- Email: [email protected]
Phase II Multicenter Study of Docetaxel and Bevacizumab With or Without Trastuzumab as First-Line Treatment for Patients With Metastatic Breast Cancer
Original Study
Phase II Multicenter Study of Docetaxel and Bevacizumab With or Without Trastuzumab as First-Line Treatment for Patients With Metastatic Breast Cancer Lee S. Schwartzberg,1 Suprith Badarinath,2 Mark R. Keaton,3 Barrett H. Childs4 Abstract The addition of bevacizumab to docetaxel at the standard dose of 75 mg/m2 with or without trastuzumab was investigated in a phase II, parallel-arm study of patients with metastatic breast cancer. Docetaxel combined with bevacizumab administered every 3 weeks (in human epidermal growth factor receptorenegative [HER2L] patients, n [ 52), and docetaxel plus trastuzumab plus bevacizumab (in HER2D patients, n [ 21) were feasible and safe, with high response rates and promising progression-free survival. Background: Adding bevacizumab to docetaxel or paclitaxel in the first-line improves the progression-free survival (PFS) of metastatic breast cancer (MBC) patients. Docetaxel has been studied with bevacizumab at the maximally tolerated dose of 100 mg/m2. We investigated the effects of combining bevacizumab with docetaxel (75 mg/m2) with or without trastuzumab for human epidermal growth factor receptor 2epositive (HER2þ) and HER2–negative (HER2) patients, respectively. Patients and Methods: We conducted a phase II study, stratified by HER2 status, of patients with locally advanced breast cancer or MBC who had received no prior chemotherapy for metastatic disease and showed no evidence or history of central nervous system metastases. Stratum 1 (HER2) treatment consisted of bevacizumab (15 mg/kg) followed by docetaxel (75 mg/m2) administered every 3 weeks; stratum 2 (HER2þ) treatment was the same as that of stratum 1 with the addition of trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles). Results: The trial accrued 73 patients (stratum 1, 52 patients; stratum 2, 21 patients). The most common grade 3 or 4 adverse event (all strata) was fatigue (stratum 1, 11.5%; stratum 2, 10%). The incidence of grade 3 hypertension was 6% for stratum 1 and 5% for stratum 2. The median PFS was 8.4 months (95% CI, 5.2-10.4 months) in stratum 1; the median PFS in stratum 2 was 13.3 months (95% CI, 11.9-35.4 months). The overall response rate for stratum 1was 58% and for stratum 2 was 81%, and the clinical benefit rates were 67% and 81%, respectively. Conclusion: In first-line treatment of MBC, adding docetaxel (75 mg/m2) to bevacizumab administered every 3 weeks in HER2 patients, and docetaxel plus trastuzumab plus bevacizumab treatment in HER2þ patients are feasible and safe, with high response rates and promising PFS compared with those of bevacizumabnaive historic controls. Clinical Breast Cancer, Vol. 14, No. 3, 161-8 ª 2014 Elsevier Inc. All rights reserved. Keywords: Antiangiogenic, Anti-VEGF, Chemotherapy, HER2, Taxane
Introduction The clinicaltrials.gov identifier for this study is NCT00364611. 1
The West Clinic, Memphis, TN 2 Integrated Community Oncology Network, Jacksonville, FL 3 Augusta Oncology Associates, Augusta, GA 4 Oncology, Sanofi US, LLC, Bridgewater, NJ Submitted: Jul 30, 2013; Revised: Dec 9, 2013; Accepted: Dec 11, 2013; Epub: Dec 27, 2013 Address for Correspondence: Lee S. Schwartzberg, MD, FACP, The West Clinic, 100 North Humphreys Boulevard, Memphis, TN 38120 E-mail contact: [email protected], [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.003
Extensive preclinical and clinical evidence suggests that tumor neoangiogenesis is critical in the pathogenesis and progression of solid tumors, including breast cancer.1 Vascular endothelial growth factor (VEGF) may be among the most important growth factors regulating tumor angiogenesis, subsequently leading to tumor invasion and metastasis,1 and the use of VEGF inhibitors in the treatment of advanced disease has received substantial interest. Docetaxel is among the most active cytotoxic chemotherapeutic agents for the treatment of advanced breast cancer. Previous phase II
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trials, primarily using a dose of 100 mg/m2 once every 3 weeks, established docetaxel response rates of up to 60% in both previously untreated and anthracycline-resistant patients.2,3 In a study of patients with human epidermal growth factor receptor 2enegative (HER2) metastatic breast cancer (MBC) (n ¼ 297, approximately 74% with prior anthracycline treatment), docetaxel monotherapy (100 mg/m2) was associated with a median progression-free survival (PFS) of 8.3 months.4 A recent meta-analysis concluded that the use of chemotherapy with docetaxel monotherapy was associated with a notable benefit in terms of time to progression (TTP) but not overall survival (OS).5 In the 3 studies examined in the metaanalysis, all of which enrolled patients previously treated with anthracyclines, the median TTPs were 4.2 months, 11.0 months, and 7.0 months for patients in the docetaxel monotherapy arm (at doses of 100 mg/m2, 100 mg/m2, and 75 mg/m2, respectively).5 Currently, the standard docetaxel dose in the United States is 75 mg/m2, and recent studies have reported response rates at this dose as high as approximately 70% and a median PFS of 10.3 months in MBC patients.6,7 The reduced docetaxel dose also offers a benefit in lowering toxicity; in patients with advanced breast cancer, notably higher rates of grade 3 or 4 febrile neutropenia and infection have been reported in patients receiving the 100 mg/m2 dose (compared with the rates in patients receiving the 75 mg/m2 dose of docetaxel) as well as numerically higher incidences of neutropenia, leucopenia, anemia, and thrombocytopenia.8 Bevacizumab (Avastin) is a recombinant, humanized anti-VEGF monoclonal antibody that binds and neutralizes all isoforms of VEGF, and it was the first antiangiogenesis therapy to be approved for use in combination with chemotherapy in human cancer.9 For firstline treatment of patients with HER2 MBC, adding bevacizumab to the taxane docetaxel or paclitaxel has resulted in improved PFS compared with that of docetaxel or paclitaxel alone.10-12 In a recently published pooled analysis of 3 randomized phase III trials (E2100 [Eastern Cooperative Oncology Group 2100], AVADO [Avastin and Docetaxel], RIBBON1 [Regimens in Bevacizumab for Breast Oncology]), substantial improvements in PFS and response rate were observed in HER2 patients treated with bevacizumab with chemotherapy compared with those of chemotherapy alone, whereas no improvement in OS was noted.13 Similarly, a meta-analysis of these same trials (n ¼ 2695 patients) demonstrated a 30% risk reduction in PFS and increased response rate with bevacizumab.14 The majority of data concerning use of bevacizumab in combination with docetaxel in HER2 MBC are from the phase III AVADO study, which also utilized a dose of 100 mg/m2 of docetaxel.10 By comparison, there are currently little data for bevacizumab combined with docetaxel at the current standard dosage of docetaxel in the United States (75 mg/m2) in patients with HER2 MBC.15 In the HER2þ breast cancer subset, bevacizumab has been studied with docetaxel 100 mg/m2 plus trastuzumab 6 mg/m2 every 3 weeks in the AVEREL (Avastin [Bevacizumab] in Combination with Herceptin [Trastuzumab]/Docetaxel in Patients With HER2þ Metastatic Breast Cancer) study (n ¼ 421 treated patients with HER2þ locally recurrent MBC).16 In this study, an improvement in PFS by independent review committee was demonstrated for patients receiving bevacizumab; toxicities that were higher in the bevacizumab arm were congestive heart failure, febrile neutropenia, and hypertension.16 Notably, no study adding
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bevacizumab to chemotherapy with or without trastuzumab has improved OS, leading the US Food and Drug Administration to withdraw approval of the agent in the treatment of MBC. The present study aimed to evaluate the efficacy and safety of the standard US dose of docetaxel and bevacizumab in combination, with or without trastuzumab, for first-line treatment of patients with HER2þ or HER2 MBC. The study also evaluated other efficacy parameters, such as overall response rate (ORR), clinical benefit rate (CBR), duration of response, and OS.
Patients and Methods Study Design This was a phase II, nonrandomized, parallel-group, open-label, prospective, multicenter study. Patients were stratified according to HER2 status as assessed by either fluorescence in situ hybridization (FISH) (ratio > 2.2) or immunohistochemistry (IHC) (3þ) analysis at the time of enrollment. The study was conducted in compliance with recommendations of the 18th World Health Congress (Helsinki) and all applicable amendments, US federal regulations relevant to the use of investigational therapeutic agents, and the Guideline for Good Clinical Practice. The protocol and all relevant information were provided to appropriate institutional review boards for review and approval prior to study commencement. Informed consent was obtained from each patient prior to the conduct of any study-related procedure.
Treatments
In stratum 1 (HER2 patients), patients received bevacizumab (15 mg/kg intravenous [I.V.] infusion over 120 minutes on day 1 of cycle 1, administered prior to chemotherapy) and docetaxel (75 mg/m2 I.V. infusion over 60 minutes, infused following completion of full bevacizumab dose). In stratum 2 (HER2þ patients), patients received bevacizumab (15 mg/kg I.V. infusion over 120 minutes on day 1 of cycle 1, administered prior to chemotherapy), docetaxel (75 mg/m2 I.V. infusion over 60 minutes, infused following completion of full bevacizumab dose), and trastuzumab, infused following full docetaxel dose (8 mg/kg I.V. infusion over 90 minutes on day 2 of cycle 1, loading dose; 6 mg/kg, subsequent cycles). In both groups, bevacizumab infusion times were incrementally decreased if no reaction was observed in the first or previous doses (day 1 of cycle 2, 90 minutes; day 1 of cycle 3, 60 minutes; day 1 of subsequent cycles, 30 minutes). Dexamethasone premedication was administered to all patients treated with docetaxel, and prophylactic acetaminophen and diphenhydramine were recommended prior to trastuzumab treatment. All patients received granulocyte colony-stimulating factor (G-CSF)/pegylated-G-CSF as primary prophylaxis for febrile neutropenia. Treatment continued until unacceptable toxicity, disease progression, or death. If docetaxel was withheld for any reason or discontinued because of toxicity, treatment with bevacizumab with or without trastuzumab continued as planned. Patients without progression of disease after 8 cycles continued with bevacizumab or bevacizumab plus trastuzumab for HER2þ patients without further docetaxel administration. Dose modifications were planned for each stratum according to the occurrence of clinically significant hematologic and/or nonhematologic toxicities (ie, therapy may have been placed “on hold” or dose reductions may have been required). Indications for
Lee S. Schwartzberg et al Figure 1 Patient Flow (Consolidated Standards of Reporting Trials [CONSORT] Diagram)
Abbreviation: ITT ¼ intention-to-treat.
docetaxel dose reduction included hematologic toxicities (eg, febrile neutropenia; grade 3 infection with or without neutropenia) or nonhematologic toxicities (eg, grade 2 nausea or vomiting; grade 3 diarrhea). Up to 2 dose reductions of docetaxel, 60 mg/m2 and 50 mg/m2, respectively, were permitted; although dose reduction of bevacizumab or trastuzumab was not permitted, the doses of these agents may have been held.
Patients Eligible patients were women 18 years old, with histologically or cytologically proven adenocarcinoma of the breast, with stage IV disease with 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors 1.0. Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1, a life expectancy 24 weeks, normal left ventricular ejection fraction (LVEF) by echocardiogram (ECG) or multigated acquisition (MUGA), and no evidence of brain metastasis by magnetic resonance imaging scan. Patients with prior chemotherapy for MBC, prior treatment with bevacizumab or other anti-VEGF therapy, concurrent treatment with any other nonprotocol anticancer therapy (with the exception of radiation therapy, as long as all target lesions being followed were not in the radiation field), a current or prior history of brain or leptomeningeal metastases, and those with a history of any other malignancy within the past 5 years (with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix) were excluded from the study.
Safety Evaluations Safety was evaluated for all registered patients who received at least 1 dose (or any portion of a planned dose) of any of the study
medications. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. The following tests or procedures were performed at each cycle: full clinical examination, including ECOG PS; vital signs, weight, and assessment of any residual toxicity as a result of previous therapy; and laboratory tests, including hematology, liver, and renal biochemistry. For patients in the trastuzumab arm only, LVEF, as assessed by MUGA or ECG, was evaluated after every 6 cycles.
Efficacy Evaluations The primary endpoint, PFS, was defined as the time from registration to first documentation of objective tumor progression or death resulting from any cause; 6- and 12-month PFSs were also evaluated. Secondary endpoints included ORR, defined as the percentage of patients with complete response (CR) or partial response (PR), and CBR, defined as the percentage of patients with CR, PR, or stable disease 26 weeks.
Statistical Analysis Primary analysis was based on the intention-to-treat (ITT) population. PFS distribution was assessed using the KaplaneMeier method; median PFS times with 95% confidence intervals (95% CIs) were computed using the Brookmeyer and Crowley method. A probability of being progression-free at 6 and 12 months was derived from this analysis, with 95% CI for these estimates computed using the Greenwood formula. For the primary endpoint, in each stratum, a sample size of 93 evaluable patients was required to ensure a power of 80% if the true PFS rate at 6 and 12 months was 0.63; maximal sample size per stratum was 93 efficacy-evaluable patients. Formal statistical comparisons and testing were not
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Docetaxel and Bevacizumab in Metastatic Breast Cancer Table 1 Baseline Demographic and Clinical Characteristics (Intention-to-Treat Population)
Age, years, mean ± SD
Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 21)
52.6 10.8
52.8 12.6
Results
Race, n (%) White
37 (71)
15 (71)
Black
14 (27)
5 (24)
Other
1 (2)
1 (5)
0
28 (54)
16 (76)
1
24 (46)
5 (24)
1.8 0.21
1.8 0.26
ECOG PS, n (%)
Body Surface Area, m2, mean ± SD LVEF, %, mean ± SD
64.1 6.9
60.2 6.8
Stage at First Diagnosis, n (%) I
9 (17)
4 (19)
II
14 (27)
3 (14)
III
10 (19)
5 (24)
IV
17 (33)
9 (43)
1609 (2305)
984 (1182)
Time Since First Diagnosis, d, mean (SD) Site of Primary Disease, n (%) Left breast
26 (50)
10 (48)
Right breast
25 (48)
10 (48)
1 (2)
1 (5)
Ductal
42 (81)
18 (86)
Lobular
5 (10)
2 (9)
Other
5 (10)
1 (5)
Bilateral Histology, n (%)
Estrogen Receptor Status, n (%) Positive
30 (57.7)
11 (52.4)
Negative
22 (42.3)
10 (47.6)
Progesterone Receptor Status, n (%) Positive
21 (40.4)
9 (42.9)
Negative
31 (59.6)
12 (57.1)
29 (55.7)
8 (38.1)
Prior Adjuvant Chemotherapy, n (%) Known Sites of Metastatic Disease at Current Diagnosis, n (%) Adrenals
1 (5)
Bone
26 (50)
12 (57)
Lung
19 (36)
7 (33)
Liver
23 (44)
7 (33)
Lymph nodes
39 (75)
14 (67)
Mediastinum
11 (21)
5 (24)
Pleura
3 (6)
0
Pleural effusion, malignant
5 (10)
1 (5)
13 (25)
6 (29)
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HER2 ¼ human epidermal growth factor receptor 2; LVEF ¼ left ventricular ejection fraction.
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Patients The ITT population consisted of 73 patients accrued from August 2006 to March 2009; 52 in stratum 1 and 21 in stratum 2 (Fig. 1). Baseline characteristics are shown in Table 1. The safety population comprised the 72 patients who received study treatment (52 in stratum 1, 20 in stratum 2). In the ITT population, 30 (57.7%) of the 52 stratum 1 and 11 (52.4%) of the 21 stratum 2 patients were estrogen receptorepositive (ERþ) and 22 of 52 (42.3%) and 10 of 21 (47.6%) patients, respectively, were progesterone receptorepositive (PRþ); all patients were assessable for hormone receptor status. HER2 status was assessed by either FISH analysis (49%) or 3þ IHC (51%). In stratum 1, 29 patients had prior adjuvant chemotherapy, and in stratum 2, 8 patients had prior adjuvant chemotherapy, 1 with trastuzumab. In all, 9 patients in stratum 1 and 3 in stratum 2 had received prior endocrine therapy for metastatic disease. At the time of data cutoff, 2 patients in stratum 1 remained on treatment (Table 2). The most common reason for treatment discontinuation was disease progression (38 of 52 [73%] in stratum 1; 8 of 21 [38%] in stratum 2). The median number of treatment cycles delivered in each stratum is shown in Table 3. In the safety population, patients in stratum 1 received a mean of 11.5 cycles of study medication overall; patients in stratum 2 received a mean of 14.8 cycles of study medication overall.
Safety In stratum 1, 52 patients reported at least 1 treatment-emergent AE (TEAE), and 33 of 52 (63%) reported at least 1 grade 3 or 4 AE as worst severity. In stratum 2, 20 patients reported at least 1 TEAE, and 13 of 20 (65%) patients reported at least 1 TEAE with grade 3 as worst severity. The most common AEs were fatigue, alopecia, and nausea (Table 4). The most common grade
Table 2 Patient Disposition Stratum 1 Stratum 2 HER2L (n [ 52)a HER2D (n [ 21)b
1 (2)
Other
164
performed. Sample size and power calculations based on PFS were no longer applicable in view of the final enrollment in the trial (stratum 1, n ¼ 52; stratum 2, n ¼ 21); generalizations from the descriptive results of the study must therefore be viewed with caution.
Treated Patients (Safety Population), n (%)c
52 (100)
20 (95)
7 (14)
4 (19)
Reason for Discontinued Treatment, n (%)c Adverse event Patient’s request Disease progression Other
3 (6)
4 (19)
38 (73)
8 (38)
3 (6)
4 (19)
Abbreviation: HER2 ¼ human epidermal growth factor receptor 2. a The treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b The treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab. c Percentages are based on number of patients enrolled (intention-to-treat population) in the study in each column.
Lee S. Schwartzberg et al acute renal failure, and 2 patients with dehydration), and no serious treatment-related AE reported for patients in stratum 2. Of note, grade 3 or 4 neutropenia was observed in 3 of 52 (5.8%) patients in stratum 1 and grade 3 neutropenia was observed in 1 of 20 (5.0%) patients in stratum 2. Grade 3 or 4 febrile neutropenia was observed in 1 of 51 (1.9%) patients in stratum 1 and was not observed in stratum 2. There was no treatment-related death, colonic perforation, or clinical congestive heart failure event. The incidence of clinically significant changes in laboratory abnormalities, vital signs, LVEF, ECG, and ECOG PS was low, and no unexpected safety risk was observed for either of the combination treatment regimens.
Table 3 Number of Treatment Cycles (Safety Population) Treatment Docetaxel, median number of cycles (range) Bevacizumab, median number of cycles (range) Trastuzumab, median number of cycles (range)
Stratum 1 Stratum 2 HER2L (n [ 52)a HER2D (n [ 20)b 8 (1-29)
8 (2-26)
8 (1-39)
12.5 (1-30)
NA
13 (2-30)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; NA ¼ not applicable. a The treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b The treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab.
Efficacy
3 or 4 AE was fatigue (6 of 52 [12%] patients in stratum 1; 2 of 20 [10%] patients in stratum 2). With the exception of mucosal inflammation (3 of 52 [6%] patients in stratum 1), all grade 3 or 4 AEs were observed in only 1 or 2 patients per stratum. The incidence of grade 3 or 4 hypertension or increased blood pressure was low (3 of 52 [6%] patients in stratum 1; 1 of 20 [5%] patients in stratum 2). There were 7 serious treatment-related AEs reported for 4 of 52 (8%) patients in stratum 1 (1 patient each with febrile neutropenia, mucosal inflammation, rectal abscess, ataxia, and
The median duration of PFS (KaplaneMeier estimate) for stratum 1 was 8.4 months (95% CI, 5.2-10.4 months) (Fig. 2), and the 6- and 12-month PFS rates were 60% (95% CI, 45%73%) and 31% (95% CI, 19%-45%), respectively. The estimated OS rates at 6 and 24 months were 92% (95% CI, 80%-97%) and 55% (95% CI, 40%-69%), respectively, whereas OS was estimated to be about 24.7 months (95% CI, 16.1-27.9 months) (Fig. 3). ORR was 58% and CBR was 67% (Table 5); the median
Table 4 Most Common Treatment-Emergent Adverse Events (‡ 25%) (Safety Population) Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 20)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
52 (100)
33 (63)
20 (100)
13 (65)
Fatigue
37 (71)
6 (12)
13 (65)
2 (10)
Alopecia
34 (65)
15 (75)
Nausea
28 (54)
10 (50)
Diarrhea
23 (44)
8 (40)
Dysgeusia
20 (39)
8 (40)
1 (5)
Nail disorder
18 (35)
7 (35)
1 (5)
Constipation
17 (33)
4 (20)
Arthralgia
17 (33)
Epistaxis
17 (33)
Event, n (%) At least 1 TEAE
2 (4)
6 (30) 8 (40)
Headache
16 (31)
9 (45)
Lacrimation increased
15 (29)
10 (50)
Mucosal inflammation
15 (29)
Pain in extremity
13 (25)
Hypertension Vomiting
8 (15)
3 (6)
4 (20) 3 (6)
12 (23)
8 (40)
9 (17)
6 (30)
Urinary tract infection
9 (17)
6 (30)
NR
6 (30)
8 (15)
5 (25)
Sinusitis
1 (5)
7 (35)
Stomatitis Rash
1 (5)
3 (15)
Decreased appetite
11 (21)
Bone pain
10 (19)
Insomnia
10 (19)
5 (25)
Cough
NR
5 (25)
Rhinorrhea
NR
5 (25)
1 (5) 1 (5)
5 (25) 2 (4)
5 (25) 1 (5)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; NR ¼ not reported; TEAEs ¼ treatment-emergent adverse events.
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Docetaxel and Bevacizumab in Metastatic Breast Cancer Figure 2 Cumulative Probability of Progression-Free Survival (KaplaneMeier Estimates; Intention-to-Treat Population) for Stratum 1 and Stratum 2
Abbreviations: Bev ¼ bevacizumab; Doce ¼ docetaxel; ITT ¼ intention-to-treat; Tras ¼ trastuzumab.
duration of response was 7.6 months (95% CI, 4.1-10.0 months) (Table 6). In stratum 2 (HER2þ patients), the median duration of PFS (KaplaneMeier estimate) was approximately 13.3 months (95% CI, 11.9-35.4 months) (Fig. 2), and the 6- and 12-month PFS rates were 90% (95% CI, 70%-99%) and 81% (95% CI, 58%95%), respectively. The estimated OS rates at 6 and 24 months were 100% (95% CI, not applicable [NA]-NA) and 74% (95% CI, 20.3%eNA) (Fig. 3); OS was estimated to be about 32.4 months (95% CI, 20.4 months-NA) (Fig. 3). ORR was 81% (Table 5), CBR was 81% (Table 5), and median duration of
response was approximately 12.0 months (95% CI, 9.6-28.3 months) (Table 6).
Discussion The AVADO study provided the clinical rationale for combining full-dose docetaxel-based chemotherapy with bevacizumab.10 In that trial, the grade 3 or 4 AE incidence rates in both study arms (bevacizumab [15 mg/kg]-docetaxel and placebo-docetaxel) were relatively high, with the treatment arm exhibiting a greater incidence of grade 3 neutropenia (49 of 247 [20%] vs. 40 of 231 [17%]), febrile neutropenia (40 of 247 [16%] vs. 26 of 231 [11%]),
Figure 3 Cumulative Probability of Overall Survival (KaplaneMeier Estimates; Intention-to-Treat Population) for Stratum 1 and Stratum 2
Abbreviations: Bev ¼ bevacizumab; Doce ¼ docetaxel; ITT ¼ intention-to-treat; Tras ¼ trastuzumab.
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Lee S. Schwartzberg et al Table 5 Efficacy Endpoints and Responses by Response Evaluation Criteria for Solid Tumors (Intention-to-Treat Population) Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 21)
8.4 mo (5.2-10.4 mo) w24.7 mo (16.1-27.9 mo)
w13.3 mo (11.9-35.4 mo) 32.4 mo (20.4 mo-NA)
Endpoints Median PFS (95% CI) Estimated OS (95% CI)
Responses Complete response (CR), n (%) Partial response (PR), n (%) Stable disease (SD), n (%) Unevaluable, n (%) Response rate (CR þ PR), n (%) Clinical benefit rate (CR þ PR þ SD 26 wk), n (%)
3 27 14 2 30 35
(6) (52) (27) (4) (58) (67)
4 13 1 2 17 17
(19) (62) (5) (10) (81) (81)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; ITT ¼ intention-to-treat; NA ¼ not applicable; OS ¼ overall response; PFS ¼ progression-free survival.
and hypertension (11 of 247 [4.5%] vs. 3 of 231 [1.3%]). Indeed, although the 100 mg/m2 docetaxel regimen is among the most efficacious treatments for MBC, it is nonetheless associated with high levels of dose-dependent toxicity.8,10 Safety results for our study population indicate that the docetaxel 75 mg/m2 plus bevacizumab with or without trastuzumab regimens were feasible for clinical practice in the first-line treatment of MBC. In stratum 1, the most common grade 3 or 4 treatment-related AE was fatigue (6 of 52 [12%]). The median number of cycles of docetaxel was 8 in both strata, demonstrating good tolerability for the regimen; the upper ranges of docetaxel cycles administered (29 and 26 in stratum 1 and 2, respectively) were also quite remarkable. We also noted a low incidence of clinically significant changes in laboratory abnormalities, vital signs, or LVEF, and there was no unexpected safety risk identified for either combination treatment regimen. Only 7 of 52 (14%) and 4 of 21 (19%) patients in stratum 1 and 2, respectively, discontinued therapy because of AEs. Grade 3 neutropenia occurred in a total of 4 of 72 (5.5%) patients and grade 3 febrile neutropenia in only 1 patient, suggesting an improved therapeutic ratio for docetaxel administered at 75 mg/m2 compared with that of the higher dosage used in the AVADO and AVEREL trials.
Table 6 Summary of Response Rate Duration (KaplaneMeier Estimates; Intention-to-Treat Population) Stratum 1 Stratum 2 HER2L (n [ 30)a HER2D (n [ 17)b KaplaneMeier Estimate of ORR Duration (%)c 6 mo (95% CI)
62 (41-78)
100 (NA-NA)
12 mo (95% CI)
23 (10-44)
54 (23-78)
7.6 (4.1-10.0)
12.0 (9.6-28.2)
KaplaneMeier Estimate of Response Duration, mod Median (95% CI)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; ITT ¼ intention-to-treat; ORR ¼ overall response rate. a Treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b Treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab. c 95% CI computed using the Greenwood formula (using the log-log transformations). d 95% CIs computed using the Brookmeyer and Crowley method (using the log-log transformations).
The combination of highly active chemotherapeutic agents with the antiangiogenic antibody bevacizumab has resulted in substantial gains in key clinical endpoints such as PFS, response rate, and duration of response.15,17 The combination of bevacizumab (15 mg/kg) and docetaxel (100 mg/m2) in the AVADO trial significantly improved PFS relative to docetaxel alone in both unstratified (8.2 vs. 10.1 months; hazard ratio [HR] ¼ 0.77; P ¼ .006) and stratified (8.1 vs. 10.0 months; HR ¼ 0.67; P < .001) analyses in patients with HER2 MBC.10 The response rate (64.1%) for docetaxel combined with bevacizumab was also significantly greater than that seen for placebo or docetaxel (46.4%; P < .001).10 In a randomized phase II trial of docetaxel with or without bevacizumab as first-line therapy for HER2e MBC (TORI B01 [Translational Oncology Research International B01]), which combined bevacizumab 15 mg/kg with docetaxel 75 mg/m2 in patients with HER2 MBC, an ORR of 51% was reported with a median TTP of 9.3 months and a safety profile similar to that in the AVADO study.15 The results of our study are similar to those of TORI B01 with regard to TTP, response rate, and OS. For the HER2þ population in the AVEREL trial, patients were randomized to receive docetaxel 100 mg/m2 plus trastuzumab with or without bevacizumab 15 mg/m2 every 3 weeks. For the bevacizumab- versus nonbevacizumab-containing arms, the median PFSs by independent review committee were 16.8 months and 13.9 months (P ¼ .012), respectively, with a response rate of 76.5% versus 65.9% (P ¼ .0265), respectively. OS was not improved, a finding consistently established in trials adding bevacizumab to chemotherapy in MBC.10-14 Among the 21 stratum 2 HER2þ breast cancer patients treated with docetaxel plus bevacizumab and trastuzumab in our study, PFS rates were 90% at 6 months and 81% at 12 months, with a median PFS estimated to be 13.3 months. Despite this limited sample size, these results demonstrated a somewhat better efficacy than what was found in the control arm of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study with the same doses of docetaxel and trastuzumab with an ORR of 69% and PFS of 12.4 months.7 These results must be interpreted in the context of alternative biologic treatment in the HER2þ population. The addition of a second HER2-targeted therapy, pertuzumab, to trastuzumab and
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Docetaxel and Bevacizumab in Metastatic Breast Cancer docetaxel in the CLEOPATRA study increased PFS to 18.5 months, with a response rate of 80.2%, seemingly superior to the results of the current trial, underscoring the value of inhibiting a validated target.7 The identification of biomarkers to define a subset of patients who derive benefit from antiangiogenic agents such as bevacizumab added to chemotherapeutic regimens remains an area of intense interest; however, this endeavor has proven difficult for a number of reasons. Angiogenic processes are complex and highly adaptive, such that multiple factors can compensate in the face of VEGF inhibition with bevacizumab. VEGF inhibition may also have differential effects based on tumor type, and because the agents are used in combination, it is not clear which clinical endpoints accurately predict a response to bevacizumab versus a response to the chemotherapy.18 Despite these challenges, in a recent review of bevacizumab biomarkers, the association of short VEGF isoforms with PFS and OS was noted in patients with breast cancer treated with docetaxel (AVADO).18,19 Further study will be needed to validate these potential biomarkers in larger numbers of patients.
Acknowledgments
Conclusion
1. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438:967-74. 2. Crown J. A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer. Semin Oncol 1999; 26(suppl 3):5-9. 3. Nabholtz J-M, Reese D, Riva A, Tonkin K. Taxanes: paclitaxel and docetaxel. In: Nabholtz J-M, Tonkin K, Reese DM, Aapro MS, Buzdar AU, eds. Breast Cancer Management: Applications of Clinical and Translational Evidence to Subject Care. 2nd ed. Baltimore, MD: Lippincott William & Wilkins; 2000:63-85. 4. Bergh J, Bondarenko IM, Lichinitser MR, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 2012; 30:921-9. 5. Belfiglio M, Fanizza C, Tinari N, Ficorella C, Iacobelli S, Natoli C, Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer. J Cancer Res Clin Oncol 2012; 138:221-9. 6. Stemmler HJ, Harbeck N, Gröll de Rivera I, et al. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology 2010; 79:197-203. 7. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366:109-19. 8. Harvey V, Mouridsen H, Semiglazov V, et al. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24:4963-70. 9. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized antiVEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333:328-35. 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. 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. 12. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 2009; 27:4966-72. 13. Miles DW, Diéras V, Cortés J, Duenne AA, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24:2773-80. 14. Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012; 2012:417673. 15. Hurvitz SA, Allen HJ, Moroose RL, et al. A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (TORI B01). Clin Breast Cancer 2010; 10:307-12. 16. Gianni L, Romieu G, Lichinitser M, et al. First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) þ docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/ metastatic breast cancer (LR/mBC). Cancer Res 2011; 71(suppl 3), abstract S4-8. 17. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-92. 18. Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 2013; 31:1219-30. 19. Miles DW, de Haas SL, Dirix L, et al. Plasma biomarker analyses in the AVADO phase III randomized study of first-line bevacizumab þ docetaxel in patients with human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer. Cancer Res 2010; 70(suppl 2), abstract P2-16-041.
Results of the current trial suggest that as a first-line treatment of MBC, docetaxel at a dose of 75 mg/m2 plus bevacizumab (15 mg/m2 every 3 weeks) in HER2 patients, or docetaxel at a dose of 75 mg/m2 plus trastuzumab every 3 weeks plus bevacizumab in HER2þ patients was safe and feasible. Response rates and PFSs for HER2 patients were similar to those of previous reports, confirming the benefit of adding bevacizumab to docetaxel, and it was notable that less overall toxicity was seen when docetaxel at 75 mg/m2 was utilized in combination with bevacizumab.
Clinical Practice Points Docetaxel is among the most active cytotoxic chemotherapeutic
agents for the treatment of advanced breast cancer. The standard docetaxel dose in the United States is currently
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75 mg/m2, and studies have reported response rates at this dose as high as 70% in patients with MBC. Combining antiangiogenesis therapy (bevacizumab) with docetaxel has demonstrated improved PFS and response rate in MBC patients. Likewise, adding trastuzumab to combined docetaxel and bevacizumab has been investigated in the subset of patients with HER2þ MBC, also resulting in gains in PFS and response rate. However, these earlier studies (most notably AVADO [docetaxel plus bevacizumab] and AVEREL [docetaxel plus bevacizumab plus trastuzumab]), utilized a higher dose of docetaxel (100 mg/m2), which is associated with higher rates of dosedependent toxicity. This phase II study evaluated the efficacy and safety of the standard US dose of docetaxel (75 mg/m2) combined with bevacizumab, with or without trastuzumab (for HER2þ patients), for the first-line treatment of patients with MBC. The results of this study demonstrate the feasibility and safety of these combination therapies for patients with MBC. Efficacy results (PFS and response rate) were comparable to those previously reported, particularly in the HER2 stratum. Less overall toxicity with use of docetaxel at the lower dose of 75 mg/m2 in combination with bevacizumab was also noted.
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This study was supported by Sanofi. Editorial support in the preparation of this article was provided by Maria Soushko, PhD, of Phase Five Communications Inc. and sponsored by Sanofi US. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.
Disclosure The authors received no financial compensation for their work on this article. Lee S. Schwartzberg is a speaker for Roche/Genentech and is a former advisor to Sanofi. Barrett H. Childs was an employee of Sanofi US, LLC, during the time the study was conducted and during manuscript preparation. The authors have stated that they have no other conflicts of interest.
References
Phase II Multicenter Study of Docetaxel and Bevacizumab With or Without Trastuzumab as First-Line Treatment for Patients With Metastatic Breast Cancer Lee S. Schwartzberg,1 Suprith Badarinath,2 Mark R. Keaton,3 Barrett H. Childs4 Abstract The addition of bevacizumab to docetaxel at the standard dose of 75 mg/m2 with or without trastuzumab was investigated in a phase II, parallel-arm study of patients with metastatic breast cancer. Docetaxel combined with bevacizumab administered every 3 weeks (in human epidermal growth factor receptorenegative [HER2L] patients, n [ 52), and docetaxel plus trastuzumab plus bevacizumab (in HER2D patients, n [ 21) were feasible and safe, with high response rates and promising progression-free survival. Background: Adding bevacizumab to docetaxel or paclitaxel in the first-line improves the progression-free survival (PFS) of metastatic breast cancer (MBC) patients. Docetaxel has been studied with bevacizumab at the maximally tolerated dose of 100 mg/m2. We investigated the effects of combining bevacizumab with docetaxel (75 mg/m2) with or without trastuzumab for human epidermal growth factor receptor 2epositive (HER2þ) and HER2–negative (HER2) patients, respectively. Patients and Methods: We conducted a phase II study, stratified by HER2 status, of patients with locally advanced breast cancer or MBC who had received no prior chemotherapy for metastatic disease and showed no evidence or history of central nervous system metastases. Stratum 1 (HER2) treatment consisted of bevacizumab (15 mg/kg) followed by docetaxel (75 mg/m2) administered every 3 weeks; stratum 2 (HER2þ) treatment was the same as that of stratum 1 with the addition of trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles). Results: The trial accrued 73 patients (stratum 1, 52 patients; stratum 2, 21 patients). The most common grade 3 or 4 adverse event (all strata) was fatigue (stratum 1, 11.5%; stratum 2, 10%). The incidence of grade 3 hypertension was 6% for stratum 1 and 5% for stratum 2. The median PFS was 8.4 months (95% CI, 5.2-10.4 months) in stratum 1; the median PFS in stratum 2 was 13.3 months (95% CI, 11.9-35.4 months). The overall response rate for stratum 1was 58% and for stratum 2 was 81%, and the clinical benefit rates were 67% and 81%, respectively. Conclusion: In first-line treatment of MBC, adding docetaxel (75 mg/m2) to bevacizumab administered every 3 weeks in HER2 patients, and docetaxel plus trastuzumab plus bevacizumab treatment in HER2þ patients are feasible and safe, with high response rates and promising PFS compared with those of bevacizumabnaive historic controls. Clinical Breast Cancer, Vol. 14, No. 3, 161-8 ª 2014 Elsevier Inc. All rights reserved. Keywords: Antiangiogenic, Anti-VEGF, Chemotherapy, HER2, Taxane
Introduction The clinicaltrials.gov identifier for this study is NCT00364611. 1
The West Clinic, Memphis, TN 2 Integrated Community Oncology Network, Jacksonville, FL 3 Augusta Oncology Associates, Augusta, GA 4 Oncology, Sanofi US, LLC, Bridgewater, NJ Submitted: Jul 30, 2013; Revised: Dec 9, 2013; Accepted: Dec 11, 2013; Epub: Dec 27, 2013 Address for Correspondence: Lee S. Schwartzberg, MD, FACP, The West Clinic, 100 North Humphreys Boulevard, Memphis, TN 38120 E-mail contact: [email protected], [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.003
Extensive preclinical and clinical evidence suggests that tumor neoangiogenesis is critical in the pathogenesis and progression of solid tumors, including breast cancer.1 Vascular endothelial growth factor (VEGF) may be among the most important growth factors regulating tumor angiogenesis, subsequently leading to tumor invasion and metastasis,1 and the use of VEGF inhibitors in the treatment of advanced disease has received substantial interest. Docetaxel is among the most active cytotoxic chemotherapeutic agents for the treatment of advanced breast cancer. Previous phase II
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Docetaxel and Bevacizumab in Metastatic Breast Cancer
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trials, primarily using a dose of 100 mg/m2 once every 3 weeks, established docetaxel response rates of up to 60% in both previously untreated and anthracycline-resistant patients.2,3 In a study of patients with human epidermal growth factor receptor 2enegative (HER2) metastatic breast cancer (MBC) (n ¼ 297, approximately 74% with prior anthracycline treatment), docetaxel monotherapy (100 mg/m2) was associated with a median progression-free survival (PFS) of 8.3 months.4 A recent meta-analysis concluded that the use of chemotherapy with docetaxel monotherapy was associated with a notable benefit in terms of time to progression (TTP) but not overall survival (OS).5 In the 3 studies examined in the metaanalysis, all of which enrolled patients previously treated with anthracyclines, the median TTPs were 4.2 months, 11.0 months, and 7.0 months for patients in the docetaxel monotherapy arm (at doses of 100 mg/m2, 100 mg/m2, and 75 mg/m2, respectively).5 Currently, the standard docetaxel dose in the United States is 75 mg/m2, and recent studies have reported response rates at this dose as high as approximately 70% and a median PFS of 10.3 months in MBC patients.6,7 The reduced docetaxel dose also offers a benefit in lowering toxicity; in patients with advanced breast cancer, notably higher rates of grade 3 or 4 febrile neutropenia and infection have been reported in patients receiving the 100 mg/m2 dose (compared with the rates in patients receiving the 75 mg/m2 dose of docetaxel) as well as numerically higher incidences of neutropenia, leucopenia, anemia, and thrombocytopenia.8 Bevacizumab (Avastin) is a recombinant, humanized anti-VEGF monoclonal antibody that binds and neutralizes all isoforms of VEGF, and it was the first antiangiogenesis therapy to be approved for use in combination with chemotherapy in human cancer.9 For firstline treatment of patients with HER2 MBC, adding bevacizumab to the taxane docetaxel or paclitaxel has resulted in improved PFS compared with that of docetaxel or paclitaxel alone.10-12 In a recently published pooled analysis of 3 randomized phase III trials (E2100 [Eastern Cooperative Oncology Group 2100], AVADO [Avastin and Docetaxel], RIBBON1 [Regimens in Bevacizumab for Breast Oncology]), substantial improvements in PFS and response rate were observed in HER2 patients treated with bevacizumab with chemotherapy compared with those of chemotherapy alone, whereas no improvement in OS was noted.13 Similarly, a meta-analysis of these same trials (n ¼ 2695 patients) demonstrated a 30% risk reduction in PFS and increased response rate with bevacizumab.14 The majority of data concerning use of bevacizumab in combination with docetaxel in HER2 MBC are from the phase III AVADO study, which also utilized a dose of 100 mg/m2 of docetaxel.10 By comparison, there are currently little data for bevacizumab combined with docetaxel at the current standard dosage of docetaxel in the United States (75 mg/m2) in patients with HER2 MBC.15 In the HER2þ breast cancer subset, bevacizumab has been studied with docetaxel 100 mg/m2 plus trastuzumab 6 mg/m2 every 3 weeks in the AVEREL (Avastin [Bevacizumab] in Combination with Herceptin [Trastuzumab]/Docetaxel in Patients With HER2þ Metastatic Breast Cancer) study (n ¼ 421 treated patients with HER2þ locally recurrent MBC).16 In this study, an improvement in PFS by independent review committee was demonstrated for patients receiving bevacizumab; toxicities that were higher in the bevacizumab arm were congestive heart failure, febrile neutropenia, and hypertension.16 Notably, no study adding
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bevacizumab to chemotherapy with or without trastuzumab has improved OS, leading the US Food and Drug Administration to withdraw approval of the agent in the treatment of MBC. The present study aimed to evaluate the efficacy and safety of the standard US dose of docetaxel and bevacizumab in combination, with or without trastuzumab, for first-line treatment of patients with HER2þ or HER2 MBC. The study also evaluated other efficacy parameters, such as overall response rate (ORR), clinical benefit rate (CBR), duration of response, and OS.
Patients and Methods Study Design This was a phase II, nonrandomized, parallel-group, open-label, prospective, multicenter study. Patients were stratified according to HER2 status as assessed by either fluorescence in situ hybridization (FISH) (ratio > 2.2) or immunohistochemistry (IHC) (3þ) analysis at the time of enrollment. The study was conducted in compliance with recommendations of the 18th World Health Congress (Helsinki) and all applicable amendments, US federal regulations relevant to the use of investigational therapeutic agents, and the Guideline for Good Clinical Practice. The protocol and all relevant information were provided to appropriate institutional review boards for review and approval prior to study commencement. Informed consent was obtained from each patient prior to the conduct of any study-related procedure.
Treatments
In stratum 1 (HER2 patients), patients received bevacizumab (15 mg/kg intravenous [I.V.] infusion over 120 minutes on day 1 of cycle 1, administered prior to chemotherapy) and docetaxel (75 mg/m2 I.V. infusion over 60 minutes, infused following completion of full bevacizumab dose). In stratum 2 (HER2þ patients), patients received bevacizumab (15 mg/kg I.V. infusion over 120 minutes on day 1 of cycle 1, administered prior to chemotherapy), docetaxel (75 mg/m2 I.V. infusion over 60 minutes, infused following completion of full bevacizumab dose), and trastuzumab, infused following full docetaxel dose (8 mg/kg I.V. infusion over 90 minutes on day 2 of cycle 1, loading dose; 6 mg/kg, subsequent cycles). In both groups, bevacizumab infusion times were incrementally decreased if no reaction was observed in the first or previous doses (day 1 of cycle 2, 90 minutes; day 1 of cycle 3, 60 minutes; day 1 of subsequent cycles, 30 minutes). Dexamethasone premedication was administered to all patients treated with docetaxel, and prophylactic acetaminophen and diphenhydramine were recommended prior to trastuzumab treatment. All patients received granulocyte colony-stimulating factor (G-CSF)/pegylated-G-CSF as primary prophylaxis for febrile neutropenia. Treatment continued until unacceptable toxicity, disease progression, or death. If docetaxel was withheld for any reason or discontinued because of toxicity, treatment with bevacizumab with or without trastuzumab continued as planned. Patients without progression of disease after 8 cycles continued with bevacizumab or bevacizumab plus trastuzumab for HER2þ patients without further docetaxel administration. Dose modifications were planned for each stratum according to the occurrence of clinically significant hematologic and/or nonhematologic toxicities (ie, therapy may have been placed “on hold” or dose reductions may have been required). Indications for
Lee S. Schwartzberg et al Figure 1 Patient Flow (Consolidated Standards of Reporting Trials [CONSORT] Diagram)
Abbreviation: ITT ¼ intention-to-treat.
docetaxel dose reduction included hematologic toxicities (eg, febrile neutropenia; grade 3 infection with or without neutropenia) or nonhematologic toxicities (eg, grade 2 nausea or vomiting; grade 3 diarrhea). Up to 2 dose reductions of docetaxel, 60 mg/m2 and 50 mg/m2, respectively, were permitted; although dose reduction of bevacizumab or trastuzumab was not permitted, the doses of these agents may have been held.
Patients Eligible patients were women 18 years old, with histologically or cytologically proven adenocarcinoma of the breast, with stage IV disease with 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors 1.0. Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1, a life expectancy 24 weeks, normal left ventricular ejection fraction (LVEF) by echocardiogram (ECG) or multigated acquisition (MUGA), and no evidence of brain metastasis by magnetic resonance imaging scan. Patients with prior chemotherapy for MBC, prior treatment with bevacizumab or other anti-VEGF therapy, concurrent treatment with any other nonprotocol anticancer therapy (with the exception of radiation therapy, as long as all target lesions being followed were not in the radiation field), a current or prior history of brain or leptomeningeal metastases, and those with a history of any other malignancy within the past 5 years (with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix) were excluded from the study.
Safety Evaluations Safety was evaluated for all registered patients who received at least 1 dose (or any portion of a planned dose) of any of the study
medications. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. The following tests or procedures were performed at each cycle: full clinical examination, including ECOG PS; vital signs, weight, and assessment of any residual toxicity as a result of previous therapy; and laboratory tests, including hematology, liver, and renal biochemistry. For patients in the trastuzumab arm only, LVEF, as assessed by MUGA or ECG, was evaluated after every 6 cycles.
Efficacy Evaluations The primary endpoint, PFS, was defined as the time from registration to first documentation of objective tumor progression or death resulting from any cause; 6- and 12-month PFSs were also evaluated. Secondary endpoints included ORR, defined as the percentage of patients with complete response (CR) or partial response (PR), and CBR, defined as the percentage of patients with CR, PR, or stable disease 26 weeks.
Statistical Analysis Primary analysis was based on the intention-to-treat (ITT) population. PFS distribution was assessed using the KaplaneMeier method; median PFS times with 95% confidence intervals (95% CIs) were computed using the Brookmeyer and Crowley method. A probability of being progression-free at 6 and 12 months was derived from this analysis, with 95% CI for these estimates computed using the Greenwood formula. For the primary endpoint, in each stratum, a sample size of 93 evaluable patients was required to ensure a power of 80% if the true PFS rate at 6 and 12 months was 0.63; maximal sample size per stratum was 93 efficacy-evaluable patients. Formal statistical comparisons and testing were not
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Docetaxel and Bevacizumab in Metastatic Breast Cancer Table 1 Baseline Demographic and Clinical Characteristics (Intention-to-Treat Population)
Age, years, mean ± SD
Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 21)
52.6 10.8
52.8 12.6
Results
Race, n (%) White
37 (71)
15 (71)
Black
14 (27)
5 (24)
Other
1 (2)
1 (5)
0
28 (54)
16 (76)
1
24 (46)
5 (24)
1.8 0.21
1.8 0.26
ECOG PS, n (%)
Body Surface Area, m2, mean ± SD LVEF, %, mean ± SD
64.1 6.9
60.2 6.8
Stage at First Diagnosis, n (%) I
9 (17)
4 (19)
II
14 (27)
3 (14)
III
10 (19)
5 (24)
IV
17 (33)
9 (43)
1609 (2305)
984 (1182)
Time Since First Diagnosis, d, mean (SD) Site of Primary Disease, n (%) Left breast
26 (50)
10 (48)
Right breast
25 (48)
10 (48)
1 (2)
1 (5)
Ductal
42 (81)
18 (86)
Lobular
5 (10)
2 (9)
Other
5 (10)
1 (5)
Bilateral Histology, n (%)
Estrogen Receptor Status, n (%) Positive
30 (57.7)
11 (52.4)
Negative
22 (42.3)
10 (47.6)
Progesterone Receptor Status, n (%) Positive
21 (40.4)
9 (42.9)
Negative
31 (59.6)
12 (57.1)
29 (55.7)
8 (38.1)
Prior Adjuvant Chemotherapy, n (%) Known Sites of Metastatic Disease at Current Diagnosis, n (%) Adrenals
1 (5)
Bone
26 (50)
12 (57)
Lung
19 (36)
7 (33)
Liver
23 (44)
7 (33)
Lymph nodes
39 (75)
14 (67)
Mediastinum
11 (21)
5 (24)
Pleura
3 (6)
0
Pleural effusion, malignant
5 (10)
1 (5)
13 (25)
6 (29)
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; HER2 ¼ human epidermal growth factor receptor 2; LVEF ¼ left ventricular ejection fraction.
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Patients The ITT population consisted of 73 patients accrued from August 2006 to March 2009; 52 in stratum 1 and 21 in stratum 2 (Fig. 1). Baseline characteristics are shown in Table 1. The safety population comprised the 72 patients who received study treatment (52 in stratum 1, 20 in stratum 2). In the ITT population, 30 (57.7%) of the 52 stratum 1 and 11 (52.4%) of the 21 stratum 2 patients were estrogen receptorepositive (ERþ) and 22 of 52 (42.3%) and 10 of 21 (47.6%) patients, respectively, were progesterone receptorepositive (PRþ); all patients were assessable for hormone receptor status. HER2 status was assessed by either FISH analysis (49%) or 3þ IHC (51%). In stratum 1, 29 patients had prior adjuvant chemotherapy, and in stratum 2, 8 patients had prior adjuvant chemotherapy, 1 with trastuzumab. In all, 9 patients in stratum 1 and 3 in stratum 2 had received prior endocrine therapy for metastatic disease. At the time of data cutoff, 2 patients in stratum 1 remained on treatment (Table 2). The most common reason for treatment discontinuation was disease progression (38 of 52 [73%] in stratum 1; 8 of 21 [38%] in stratum 2). The median number of treatment cycles delivered in each stratum is shown in Table 3. In the safety population, patients in stratum 1 received a mean of 11.5 cycles of study medication overall; patients in stratum 2 received a mean of 14.8 cycles of study medication overall.
Safety In stratum 1, 52 patients reported at least 1 treatment-emergent AE (TEAE), and 33 of 52 (63%) reported at least 1 grade 3 or 4 AE as worst severity. In stratum 2, 20 patients reported at least 1 TEAE, and 13 of 20 (65%) patients reported at least 1 TEAE with grade 3 as worst severity. The most common AEs were fatigue, alopecia, and nausea (Table 4). The most common grade
Table 2 Patient Disposition Stratum 1 Stratum 2 HER2L (n [ 52)a HER2D (n [ 21)b
1 (2)
Other
164
performed. Sample size and power calculations based on PFS were no longer applicable in view of the final enrollment in the trial (stratum 1, n ¼ 52; stratum 2, n ¼ 21); generalizations from the descriptive results of the study must therefore be viewed with caution.
Treated Patients (Safety Population), n (%)c
52 (100)
20 (95)
7 (14)
4 (19)
Reason for Discontinued Treatment, n (%)c Adverse event Patient’s request Disease progression Other
3 (6)
4 (19)
38 (73)
8 (38)
3 (6)
4 (19)
Abbreviation: HER2 ¼ human epidermal growth factor receptor 2. a The treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b The treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab. c Percentages are based on number of patients enrolled (intention-to-treat population) in the study in each column.
Lee S. Schwartzberg et al acute renal failure, and 2 patients with dehydration), and no serious treatment-related AE reported for patients in stratum 2. Of note, grade 3 or 4 neutropenia was observed in 3 of 52 (5.8%) patients in stratum 1 and grade 3 neutropenia was observed in 1 of 20 (5.0%) patients in stratum 2. Grade 3 or 4 febrile neutropenia was observed in 1 of 51 (1.9%) patients in stratum 1 and was not observed in stratum 2. There was no treatment-related death, colonic perforation, or clinical congestive heart failure event. The incidence of clinically significant changes in laboratory abnormalities, vital signs, LVEF, ECG, and ECOG PS was low, and no unexpected safety risk was observed for either of the combination treatment regimens.
Table 3 Number of Treatment Cycles (Safety Population) Treatment Docetaxel, median number of cycles (range) Bevacizumab, median number of cycles (range) Trastuzumab, median number of cycles (range)
Stratum 1 Stratum 2 HER2L (n [ 52)a HER2D (n [ 20)b 8 (1-29)
8 (2-26)
8 (1-39)
12.5 (1-30)
NA
13 (2-30)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; NA ¼ not applicable. a The treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b The treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab.
Efficacy
3 or 4 AE was fatigue (6 of 52 [12%] patients in stratum 1; 2 of 20 [10%] patients in stratum 2). With the exception of mucosal inflammation (3 of 52 [6%] patients in stratum 1), all grade 3 or 4 AEs were observed in only 1 or 2 patients per stratum. The incidence of grade 3 or 4 hypertension or increased blood pressure was low (3 of 52 [6%] patients in stratum 1; 1 of 20 [5%] patients in stratum 2). There were 7 serious treatment-related AEs reported for 4 of 52 (8%) patients in stratum 1 (1 patient each with febrile neutropenia, mucosal inflammation, rectal abscess, ataxia, and
The median duration of PFS (KaplaneMeier estimate) for stratum 1 was 8.4 months (95% CI, 5.2-10.4 months) (Fig. 2), and the 6- and 12-month PFS rates were 60% (95% CI, 45%73%) and 31% (95% CI, 19%-45%), respectively. The estimated OS rates at 6 and 24 months were 92% (95% CI, 80%-97%) and 55% (95% CI, 40%-69%), respectively, whereas OS was estimated to be about 24.7 months (95% CI, 16.1-27.9 months) (Fig. 3). ORR was 58% and CBR was 67% (Table 5); the median
Table 4 Most Common Treatment-Emergent Adverse Events (‡ 25%) (Safety Population) Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 20)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
52 (100)
33 (63)
20 (100)
13 (65)
Fatigue
37 (71)
6 (12)
13 (65)
2 (10)
Alopecia
34 (65)
15 (75)
Nausea
28 (54)
10 (50)
Diarrhea
23 (44)
8 (40)
Dysgeusia
20 (39)
8 (40)
1 (5)
Nail disorder
18 (35)
7 (35)
1 (5)
Constipation
17 (33)
4 (20)
Arthralgia
17 (33)
Epistaxis
17 (33)
Event, n (%) At least 1 TEAE
2 (4)
6 (30) 8 (40)
Headache
16 (31)
9 (45)
Lacrimation increased
15 (29)
10 (50)
Mucosal inflammation
15 (29)
Pain in extremity
13 (25)
Hypertension Vomiting
8 (15)
3 (6)
4 (20) 3 (6)
12 (23)
8 (40)
9 (17)
6 (30)
Urinary tract infection
9 (17)
6 (30)
NR
6 (30)
8 (15)
5 (25)
Sinusitis
1 (5)
7 (35)
Stomatitis Rash
1 (5)
3 (15)
Decreased appetite
11 (21)
Bone pain
10 (19)
Insomnia
10 (19)
5 (25)
Cough
NR
5 (25)
Rhinorrhea
NR
5 (25)
1 (5) 1 (5)
5 (25) 2 (4)
5 (25) 1 (5)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; NR ¼ not reported; TEAEs ¼ treatment-emergent adverse events.
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Docetaxel and Bevacizumab in Metastatic Breast Cancer Figure 2 Cumulative Probability of Progression-Free Survival (KaplaneMeier Estimates; Intention-to-Treat Population) for Stratum 1 and Stratum 2
Abbreviations: Bev ¼ bevacizumab; Doce ¼ docetaxel; ITT ¼ intention-to-treat; Tras ¼ trastuzumab.
duration of response was 7.6 months (95% CI, 4.1-10.0 months) (Table 6). In stratum 2 (HER2þ patients), the median duration of PFS (KaplaneMeier estimate) was approximately 13.3 months (95% CI, 11.9-35.4 months) (Fig. 2), and the 6- and 12-month PFS rates were 90% (95% CI, 70%-99%) and 81% (95% CI, 58%95%), respectively. The estimated OS rates at 6 and 24 months were 100% (95% CI, not applicable [NA]-NA) and 74% (95% CI, 20.3%eNA) (Fig. 3); OS was estimated to be about 32.4 months (95% CI, 20.4 months-NA) (Fig. 3). ORR was 81% (Table 5), CBR was 81% (Table 5), and median duration of
response was approximately 12.0 months (95% CI, 9.6-28.3 months) (Table 6).
Discussion The AVADO study provided the clinical rationale for combining full-dose docetaxel-based chemotherapy with bevacizumab.10 In that trial, the grade 3 or 4 AE incidence rates in both study arms (bevacizumab [15 mg/kg]-docetaxel and placebo-docetaxel) were relatively high, with the treatment arm exhibiting a greater incidence of grade 3 neutropenia (49 of 247 [20%] vs. 40 of 231 [17%]), febrile neutropenia (40 of 247 [16%] vs. 26 of 231 [11%]),
Figure 3 Cumulative Probability of Overall Survival (KaplaneMeier Estimates; Intention-to-Treat Population) for Stratum 1 and Stratum 2
Abbreviations: Bev ¼ bevacizumab; Doce ¼ docetaxel; ITT ¼ intention-to-treat; Tras ¼ trastuzumab.
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Lee S. Schwartzberg et al Table 5 Efficacy Endpoints and Responses by Response Evaluation Criteria for Solid Tumors (Intention-to-Treat Population) Stratum 1 HER2L (n [ 52)
Stratum 2 HER2D (n [ 21)
8.4 mo (5.2-10.4 mo) w24.7 mo (16.1-27.9 mo)
w13.3 mo (11.9-35.4 mo) 32.4 mo (20.4 mo-NA)
Endpoints Median PFS (95% CI) Estimated OS (95% CI)
Responses Complete response (CR), n (%) Partial response (PR), n (%) Stable disease (SD), n (%) Unevaluable, n (%) Response rate (CR þ PR), n (%) Clinical benefit rate (CR þ PR þ SD 26 wk), n (%)
3 27 14 2 30 35
(6) (52) (27) (4) (58) (67)
4 13 1 2 17 17
(19) (62) (5) (10) (81) (81)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; ITT ¼ intention-to-treat; NA ¼ not applicable; OS ¼ overall response; PFS ¼ progression-free survival.
and hypertension (11 of 247 [4.5%] vs. 3 of 231 [1.3%]). Indeed, although the 100 mg/m2 docetaxel regimen is among the most efficacious treatments for MBC, it is nonetheless associated with high levels of dose-dependent toxicity.8,10 Safety results for our study population indicate that the docetaxel 75 mg/m2 plus bevacizumab with or without trastuzumab regimens were feasible for clinical practice in the first-line treatment of MBC. In stratum 1, the most common grade 3 or 4 treatment-related AE was fatigue (6 of 52 [12%]). The median number of cycles of docetaxel was 8 in both strata, demonstrating good tolerability for the regimen; the upper ranges of docetaxel cycles administered (29 and 26 in stratum 1 and 2, respectively) were also quite remarkable. We also noted a low incidence of clinically significant changes in laboratory abnormalities, vital signs, or LVEF, and there was no unexpected safety risk identified for either combination treatment regimen. Only 7 of 52 (14%) and 4 of 21 (19%) patients in stratum 1 and 2, respectively, discontinued therapy because of AEs. Grade 3 neutropenia occurred in a total of 4 of 72 (5.5%) patients and grade 3 febrile neutropenia in only 1 patient, suggesting an improved therapeutic ratio for docetaxel administered at 75 mg/m2 compared with that of the higher dosage used in the AVADO and AVEREL trials.
Table 6 Summary of Response Rate Duration (KaplaneMeier Estimates; Intention-to-Treat Population) Stratum 1 Stratum 2 HER2L (n [ 30)a HER2D (n [ 17)b KaplaneMeier Estimate of ORR Duration (%)c 6 mo (95% CI)
62 (41-78)
100 (NA-NA)
12 mo (95% CI)
23 (10-44)
54 (23-78)
7.6 (4.1-10.0)
12.0 (9.6-28.2)
KaplaneMeier Estimate of Response Duration, mod Median (95% CI)
Abbreviations: HER2 ¼ human epidermal growth factor receptor 2; ITT ¼ intention-to-treat; ORR ¼ overall response rate. a Treatment regimen for stratum 1 (HER2) is docetaxel and bevacizumab. b Treatment regimen for stratum 2 (HER2þ) is docetaxel, bevacizumab, and trastuzumab. c 95% CI computed using the Greenwood formula (using the log-log transformations). d 95% CIs computed using the Brookmeyer and Crowley method (using the log-log transformations).
The combination of highly active chemotherapeutic agents with the antiangiogenic antibody bevacizumab has resulted in substantial gains in key clinical endpoints such as PFS, response rate, and duration of response.15,17 The combination of bevacizumab (15 mg/kg) and docetaxel (100 mg/m2) in the AVADO trial significantly improved PFS relative to docetaxel alone in both unstratified (8.2 vs. 10.1 months; hazard ratio [HR] ¼ 0.77; P ¼ .006) and stratified (8.1 vs. 10.0 months; HR ¼ 0.67; P < .001) analyses in patients with HER2 MBC.10 The response rate (64.1%) for docetaxel combined with bevacizumab was also significantly greater than that seen for placebo or docetaxel (46.4%; P < .001).10 In a randomized phase II trial of docetaxel with or without bevacizumab as first-line therapy for HER2e MBC (TORI B01 [Translational Oncology Research International B01]), which combined bevacizumab 15 mg/kg with docetaxel 75 mg/m2 in patients with HER2 MBC, an ORR of 51% was reported with a median TTP of 9.3 months and a safety profile similar to that in the AVADO study.15 The results of our study are similar to those of TORI B01 with regard to TTP, response rate, and OS. For the HER2þ population in the AVEREL trial, patients were randomized to receive docetaxel 100 mg/m2 plus trastuzumab with or without bevacizumab 15 mg/m2 every 3 weeks. For the bevacizumab- versus nonbevacizumab-containing arms, the median PFSs by independent review committee were 16.8 months and 13.9 months (P ¼ .012), respectively, with a response rate of 76.5% versus 65.9% (P ¼ .0265), respectively. OS was not improved, a finding consistently established in trials adding bevacizumab to chemotherapy in MBC.10-14 Among the 21 stratum 2 HER2þ breast cancer patients treated with docetaxel plus bevacizumab and trastuzumab in our study, PFS rates were 90% at 6 months and 81% at 12 months, with a median PFS estimated to be 13.3 months. Despite this limited sample size, these results demonstrated a somewhat better efficacy than what was found in the control arm of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study with the same doses of docetaxel and trastuzumab with an ORR of 69% and PFS of 12.4 months.7 These results must be interpreted in the context of alternative biologic treatment in the HER2þ population. The addition of a second HER2-targeted therapy, pertuzumab, to trastuzumab and
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Docetaxel and Bevacizumab in Metastatic Breast Cancer docetaxel in the CLEOPATRA study increased PFS to 18.5 months, with a response rate of 80.2%, seemingly superior to the results of the current trial, underscoring the value of inhibiting a validated target.7 The identification of biomarkers to define a subset of patients who derive benefit from antiangiogenic agents such as bevacizumab added to chemotherapeutic regimens remains an area of intense interest; however, this endeavor has proven difficult for a number of reasons. Angiogenic processes are complex and highly adaptive, such that multiple factors can compensate in the face of VEGF inhibition with bevacizumab. VEGF inhibition may also have differential effects based on tumor type, and because the agents are used in combination, it is not clear which clinical endpoints accurately predict a response to bevacizumab versus a response to the chemotherapy.18 Despite these challenges, in a recent review of bevacizumab biomarkers, the association of short VEGF isoforms with PFS and OS was noted in patients with breast cancer treated with docetaxel (AVADO).18,19 Further study will be needed to validate these potential biomarkers in larger numbers of patients.
Acknowledgments
Conclusion
1. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438:967-74. 2. Crown J. A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer. Semin Oncol 1999; 26(suppl 3):5-9. 3. Nabholtz J-M, Reese D, Riva A, Tonkin K. Taxanes: paclitaxel and docetaxel. In: Nabholtz J-M, Tonkin K, Reese DM, Aapro MS, Buzdar AU, eds. Breast Cancer Management: Applications of Clinical and Translational Evidence to Subject Care. 2nd ed. Baltimore, MD: Lippincott William & Wilkins; 2000:63-85. 4. Bergh J, Bondarenko IM, Lichinitser MR, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 2012; 30:921-9. 5. Belfiglio M, Fanizza C, Tinari N, Ficorella C, Iacobelli S, Natoli C, Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer. J Cancer Res Clin Oncol 2012; 138:221-9. 6. Stemmler HJ, Harbeck N, Gröll de Rivera I, et al. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology 2010; 79:197-203. 7. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366:109-19. 8. Harvey V, Mouridsen H, Semiglazov V, et al. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24:4963-70. 9. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized antiVEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333:328-35. 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. 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. 12. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 2009; 27:4966-72. 13. Miles DW, Diéras V, Cortés J, Duenne AA, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24:2773-80. 14. Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012; 2012:417673. 15. Hurvitz SA, Allen HJ, Moroose RL, et al. A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (TORI B01). Clin Breast Cancer 2010; 10:307-12. 16. Gianni L, Romieu G, Lichinitser M, et al. First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) þ docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/ metastatic breast cancer (LR/mBC). Cancer Res 2011; 71(suppl 3), abstract S4-8. 17. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-92. 18. Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 2013; 31:1219-30. 19. Miles DW, de Haas SL, Dirix L, et al. Plasma biomarker analyses in the AVADO phase III randomized study of first-line bevacizumab þ docetaxel in patients with human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer. Cancer Res 2010; 70(suppl 2), abstract P2-16-041.
Results of the current trial suggest that as a first-line treatment of MBC, docetaxel at a dose of 75 mg/m2 plus bevacizumab (15 mg/m2 every 3 weeks) in HER2 patients, or docetaxel at a dose of 75 mg/m2 plus trastuzumab every 3 weeks plus bevacizumab in HER2þ patients was safe and feasible. Response rates and PFSs for HER2 patients were similar to those of previous reports, confirming the benefit of adding bevacizumab to docetaxel, and it was notable that less overall toxicity was seen when docetaxel at 75 mg/m2 was utilized in combination with bevacizumab.
Clinical Practice Points Docetaxel is among the most active cytotoxic chemotherapeutic
agents for the treatment of advanced breast cancer. The standard docetaxel dose in the United States is currently
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75 mg/m2, and studies have reported response rates at this dose as high as 70% in patients with MBC. Combining antiangiogenesis therapy (bevacizumab) with docetaxel has demonstrated improved PFS and response rate in MBC patients. Likewise, adding trastuzumab to combined docetaxel and bevacizumab has been investigated in the subset of patients with HER2þ MBC, also resulting in gains in PFS and response rate. However, these earlier studies (most notably AVADO [docetaxel plus bevacizumab] and AVEREL [docetaxel plus bevacizumab plus trastuzumab]), utilized a higher dose of docetaxel (100 mg/m2), which is associated with higher rates of dosedependent toxicity. This phase II study evaluated the efficacy and safety of the standard US dose of docetaxel (75 mg/m2) combined with bevacizumab, with or without trastuzumab (for HER2þ patients), for the first-line treatment of patients with MBC. The results of this study demonstrate the feasibility and safety of these combination therapies for patients with MBC. Efficacy results (PFS and response rate) were comparable to those previously reported, particularly in the HER2 stratum. Less overall toxicity with use of docetaxel at the lower dose of 75 mg/m2 in combination with bevacizumab was also noted.
Clinical Breast Cancer June 2014
This study was supported by Sanofi. Editorial support in the preparation of this article was provided by Maria Soushko, PhD, of Phase Five Communications Inc. and sponsored by Sanofi US. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.
Disclosure The authors received no financial compensation for their work on this article. Lee S. Schwartzberg is a speaker for Roche/Genentech and is a former advisor to Sanofi. Barrett H. Childs was an employee of Sanofi US, LLC, during the time the study was conducted and during manuscript preparation. The authors have stated that they have no other conflicts of interest.
References