are warranted.
Acknowledgments We thank Li Li of Celgene Corporation for assistance with the biostatistical analyses and John McGuire of MediTech Media for editorial and formatting assistance. The research was supported by Abraxis Bioscience, a wholly owned subsidiary of Celgene Corporation, and Genentech, a Member of the Roche Group. The content of this article is solely the responsibility of the authors.
Disclosure A. Seidman is a consultant for Celgene Corporation and Genentech. A. Clawson is an employee of Celgene Corporation. The remaining authors have stated that they have no conflicts of interest.
Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clbc.2013.02.008
References 1. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23:7794-803. 2. Ibrahim NK, Desai N, Legha S, et al. Phase I and pharmacokinetic study of ABI007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 2002; 8:1038-44. 3. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol 2005; 23:7785-93. 4. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progressionfree survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2009; 27:3611-9. 5. Blum JL, Savin MA, Edelman G, et al. Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 2007; 7:850-6. 6. Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival. Clin Breast Cancer 2012; 12:313-21. 7. Avastin (bevacizumab) [prescibing information]. South San Francisco, CA: Genentech; 2012. 8. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792-9. 9. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666-76. 10. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28:3239-47. 11. Robert NJ, Dieras V, Glaspy J, et al. Ribbon-1: Randomized, double blind, placebo-controlled, phase II trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor-2 negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29:1252-60. 12. Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2011; 29: 4286-93. 13. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 2003; 21:1431-9. 14. Robert N, Krekow L, Stokoe C, et al. Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab-paclitaxel is safe in women with early-stage breast cancer: a pilot study. Breast Cancer Res Treat 2011; 125:115-20. 15. McArthur HL, Rugo H, Nulsen B, et al. A feasibility study of bevacizumab plus dosedense doxorubicin-cyclophosphamide (AC) followed by nanoparticle albuminbound paclitaxel in early-stage breast cancer. Clin Cancer Res 2011; 17:3398-407. 16. Volk LD, Flister MJ, Chihade D, et al. Synergy of nab-paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases. Neoplasia 2011; 13:327-38. 17. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205-16.
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer 18. Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26:1642-9. 19. Verrill MW, Lee J, Cameron DA, et al. Anglo-Celtic IV: first results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC). J Clin Oncol 2007; 25(suppl 18S):abstract LBA1005. 20. Insa A, Lluch A, Prosper F, et al. Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients. Breast Cancer Res Treat 1999; 56:67-78. 21. Koenders PG, Beex LV, Kloppenborg PW, et al. Human breast cancer: survival from first metastasis. Breast Cancer Study Group. Breast Cancer Res Treat 1992; 21:173-80. 22. Imkampe A, Bendall S, Bates T. The significance of the site of recurrence to subsequent breast cancer survival. Eur J Surg Oncol 2007; 33:420-3.
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23. Danso MA, Blum JL, Robert NJ, et al. Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer. J Clin Oncol 2008; 26(suppl 15S):1075 (abstract). 24. Mirtsching B, Cosgriff T, Harker G, et al. A phase II study of weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab in metastatic breast cancer. Clin Breast Cancer 2011; 11:121-8. 25. Roy V, LaPlant BR, Gross GG, et al. Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann Oncol 2009; 20: 449-53. 26. Schwartzberg LS, Arena FP, Mintzer DM, et al. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer 2012; 12:87-93. 27. Rugo HS, Barry WT, Moreno-Aspitia A, et al. CALGB 40502/NCCTG N063H: randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 2012; 30(suppl 15S):1002 (abstract).
Andrew D. Seidman et al Supplementary Material Supplementary Table 1 Summary of nab-Paclitaxel Dose Reduction Levels Dose Level
ARM A (mg/m2)
ARM B (mg/m2)
ARM C (mg/m2)
(Starting Dose) 0
260
260
130
1 2
220 180
220 180
110 90
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Randomized Phase II Trial of Weekly vs. Every 2 Weeks vs. Every 3 Weeks Nanoparticle AlbuminBound Paclitaxel With Bevacizumab as First-Line Chemotherapy for Metastatic Breast Cancer Andrew D. Seidman,1 Alison K. Conlin,2 Ariadne Bach,1 Mary Ellen Moynahan,1 Diana Lake,1 Andres Forero,3 Gail Shaw Wright,4 Mary Helen Hackney,5 Alicia Clawson,6 Larry Norton,1 Clifford A. Hudis1 Abstract This randomized phase II trial tested nanoparticle albumin-bound paclitaxel (nab-P) in 3 different schedules: weekly, every 2 weeks (q2W), and every 3 weeks (q3W). Because bevacizumab prolonged progression-free survival in earlier trials with taxanes in metastatic breast cancer (MBC), all the patients received this agent. Weekly nanoparticle albumin-bound paclitaxel (nab-P) appeared to have the highest therapeutic index, but treatment was limited by sensory neuropathy. Background: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC. Patients and Methods: This open-label phase II study randomized patients to nab-P 260 mg/m2 q3w (arm A) vs. 260 mg/m2 q2w with filgrastim (arm B) vs. 130 mg/m2 weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints. Results: Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P ¼ .105). Conclusions: Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored. Clinical Breast Cancer, Vol. 13, No. 4, 239-46 ª 2013 Elsevier Inc. All rights reserved. Keywords: Nanoparticle albumin-bound paclitaxel, Taxanes, Combination therapy, Neuropathy, Human epidermal growth factor receptor 2 negative
Introduction The efficacy and safety profiles of nanoparticle albumin-bound paclitaxel (nab-P) were established in a phase III trial of patients This article contains original material that was presented at the 34th San Antonio Breast Cancer Symposium Meeting, December 2011, and the American Society of Clinical Oncology Meeting, June 2009, Chicago, Illinois
with metastatic breast cancer (MBC).1 Compared with solvent-based paclitaxel 175 mg/m2 every 3 weeks (q3w), nab-P 260 mg/m2 q3w demonstrated a significantly higher overall response rate (ORR) (the 5
Virginia Commonwealth University, Richmond, VA Celgene Corporation, Summit, NJ
6
Submitted: Nov 27, 2012; Accepted: Feb 26, 2013 1
Memorial Sloan-Kettering Cancer Center, Department of Medicine, Division of Solid Tumor Oncology, New York, NY 2 Providence Cancer Center, Department of Medicine, Portland, OR 3 University of Alabama at Birmingham, Department of Medicine, Birmingham, AL 4 Florida Cancer Specialists, New Port Richey, FL
1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.02.008
Address for correspondence: Andrew D. Seidman, MD, Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY 10065 Fax: (646) 888-4555; e-mail contact: [email protected]
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Figure 1 Consort Diagram
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; nab-P ¼ nanoparticle albumin-bound paclitaxel.
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primary endpoint, 33% vs. 19%; P ¼ .001) and a significantly longer time to tumor progression (TTP) (23.0 vs. 16.9 weeks, hazard ratio [HR], 0.75; P ¼ .006). Although a 49% higher dose of paclitaxel was achieved with nab-P compared with solvent-based paclitaxel, the incidence of treatment-related grade 4 neutropenia was significantly lower for patients who received nab-P vs. solventbased paclitaxel (9% vs. 22%, respectively; P < .001). Efforts to optimize clinical outcomes with nab-P for MBC have focused on different schedules and doses.2-4 In a phase II trial of patients with MBC who previously had been heavily treated with taxanes for MBC (N ¼ 181), nab-P on a first 3 of 4 weeks (qw 3/4) schedule produced similar median overall survival (OS) durations when given at a dose of 100 or 125 mg/m2 qw 3/4 (9.2 and 9.1 months, respectively).5 The ORRs of 14% and 16%, respectively, demonstrated the activity of nab-P in taxane-resistant MBC. More recently, a second randomized phase II trial compared different schedules and doses of nab-P vs. docetaxel as first-line treatment for patients with MBC.4 Results of this trial suggested that, at least at the maximum tolerated doses for q3w and qw 3/4, the qw 3/4 schedule of nab-P had greater efficacy than the q3w nab-P schedule.4,6 However, 47% of patients in the qw 3/4 treatment arm
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required 1 dose reduction due to adverse events (AEs), which alluded to the need for yet further research on optimal dosing.6 Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor.7 A total of 5 phase III trials demonstrated varying advantages for the combination of bevacizumab with chemotherapy with respect to progression-free survival (PFS), but none of these trials revealed a significant difference in terms of median OS.8-12 Although the US Food and Drug Administration (FDA) approval for bevacizumab was rescinded,7 taxanes were routinely administered with this antiangiogenic agent both on and off study when the present trial was designed. Every 2 weeks (q2w) solvent-based paclitaxel as a component of dose-dense adjuvant chemotherapy improved relapse-free survival and median OS compared with q3w solvent-based paclitaxel.13 Dose-dense therapy with nab-P as part of a sequential chemotherapy treatment regimen has been demonstrated to be feasible in early breast cancer trials.11,14,15 Preclinical models show unique antiangiogenic synergy for nab-P and bevacizumab,16 and a recent trial demonstrated a reasonable tolerability profile for patients with early-stage breast cancer treated with concurrent dose-dense nab-P and bevacizumab.14,15 Motivated by these observations, we
Andrew D. Seidman et al
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Figure 2 Trial Design: Bevacizumab Is Administered at 10 mg/kg in Weekly and Every 2 Weeks (q2W) Arms and 15 mg/kg in Every 3 Weeks (q3W) Arm
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HER2 ¼ human epidermal growth factor receptor 2 negative; MBC ¼ metastatic breast cancer; nab-P ¼ nanoparticle albumin-bound paclitaxel; qw ¼ weekly; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
performed a randomized phase II trial that compared q3w, q2w, and continuous weekly nab-P, all with bevacizumab, as first-line chemotherapy for MBC, with the aim of optimizing this doublet for future randomized phase III comparison in the metastatic setting and possibly the adjuvant setting.
This study was performed in compliance with the Declaration of Helsinki, and the study protocol was approved by the responsible institutional review boards or ethics committees of participating centers. All patients gave voluntary written institutional review board-approved, protocol-specific informed consent.
Patients and Methods
Study Design
Patients
Patients were randomly assigned to receive nab-P 260 mg/m2 q3w with bevacizumab 15 mg/kg q3w (arm A), nab-P 260 mg/m2 q2w with bevacizumab 10 mg/kg q2w with prophylactic filgrastim or pegfilgrastim (arm B), or nab-P 130 mg/m2 weekly uninterrupted with bevacizumab 10 mg/kg q2w (arm C) (Figure 2). Both nab-P and bevacizumab were to be continued until disease progression or limiting toxicity. All patients who received 1 dose of treatment were evaluable for response and toxicity. In the absence of progression, patients continued in the study unless they developed prohibitive toxicity. Progressive disease or unacceptable toxicities were the criteria for treatment failure and discontinuation from the study. Baseline imaging studies were performed within 30 days of registration, and an electrocardiogram was performed within 42 days. Complete blood cell counts were obtained q3w. Prophylactic filgrastim was not generally used in arms A or C but could be used as required for treatment-limiting neutropenia. A 21-day cycle of therapy could be initiated in patients in the weekly nab-P group provided the absolute neutrophil count (ANC) was 1000/mL; for q2w and q3w nab-P, the ANC had to be 1500/mL. Platelets had to be 100 109/L for all schedules on day 1 of each cycle. No steroid or antihistamine premedication was planned. The protocol was amended on November 1, 2007, to remove arm B, based on an interim analysis that showed excessive toxicity and the recommendation of the Independent Data Safety Monitoring Committee.
The study population consisted of women with measurable histologically confirmed MBC. Up to one line of prior chemotherapy (adjuvant or neoadjuvant) for early-stage breast cancer was allowed. Bone-only metastases, lymphangitic pulmonary metastases, and previously irradiated tumors without subsequent progression were considered nonmeasurable. Prior adjuvant taxane-containing therapy was allowed, provided that 1 year had transpired from its completion to protocol entry. For a nonetaxane-based adjuvant regimen, 6 months had to have elapsed from treatment to relapse. Adequate renal, hepatic, and hematologic function was required. Patients were not eligible for inclusion in this study if they had parenchymal brain metastases, including leptomeningeal involvement; uncontrolled hypertension (defined as blood pressure of > 150/100 mm Hg) or New York Heart Association grade 2 congestive heart failure; or a history of coagulopathy, thromboembolism, bleeding diathesis, or therapeutic anticoagulation (including chronic use of aspirin or nonsteroidal anti-inflammatory drugs). Low-dose warfarin for anticoagulation of venous access device or low-dose low-molecular-weight heparin for deep venous thrombosis prophylaxis was permitted. Patients with preexisting sensory neuropathy of grade > 1 were excluded. The urine proteincreatinine ratio had to be < 1.0 at screening. Women of childbearing potential required a negative serum behuman chorionic gonadotropin test.
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Table 1 Baseline Demographic and Patient Characteristics Characteristic
Arm A, nab-P 260 mg/m2 q3w D Bevacizumab (n [ 75)
Arm B, nab-P 260 mg/m2 q2w D Bevacizumab (n [ 54)
Arm C, nab-P 130 mg/m2 Weekly D Bevacizumab (n [ 79)
59 (29-80)
56 (36-79)
56 (32-85)
Median age (range), y Age, n (%) < 65 y
53 (71)
41 (76)
63 (80)
65 y
22 (29)
13 (24)
16 (20)
ECOG performance status, no. (%) 0
43 (57)
33 (61)
48 (61)
1
29 (39)
17 (31)
27 (34)
2
3 (4)
4 (7)
4 (5)
70 (89)
Visceral-dominant disease, no. (%) Yes
65 (87)
51 (94)
No
9 (12)
2 (4)
9 (11)
Unknown
1 (1)
1 (2)
0
Premenopausal, no. (%) Yes
11 (15)
11 (20)
16 (20)
No
64 (85)
43 (80)
63 (80)
Prior chemotherapy, no. (%)
46 (61)
35 (65)
48 (61)
Prior neoadjuvant or adjuvant taxane, no. (%)
27 (36)
21 (39)
31 (39)
Solvent-based paclitaxel
18 (24)
14 (26)
18 (23)
9 (12)
7 (13)
13 (16)
38 (54)
28 (52)
41 (52)
35 (47)
23 (43)
38 (48)
3 (4)
5 (9)
3 (4)
33 (44)
28 (52)
36 (46)
Docetaxel Prior neoadjuvant or adjuvant anthracycline, no. (%) Doxorubicin Epirubicin Disease-free interval < 2 y, no. (%)
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; nab-P ¼ nanoparticle albumin-bound paclitaxel; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
Dose Modifications nab-P could be given at the start of each cycle provided the ANC returned to the level specified below and the platelet count returned to > 100 109/L. For each subsequent dose of nab-P within a cycle, the patients had to have an ANC as specified below and platelets > 75 109/L. The q3w schedule. Treatment should be delayed for a patient with ANC < 1500/mL on the day of the next dose until ANC rises to 1500/mL. Filgrastim or pegfilgrastim would be administered on subsequent cycles. The q2w schedule. Treatment should be delayed for a patient with ANC < 1500/mL on the day of the next dose until ANC rises to 1500/mL (prophylactic filgrastim or pegfilgrastim is already part of this schedule). Dose should then be reduced by 1 dose level for subsequent cycles.
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Weekly schedule. For a patient with ANC < 1000/mL on the day of any weekly dose, filgrastim should be administered on days 2 to 5, 24 hours after dosing. For a second ANC < 1000/mL (despite filgrastim on days 2-5), nab-P should be reduced by 1 dose level for subsequent treatments.
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In the event of grade 3 or nonhematologic toxicity, nab-P was to be held until resolution to grade 2. The dose of nab-P could be reduced by approximately 15% of the starting dose level and subsequently by 18% of the previous dose level (Supplementary Table 1). Doses were not to be re-escalated.
Statistical Methods The primary efficacy endpoint was the percentage of patients who achieved an objective confirmed complete or partial overall lesion response based on the Response Evaluation Criteria in Solid Tumors.17 Treatment group differences for the ORR were tested by using the Cochran-Mantel-Haenszel test stratified by study center. Secondary efficacy endpoints included the percentage of patients with stable disease for 16 weeks, time to disease progression, duration of response, and patient survival. The safety and/or tolerability endpoints were the incidence of treatmentemergent AEs and serious AEs, nadir of myelosuppression, and the incidence of patients who experienced dose modifications, dose interruptions, and/or premature discontinuation of the study drug. In exploratory analyses, these endpoints also were evaluated among patients with a disease-free interval (DFI) of < 2 years, defined as
Andrew D. Seidman et al Figure 4 Overall Survival
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Figure 3 Time to Tumor Progression
Abbreviations: nab-P ¼ nanoparticle albumin-bound paclitaxel; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks; TTP ¼ time to tumor progression.
the length of time from completion of (neo)adjuvant therapy to the diagnosis of MBC, and among patients with visceral dominant metastases. Survival was measured from the date of the first dose of the study drug until the date of death due to any cause. Surviving patients were censored at the date last known to be alive. TTP was measured from the date of the first dose until the date of first disease progression. Surviving patients without disease progression were censored at the date last known to be progression free. Patient survival and TTP were analyzed by using Kaplan-Meier methods. Because all the regimens were expected to result in responses in > 30% of patients, there was no early stopping rule for efficacy; however, interim safety analyses were conducted separately for each treatment group when 20, 40, and 60 patients had completed 4 cycles of therapy. If 7 of 20 patients, 12 of 40 patients, or 16 of 60 patients in a treatment group experienced grade 3 to 4 nonhematologic toxicity or grade 3 to 4 febrile neutropenia, accrual would be stopped in that group and the dosage and schedule would be re-evaluated. If all regimens met the criterion for continuation, the patients were to continue to be randomly assigned to the treatment arms until the trial was completed. In this case, “the winner” would be chosen based on an aggregate of efficacy and toxicity. If all 3 regimens had similar apparent efficacy, the least toxic regimen would be taken forward. If all 3 regimens had similar toxicity, the most-effective regimen would be taken forward. As per the protocol-specified stopping rule, arm B was closed early because of the unacceptable safety profile of interim safety analyses. Therefore, the group comparisons of efficacy and safety were performed between arms A and C only. However, descriptive statistics are presented for arm B.
Results Patient Characteristics Of the 212 patients randomized, 208 patients were treated (Figure 1). Demographic and clinical characteristics for the 208 patients treated with nab-P and bevacizumab are shown in Table 1. Arms A, B, and C were well balanced for prior adjuvant anthracycline and taxane exposure. The patients had a preponderance of
Abbreviations: nab-P ¼ nanoparticle albumin-bound paclitaxel; OS ¼ overall survival; q2w ¼ every 2 weeks; q3w ¼ every 3 weeks.
visceral-dominant disease. Approximately one-fourth of patients were aged > 65 years.
Treatment Exposure Dose delay and/or dose reduction impacted the relative dose intensity (delivered and/or planned dose in mg/m2/wk). The median delivered dose intensity of nab-P was higher in arm B (117.04 mg/m2/wk) than in arm A (82.11 mg/m2/wk) and in arm C (95.42 mg/m2/wk). The median cumulative dose for nab-P during the study in arm A (1740 mg/m2) was higher than that in arm B (1570 mg/m2) and was similar to that in arm C (1700 mg/ m2). Dose reductions occurred more frequently in arms B (61%) and C (67%) than in arm A (47%). More patients in arm C required dose delays (86%) compared with the other treatment arms (arm A, 53%; arm B, 52%).
Efficacy The response proportions for arms A, B, and C were 45%, 41%, and 46%, respectively (P ¼ .664 for arm A vs. arm C). There was no statistically significant differences among the arms. As shown in Figure 3, the median TTP for arms A, B, and C were 8.0, 5.8, and 9.0 months, respectively (P ¼ .494 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.7, 5.8, and 8.8 months, respectively (P ¼ .537 for arm A vs. arm C). The median OS for arms A, B, and C was 21.3, 19, and 23.7 months, respectively (P ¼ .650 for arm A vs. arm C) (Figure 4).
Subset Analyses Among patients with a DFI of < 2 years, response rates were 33%, 50%, and 44% (P ¼ .275 for arm A vs. arm C) in arms A (n ¼ 33), B (n ¼ 28), and C (n ¼ 36), respectively. The median TTP for arms A, B, and C was 7.0, 5.8, and 8.8 months, respectively (P ¼ .200 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.3, 5.8, and 8.8 months, respectively (P ¼ .177 for arm A vs. arm C), and the median OS was 19.1, 21.9, and 22.3 months, respectively (P ¼ .592 for arm A vs. arm C).
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nab-Paclitaxel and Bevacizumab for Metastatic Breast Cancer Table 2 Toxicity by Treatment Arm Arm A, 260 mg/m2 q3w, no. (%) (n [ 75)
Arm B, 260 mg/m2 q2w, no. (%) (n [ 54)
Grade 1-2
Grade 1-2
Grade 3-4
Grade 3-4
Arm C, 130 mg/m2 Weekly, no. (%) (n [ 79) Grade 1-2
Grade 3-4
P Value (arm A vs. arm C)a
Hematologicb Thrombocytopeniac Neutropenia Anemiac
4 (5) 6 (8) 17 (23)
Febrile neutropenia
0
0 12 (16) 0 2 (3)
2 (4)
0
6 (11)
3 (6)
7 (9)
26 (33)
.044
21 (39)
2 (4)
28 (35)
6 (8)
.019
0
.149
0
1 (2)
3 (4)
0
0
.829
Nonhematologic Neuropathy c
41 (55)
25 (33)
18 (33)
30 (56)
30 (38)
36 (46)
.407
Arthralgia
19 (25)
4 (5)
20 (37)
1 (2)
11 (14)
Fatigue
43 (57)
13 (17)
29 (54)
19 (35)
51 (65)
15 (19)
Skin rashc
20 (27)
2 (3)
17 (31)
1 (2)
35 (44)
1 (1)
.053
Diarrheac
24 (32)
0
21 (39)
3 (6)
40 (51)
6 (8)
.001
Nauseac
34 (45)
3 (4)
32 (59)
4 (7)
38 (48)
2 (3)
.983
Nail changesc
13 (17)
0
13 (24)
3 (6)
29 (37)
7 (9)
<.001
Epistaxisc
32 (43)
1 (1)
23 (43)
0
43 (54)
1 (1)
.209
Hypertensionc
20 (27)
3 (4)
9 (17)
8 (10)
4 (5)
.070
1 (2)
0
.002 .134
Abbreviations: q2w ¼ every 2 weeks; q3w ¼ every 3 weeks. a P values are based on a Cochran-Mantel-Haenszel test for all grades. b Hematologic toxicities are based on investigator-reported events. c No grade 4 toxicity was reported.
Among patients with visceral-dominant metastases, response rates were 45%, 39%, and 46% in arms A (n ¼ 65), B (n ¼ 51), and C (n ¼ 70), respectively (P ¼ .465 for arm A vs. arm C). The median TTP for arms A, B, and C was 7.7, 5.8, and 9.0 months, respectively (P ¼ .146 for arm A vs. arm C). The median PFS for arms A, B, and C was 7.6, 5.8, and 9.0 months, respectively (P ¼ .166 for arm A vs. arm C), and the median OS was 19.8, 18.9, and 24.6 months, respectively (P ¼ .335 for arm A vs. arm C).
Safety AE data are presented in Table 2. Peripheral neuropathy was common and treatment limiting, which resulted in protocol withdrawal in 19%, 43%, and 27% of patients in arms A, B, and C, respectively. As per prior reports,1,4 encountered neurotoxicity was primarily sensory and commonly readily reversible upon treatment delay and dose reduction; 34 of 36 patients who experienced grade 3 or 4 peripheral neuropathy with weekly nab-P dosing improved to grade 2 after a median of 15 days. The most common grade 3 or 4 AEs experienced by patients with a DFI < 2 years or those with visceral-dominant metastases were sensory neuropathy (44% in both groups), fatigue (24% in both groups), and neutropenia (22% and 19%, respectively). The majority of patients discontinued treatment due to disease progression (36%) or unacceptable toxicity (40%). No new or unique safety signals were associated with the use of bevacizumab.
Discussion
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Regardless of administration schedule, nab-P with bevacizumab is an active regimen as first-line therapy in human epidermal growth factor receptor 2enegative MBC. Although there were no statistically significant differences in response rates (the primary endpoint)
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or TTP between arm A and arm C, statistically nonsignificant trends in these endpoints appear to favor weekly dosing, a finding consistent with prior published experience with nab-P and solventbased paclitaxel.4,6,18,19 Shorter DFI and visceral-dominant metastases typically predict less favorable efficacy outcomes in patients with MBC.20-22 These 2 patient subsets were examined among the 3 treatment arms in this trial to determine whether patients with poor prognostic factors would experience the same clinical efficacy from nab-P plus bevacizumab compared with the intent-to-treat population. The results of these exploratory analyses revealed that both subsets of patients experienced similar efficacy and AEs as those of the intent-to-treat population. Of particular note, these patients did not demonstrate higher rates of grade 3 or 4 AEs in arm B, which was closed early due to toxicity. Thus, a DFI < 2 years or the presence of visceraldominant metastases should not preclude patients who would otherwise be eligible from receiving nab-P plus bevacizumab. The administration of nab-P 260 mg/m2 q2w caused clinically unacceptable cumulative toxicity, which resulted in the early closure of that arm. Peripheral neuropathy was the limiting toxicity in general and resulted in frequent dose reductions and delays in the weekly arm in particular. However, the grade 3 neurotoxicity encountered in the present trial, as per previous reports,1,4,5 was commonly and readily reversible upon treatment interruption. Taken together with prior published clinical experience for weekly nab-P, the use of a qw 3/4 schedule, with or without bevacizumab, may be preferable to uninterrupted weekly dosing to mitigate treatment-limiting neuropathy.4,5,23,24 Furthermore, weekly nab-P has served as a feasible foundation on which gemcitabine or capecitabine could be added for patients deemed appropriate for combination chemotherapy for MBC.25,26
Andrew D. Seidman et al Although the intermittent weekly schedule was not directly tested in our trial, nab-P on a qw 3/4 schedule has been studied in other phase II trials in MBC.4-6,23,24 The doses studied included 100, 125, and 150 mg/m2. The higher 150 mg/m2 qw 3/4 dose was selected for a phase III comparison with solvent-based paclitaxel 90 mg/m2 qw 3/4, both in combination with bevacizumab 10 mg/ kg q2w in the Cancer and Leukemia Group B (CALGB) 40502 trial that was reported at the 2012 annual meeting of the American Society for Clinical Oncology.27 Although a protocol amendment made the use of bevacizumab optional in March 2011, after the withdrawal of US Food and Drug Administration approval of bevacizumab, 98% of patients did receive the drug. The median PFS, the primary endpoint, was not statistically different between the nab-P (n ¼ 271) and solvent-based paclitaxel (n ¼ 283) arms (9.2 and 10.6 months, respectively; HR, 1.19 [95% CI, 0.96-1.49]; P ¼ .12). Median OS durations also were similar between the 2 groups (27 and 26 months, respectively; HR, 1.02 [95% CI, 0.75-1.38]; P ¼ .92). The nab-P arm was associated with higher rates of grade 3 hematologic (51% vs. 21%; P < .0001) and nonhematologic (60% vs. 44%; P ¼ .0002) toxicities and a higher rate of dose reductions by cycle 3 (45% vs. 15%). A high percentage of patients (67% in the continuous nab-P 130 mg/m2 weekly arm) in the current trial also underwent dose reductions; however, the continuous schedule set this trial apart from the CALGB study just described. Complete published results of CALGB 40502 are eagerly awaited. Although the 260 mg/m2 q2w arm B was closed early due to excessive cumulative toxicity, it is noteworthy that this dose can be safely incorporated into dose-dense sequential adjuvant chemotherapy regimens, as has been demonstrated in 2 pilot studies.11,15 Notably, these trials also used prophylactic filgrastim support, and the number of nab-P cycles was limited to 4. Indeed, many of the grade 3 events in our arm B emerged later in patients who continued beyond 4 cycles in the absence of disease progression.
Conclusion nab-P q3w or weekly with bevacizumab is active, with manageable toxicity. Future clinical studies might compare weekly uninterrupted nab-P with a qw 3/4 schedule because peripheral neuropathy, although generally quickly reversible, is dose limiting on an uninterrupted schedule. Optimizing treatment with nab-P by modifying dose, schedule, and combination partners will remain a key objective in tailoring therapy for patients with MBC.
Clinical Practice Points Weekly dosing of nab-P has been shown to result in a higher ORR
and longer PFS vs. a q3w schedule All 3 regimens tested in this first-line trial in MBC demonstrated significant clinical activity. 2 nab-P 260 mg/m plus bevacizumab 10 mg/kg q2w dosing did not appear feasible for patients with MBC due to the high rate of toxicity. Grade 3/4 sensory neuropathy appeared to be treatment limiting, which led to protocol withdrawal in 19%, 43%, and 27% of patients in arms A, B, and C, respectively; however, sensory neuropathy was reversible in the vast majority of the patients. Future trials to examine the effectiveness of continuous weekly dosing of nab-P vs. a qw 3/4 schedule are warranted.
Acknowledgments We thank Li Li of Celgene Corporation for assistance with the biostatistical analyses and John McGuire of MediTech Media for editorial and formatting assistance. The research was supported by Abraxis Bioscience, a wholly owned subsidiary of Celgene Corporation, and Genentech, a Member of the Roche Group. The content of this article is solely the responsibility of the authors.
Disclosure A. Seidman is a consultant for Celgene Corporation and Genentech. A. Clawson is an employee of Celgene Corporation. The remaining authors have stated that they have no conflicts of interest.
Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clbc.2013.02.008
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Andrew D. Seidman et al Supplementary Material Supplementary Table 1 Summary of nab-Paclitaxel Dose Reduction Levels Dose Level
ARM A (mg/m2)
ARM B (mg/m2)
ARM C (mg/m2)
(Starting Dose) 0
260
260
130
1 2
220 180
220 180
110 90
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