NOT PRINTABLE. Keywords HER2-negative metastatic breast cancer First-line therapy Nab-paclitaxel Bevacizumab Gemcitabine.

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1 Breast Cancer Res Treat (2010) : DOI /s CLINICAL TRIAL Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer Christopher Lobo Gilberto Lopes Odalys Baez Aurelio Castrellon Annapoorna Ferrell Connie Higgins Erin Hurley Judith Hurley Isildinha Reis Stephen Richman Pearl Seo Orlando Silva Joyce Slingerland Keleni Tukia Catherine Welsh Stefan Glück Received: 11 June 2010 / Accepted: 15 June 2010 / Published online: 29 June 2010 Ó Springer Science+Business Media, LLC Abstract In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-p) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, openlabel phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m 2, nab-paclitaxel 150 mg/m 2, and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete Christopher Lobo and Gilberto Lopes contributed equally to the design and conduction of this trial and should be considered first authors. Declaration: Presented in part (Interim Analysis) at the ASCO Annual Meeting 2008, Abstract 1089 and at the ESMO Conference 2008, Abstract 152P. Final results presented at EBCC C. Lobo Florida Cancer Specialists and Research Institute, Gainesville, FL, USA G. Lopes The Johns Hopkins Singapore International Medical Centre, Singapore, Singapore (CR) and partial (PR) response rates, clinical benefit (ORR? stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: %). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-p, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study. Keywords HER2-negative metastatic breast cancer First-line therapy Nab-paclitaxel Bevacizumab Gemcitabine G. Lopes The Johns Hopkins University School of Medicine, Baltimore, MD, USA O. Baez A. Castrellon A. Ferrell C. Higgins E. Hurley J. Hurley I. Reis S. Richman P. Seo O. Silva J. Slingerland K. Tukia C. Welsh S. Glück (&) Division of Hematology/Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Braman Family Breast Cancer Institute Miller School of Medicine in Miami, The University of Miami, 1475 NW 12 Avenue, SCCC, Suite 3510 (D8-4), Miami, FL 33136, USA SGluck@med.miami.edu Introduction An American Cancer Society statistic estimates that 192,370 new cases of invasive breast cancer will be diagnosed in the year 2009 in the United States [1]. Only 6% of these new cases of breast cancer will be metastatic; however, it is estimated that 30% of early stage patients will develop MBC [2]. Currently, the estimated 5-year survival rate for patients with metastases is 27%, with a median survival of 2 3 years [1, 3]. The incurability of MBC is

2 428 Breast Cancer Res Treat (2010) : well documented and researched; palliative chemotherapy options are numerous, with diverse regimens based on class of drug, number of agents, dosage, and schedule. Eventually, all MBC patients will develop refractory disease. Therefore, more efficacious, less toxic first-line therapy options for MBC are needed. Since the early 1970s, chemotherapeutic treatments for MBC have been assessed, including anthracyclines and taxanes, in the first-line setting. Cremophor-based paclitaxel (cbp) is one of the taxanes active in MBC, and nanoparticles albumin-bound paclitaxel (nab-p) has recently been shown to improve overall response rates (ORR) and time to tumor progression (TTP) when compared to cbp in patients with MBC [4]. Nab-P was designed to prevent the adverse events associated with polyethyoxylated castor oil. Nab-P is indicated for the treatment of MBC after failure of polychemotherapy (e.g., anthracycline) or relapse within 6 months of adjuvant therapy. A phase III trial confirmed the superior efficacy and reduced toxicity associated with nab-p versus cbp in patients with MBC [4]. The efficacy and safety of nab-p in the first-line setting were compared with those of another taxane, docetaxel, in a phase II study. Weekly nab-p revealed a significantly longer progression-free survival (PFS) than docetaxel (12.9 vs. 7.5 months, respectively) with less grade 3 and 4 toxicities in patients with MBC, and first-line therapy [5]. CbP and gemcitabine (G) are FDA approved as a doublet regimen in the first-line treatment of MBC, after failure of an anthracycline. A phase II trial by Tomao et al.[6] illustrated that the combination of cbp and G was well tolerated on a biweekly basis, resulting in an ORR of 64% in patients with previous anthracycline exposure. In 2008, a phase III study of advanced breast cancer confirmed the improved activity of G with cbp when compared to cbp monotherapy; this combination resulted in a median overall survival (OS) of 18.6 months compared with 15.8 months, respectively [7]. Another regimen that has been indicated for the use in HER2-negative patients with untreated metastatic disease is cbp together with the anti-vascular endothelial growth factor monoclonal antibody, bevacizumab (B). A phase III trial of B? cbp compared with cbp alone demonstrated significantly improved PFS (11.8 vs. 5.9 months, respectively); however, there was not a significant improvement in OS with B [8, 9]. Preliminary data have suggested a prolongation of PFS and an adequate safety profile with the addition of B to nab-p [10]. The objective of exploring various polychemotherapy regimens involving cytotoxic and biologic agents is to prolong PFS and OS. The doublet regimens G? cbp and B? cbp have demonstrated improved efficacy compared with any of these agents as monotherapy, suggesting that combining the three agents could potentially lead to a further improvement in efficacy. In addition, the greater efficacy and better tolerability of nab-p compared to cbp suggests that replacing cbp with nab-p may lead to further improvements of PFS and ORR. Preliminary data from our pilot study involving heavily pre-treated women with MBC demonstrated the feasibility of uniting nab-p, B, and G [11]. The combination was well tolerated, and objective responses were noted [11]. In this phase II study, we examined the efficacy and safety of this novel triplet combination (2-week schedule of nab-p, G, and B) in the first-line MBC setting. Patients and methods This open-label, single-center phase II trial enrolled 30 patients with HER2/neu negative MBC at University of Miami (UM), Sylvester Comprehensive Cancer Center (SCCC)/Braman Family Breast Cancer Institute (BFBCI) and Jackson Memorial Hospital (JMH). The SCCC was the sponsor of this study and determined the study design, reporting, and conduct. The study was approved by the UM Institutional Review Board, and all patients provided written informed consent. This study was partially funded by the manufacturing companies, and all three drugs were provided. Patient selection Male and nonpregnant female patients who were C18 years of age, with measurable (by response evaluation criteria in solid tumors, RECIST) HER2/neu non-overexpressing or non-amplified (by FISH) MBC were eligible for this study. Patients were required to have a life expectancy greater than 3 months, with an ECOG performance status of 0 or 1. Eligibility criteria included treatment-naïve, newly diagnosed MBC or patients with metastasis diagnosed C6 months after completing primary systemic treatment in the neoadjuvant or adjuvant setting. Patients with estrogen receptor-positive breast cancer who progressed on prior endocrine treatment in the adjuvant and/or palliative settings were eligible. Good end-organ function was required as follows: neutrophils, /L or greater; platelets, /L or greater; hemoglobin, C9.0 g/dl; serum creatinine, B1.5 mg/dl; bilirubin, Bupper limit of normal; ALT/AST, B2.5 times the upper limit of the normal range except when caused by metastatic disease; urine protein/creatinine (UPC) ratio \1.0 at screening. Patients had to comply with all trial requirements; specifically, birth control measures were mandatory for all patients capable of reproduction.

3 Breast Cancer Res Treat (2010) : Patients with any exposure to G or other chemotherapy within one month of enrollment were excluded. In addition, the presence of active central nervous system metastases or simultaneous malignancies (excluding inactive skin nonmelanoma or inactive cervical cancer) disqualified patients from participation. Pre-existing conditions excluded patients from enrollment, including: gastrointestinal bleeding in the previous 3 months, inadequately controlled hypertension, grade 1? peripheral neuropathy, known AIDS or HIV positive serology, unstable angina, congestive heart failure NYHA grade 2?, history of myocardial infarction or stroke within the last 6 months, significant peripheral vascular disease, and a history of an abdominal fistula within 6 months of enrollment. Treatment protocol Patients received treatment with G 1500 mg/m 2 intravenously (IV) over 30 min, followed by nab-p 150 mg/m 2 IV over 30 min, and then with B 10 mg/kg IV over 30 min on days 1 and 15 of a 28-day cycle. All dose reductions followed the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 3.0) for hematologic and nonhematologic toxicity. Chemotherapy, including bevacizumab, was continued until disease progression, excessive toxicity, or withdrawal of consent. Bevacizumab was not continued alone in the advent of unacceptable toxicity induced by the cytotoxic drugs. Supportive care with granulocyte colony-stimulating factor (G-CSF) was administered when necessary. Premedication with antiemetic and steroid agents was dispensed according to institutional standards. Early stopping rules were in place for unacceptable toxicity and/or lack of efficacy. Assessments Initial patient evaluations included a full medical history and a complete physical examination. Baseline-computed tomography (CT) scans with contrast of the head, chest, abdomen, and pelvis were obtained, and follow-up scans were repeated every two cycles. Tumor response was confirmed according to RECIST. Laboratory samples were collected before treatment, including complete blood count with differential and platelet count, glucose, BUN, creatinine, uric acid, bilirubin, alkaline phosphatase, SGOT, electrolytes, urine pregnancy test, and protein/creatinine ratio on spot urinalysis. All adverse events and laboratory values were classified according to the NCI CTCAE version 3.0. Study size, endpoints, and statistical analysis The primary endpoint of the trial was PFS. The sample size of 30 patients, which was chosen on the basis of expected 1-year accrual for this single institution trial, provides good precision in estimating the 1-year PFS rate. More specifically, with 30 patients the maximum standard error for oneyear PFS is 9.1% based on Peto s method assuming no losses to follow up [12]. The PFS was defined as the time from the first treatment date to the earliest date of documented progression measured by CT scans or date of death due to any cause. Secondary endpoint included ORR, OS, and safety. OS was determined from the date of enrollment to the date of death; event-free patients were censored at last contact. The baseline characteristics were summarized using descriptive statistics, and adverse events were characterized by type, grade, and attribution to treatment. The Kaplan Meier method was used to estimate median PFS and median OS. The rates of PFS and OS were summarized by point estimates and 95% confidence intervals (CI) at selected times: 6, 12, 18, and 24 months following initiation of treatment. As much as possible, considering the sample size limitations, Cox proportional hazards regression was used to determine whether PFS and OS were affected by response to treatment, age at diagnosis, race/ethnicity, and hormonal receptor status [12]. Results Patient characteristics Thirty patients were enrolled between July 2007 and September Subsequently, one patient, having received one dose of treatment before evidence of active brain metastases, was disqualified from the trial. The median age of these 29 patients (28 females and 1 male) was 54 (Table 1). The majority of patients were Hispanic (58.6%), and the remainders were African American (27.6%), non- Hispanic Caucasian (10.3%), and Asian (3.4%). All the patients had stage IV breast cancer; the most common sites of metastases were the liver, bone, and lung (34.5% of patients each), and 17.5% of patients had lymph node involvement. Other sites of metastasis included the chest wall (6.9%), brain (3.4%), and gastrohepatic ligament (3.4%). All patients who received C1 cycle of the study treatment and met the study criteria were evaluated for efficacy and toxicity (N = 29). The median number of treatment cycles received was 6.5 (range ), and one patient remained on study (Table 1).

4 430 Breast Cancer Res Treat (2010) : Table 1 Patient Demographics and Disease Characteristics Characteristic N (%), unless otherwise specified Table 1 continued Characteristic N (%), unless otherwise specified Median age, y (range) 53.8 (34 69) Mean (std) 52.3 (9.2) Sex: Female 28 (96.6) Male 1 (3.4) Ethnicity Hispanic or Latino 17 (58.6) Non-Hispanic 12 (41.4) Race White 20 (69.0) Black 8 (27.6) Asian 1 (3.4) Stage at Initial Diagnosis Stage 0 1 (3.4) Stage I II 12 (41.4) Stage III 2 (6.9) Stage IV 14 (48.3) Prior systemic therapy Adjuvant chemotherapy naïve 18 (62.1) Adjuvant chemotherapy exposure 11 (37.9) Adjuvant or palliative endocrine therapy naïve 17 (58.6) Adjuvant or palliative endocrine therapy exposure 12 (41.4) No. Visceral Sites 0 9 (31.0) 1 18 (62.1) 2 2 (6.9) Location of metastases Bone 10 (34.5) Liver 10 (34.5) Lung 10 (34.5) Lymph nodes 5 (17.2) Chest wall 2 (6.9) Brain 1 (3.4) Gastrohepatic ligament 1 (3.4) ER status Negative 13 (44.8) Positive 16 (55.2) R status Negative 19 (65.5) Positive 7 (24.1) Unknown 3 (10.3) HER2 status Negative 29 (100) Triple-negative 13 (44.8) Treatment cycles (3.4) (27.6) [ (51.7) [10 5 (17.2) Median (range) 6.5 (1.5 23) ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor-2 Efficacy In this study, the median PFS was 10.4 months (95% CI: ) (Fig. 1). The ORR was 75.9%. Eight patients (27.6%) achieved a complete response (CR); while 14 patients (48.3%) had a partial response (PR); 5 (17.2%) stable disease (SD); and 2 (6.9%) had progressive disease (PD) as their best response to treatment (Table 2). The clinical benefit rate (CBR) (ORR?SD) for this triplet regimen is 93.1% (95% CI:77 99). In addition, the 18- month OS rate was 77.2% (95% CI: %) (Fig. 2). Notably, among the patients in this study with triplenegative (TN) disease (i.e., negative for human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR)) (13 [44.8%]), 5 (38.4%) had CR, 4 (30.7%) patients had PR, and 2 (6.9%) patients had SD as their best response. 2 (6.9%) patients had PD. At 18-months, the PFS rate was 10.6% in this subgroup (95% CI: ) and 25.0% in patients with tumor receptor positivity (95% CI: ) (Fig. 3). The CBR for triplenegative patients was 84.6%. The 18-month OS rate in this subgroup was 82.5% (95% CI: %). In the univariate Cox Regression analysis only two prognostic factors associated with tumor response were significant for effect on PFS (CR vs. Other and CR/PR vs. Other) (Table 3). Proportion progression-free Month PFS (%) 95% CI At risk ( ) ( ) ( ) Median 10.4 months (95%CI: 5.6 to 15.2) 23 events in 29 patients Months Fig. 1 Kaplan Meier plot for Progression Free Survival

5 Breast Cancer Res Treat (2010) : Table 2 Best response to treatment Best response Patients, no. (%) (N = 29) 95% CI Complete response (CR) 8 (27.6) Partial response (PR) 14 (48.3) Stable disease a (SD) 5 (17.2) 6 36 Progressive disease 2 (6.9) Clinical Benefit Rate 27 (93.1) (CR? PR? SD) a \30% reduction according to RECIST Proportion surviving Toxicity Month OS (%) 95% CI ( ) ( ) ( ) ( ) 6 events in 29 patients At risk Months Fig. 2 Kaplan Meier plot for overall survival Proportion progression-free ER+ TN At risk Months Fig. 3 Kaplan Meier plot for PFS comparison for triple-negative patients and non-triple-negative patients (log-rank P = 0.707) Safety analysis included all the 29 eligible patients. The most common grade 1 and grade 2 toxicities were alopecia (65.5%), fatigue (37.9%), bone pain (31%), nausea (31%), and skin rash/lesions (27.6%) (Table 4). There were also three cases (10.3%) of neutropenia, which were all grade 2. Eight (27.6%) patients experienced grade 3 or 4 toxicity potentially related to the study treatment, including Table 3 Cox Regression Analysis: univariate effect of prognostic factors for PFS Prognostic factor Hazard Ratio (95% CI) P value Age: 1-year increment 1.02 (0.97, 1.07) 0.43 Age: 10-year increment 1.20 (0.76, 1.90) 0.43 Age: [ 50 vs. B (0.65, 3.96) Race: White vs. Other 0.68 (0.28, 1.63) Ethnicity: Hispanic vs. NH 0.60 (0.26, 1.38) ER: Positive vs. negative 0.85 (0.37, 1.96) PR: Positive vs. Other 1.31 (0.51, 3.35) TN: TN vs. Other 1.17 (0.51, 2.69) Response: CR vs. Other 0.12 (0.03, 0.54) Response: CR/PR vs. Other 0.34 (0.13, 0.89) portacath infections (6.9%) and abscess, fever/sepsis, breast abscess, hematuria, leukopenia, peripheral neuropathy, seizure/syncope, shortness of breath, cardiac tamponade, thrombocytopenia, and UTI (3.4% each). There was only one case of grade 4 toxicity, neutropenic fever. This patient was hospitalized for neutropenic fever, hematuria, and thrombocytopenia. There were a total of ten hospitalizations on trial and no toxicity-related deaths. Discussion This single-center, open-label, phase II study is the first to investigate the combination of nab-p, B and G as first-line therapy for patients with MBC. The trial accrued 30 patients with recently diagnosed HER2-negative metastatic disease over a 15-month period. The rationale for this novel treatment regimen was based on prior success with the single-agent use of each of these agents, as well as their combinations as doublet therapy. We hypothesized that response rates after treatment with this triplet combination would be higher than those currently found in MBC. We also recognized the potential for improvement in toxicity management; our dosage schedule would allow chemotherapy infusions to be given on day 1 and day 15, while omitting the standard Day 8 dose. The 2 week interval period would allow for toxicity recovery, in an attempt to prevent treatment delays. In this study, treatment with the triplet nab-p, B, and G resulted in a very low incidence of severe adverse events. One patient had grade 4 toxicity (neutropenic fever) which resolved on therapy after two weeks of hospitalization. In addition, the reported incidence of hematologic toxicity was low. Compared with a study using single-agent docetaxel (100 mg/m 2 ) in patients with MBC, the incidence of neutropenia was lower in this study using the triplet

6 432 Breast Cancer Res Treat (2010) : Table 4 Adverse events Toxicity Any Grade, Grade 1, Grade 2, Grade 3, Grade 4, no. (%) no. (%) no. (%) no. (%) no. (%) Hematologic Neutropenia 3 (10.3) 3 (10.3) Leukopenia 2 (6.9) 1 (3.4) 1 (3.4) Thrombocytopenia 2 (6.9) 1 (3.4) 1 (3.4) Anemia 1 (3.4) 1 (3.4) Nonhematologic Alopecia 19 (65.5) 3 (10.3) 16 (55.2) Fatigue 11 (37.9) 6 (20.7) 5 (17.2) Bone pain 9 (31.0) 2 (6.9) 7 (24.1) Nausea 9 (31.0) 1 (3.4) 8 (27.6) Skin rash/lesion 8 (27.6) 2 (6.9) 6 (20.7) Hand/Foot syndrome 7 (24.1) 7 (24.1) Headache 7 (24.1) 2 (6.9) 5 (17.2) Epistaxis 6 (20.7) 4 (13.8) 2 (6.9) Peripheral neuropathy 6 (20.7) 5 (17.2) 1 (3.4) Diarrhea 4 (13.8) 4 (13.8) Insomnia 4 (13.8) 4 (13.8) Anxiety 3 (10.3) 3 (10.3) Hypertension 3 (10.3) 3 (10.3) PortAcath infection 3 (10.3) 1 (3.4) 2 (6.9) Abscess 2 (6.9) 1 (3.4) 1 (3.4) Amenorrhea 2 (6.9) 2 (6.9) Blurred vision 2 (6.9) 2 (6.9) Cough 2 (6.9) 1 (3.4) 1 (3.4) Depression 2 (6.9) 1 (3.4) 1 (3.4) Dysgeusia 2 (6.9) 2 (6.9) Flu-like symptoms 2 (6.9) 1 (3.4) 1 (3.4) Loss of appetite 2 (6.9) 2 (6.9) Lymphedema 2 (6.9) 2 (6.9) Oral infection 2 (6.9) 2 (6.9) Rhinorrhea 2 (6.9) 2 (6.9) Shortness of breath 2 (6.9) 1 (3.4) 1 (3.4) Skin discoloration 2 (6.9) 2 (6.9) Weight loss 2 (6.9) 1 (3.4) 1 (3.4) Acute renal insufficiency 1 (3.4) 1 (3.4) Breast abscess 1 (3.4) 1 (3.4) Chest pain 1 (3.4) 1 (3.4) Conjunctivitis 1 (3.4) 1 (3.4) Constipation 1 (3.4) 1 (3.4) Epigastric pain 1 (3.4) 1 (3.4) Fever/sepsis 1 (3.4) 1 (3.4) Heartburn 1 (3.4) 1 (3.4) Heat intolerance 1 (3.4) 1 (3.4) Hematuria 1 (3.4) 1 (3.4) Hot flashes 1 (3.4) 1 (3.4) Jaundice 1 (3.4) 1 (3.4) Mucositis 1 (3.4) 1 (3.4)

7 Breast Cancer Res Treat (2010) : Table 4 continued Toxicity Any Grade, Grade 1, Grade 2, Grade 3, Grade 4, no. (%) no. (%) no. (%) no. (%) no. (%) Neutropenic fever 1 (3.4) 1 (3.4) Painful edema 1 (3.4) 1 (3.4) Pedal edema 1 (3.4) 1 (3.4) Pelvic pain 1 (3.4) 1 (3.4) Pericardial effusion 1 (3.4) 1 (3.4) Pharyngitis 1 (3.4) 1 (3.4) Reflux 1 (3.4) 1 (3.4) Regurgition (valve) 1 (3.4) 1 (3.4) Scotoma 1 (3.4) 1 (3.4) Seizure/syncope 1 (3.4) 1 (3.4) Tachycardia 1 (3.4) 1 (3.4) Tamponade 1 (3.4) 1 (3.4) Thrombus 1 (3.4) 1 (3.4) Tricuspid regurg 1 (3.4) 1 (3.4) Upper respiratory infection 1 (3.4) 1 (3.4) UTI 1 (3.4) 1 (3.4) Vomiting 1 (3.4) 1 (3.4) regimen (all grades, 100 vs. 10.3%, respectively) [5]. The incidence of neurotoxicity in this study is also noticeably less than other studies using nab-p in combination for HER2-negative MBC; Conlin et al. reported greater than 50% incidence of sensory neuropathy grade C2 in all the 3 arms of nab-p and B combination therapy (Arm A = 260 mg/m 2 of nab-p? 15 mg/kg B q 3 weeks; Arm B = 260 mg/m 2 of nab-p? 10 mg/kg B q 2 weeks; and Arm C = 130 mg/m 2 of nab-p q 1 week? 10 mg/kg B q 2 weeks) compared to 20.7% incidence of peripheral neuropathy grade C2 with this triplet combination. This reduction in neurotoxicity can be partially attributed to the use of lower infusion dose of nab-p in our study (in terms of comparison to Arms A and B) and extended time between doses (in terms of comparison to Arm C) [13]. Similar to other chemotherapy, the most common adverse events included alopecia (65.5%), fatigue (37.9%), and nausea (31.0%); these events were limited to grades 1 and 2. All grade 3 and 4 toxicities were treated during hospitalization (N = 10), and all symptoms were resolved (mean 7.6 days, range 3 14 days). Combining chemotherapeutic agents in an effort to increase efficacy with MBC is not a novel approach. In the early stages of treating breast cancer, cyclophosphamide, methotrexate, and 5-fluorouracil and later, anthracycline combinations, were developed for use in MBC [14]. It was not until Sledge et al. published a landmark study comparing cbp and doxorubicin as single agents, and with the combination of both agents, that the treatment of MBC changed in North America [15]. The ORR and time-totreatment failure were greater in the doxorubicin and cbp combination arm; however, there was no significant difference in OS between arms and toxicity that proved to be unacceptably high with simultaneous combination treatment [15]. Therefore, most medical oncologists in this country have embraced the sequential single-agent approach. O Shaughnessy et al. and later, Albain et al. showed that the addition of either capecitabine or G to a taxane led to improvements not only in response rates, but also in TTP and OS (a formal cross-over was not allowed in either study) [7, 16]. In addition, in 2005, Miller et al.[17] demonstrated that the addition of B to capecitabine significantly increased response rates. However, this did not translate to longer PFS. Another important change in the treatment of MBC was the introduction of nab-p to the treatment armamentarium. The relatively toxic side effects of cbp require the administration of steroids and H1 and H2 antagonist premedication, as well as a lengthy infusion time. The improved efficacy and reduced toxicity of nab-p over cbp have been demonstrated [4, 18]. Nab-P in combination with B has been recently tested in a multi-arm phase II study; the longest reported TTP occurred in arm C, which randomized patients to receive 130 mg/m 2 of nab-p weekly with 10 mg/kg B q 2 weeks [13]. The TTP for this triplet regime is only minimally higher (10.4 months), but the aforementioned reduction in neurotoxicity is notable. The promising results from these studies, combined with the convenience of delivering chemotherapy every two

8 434 Breast Cancer Res Treat (2010) : weeks, led to the concept for our combination of two cytotoxic agents and one biologic agent. We examined the feasibility of this combination in a pilot study in heavily pretreated patients with MBC; at the time of first evaluation two patients had a PR and four patients had SD [11]. Standard response rates observed with combination regimen including cbp have published values of 36.9% and 41.4% [7, 8]. With the addition of biologic agents, particularly trastuzumab in patients with HER2-positive disease, response rates have increased to values over 50% [19]. This study suggests that this triplet combination is notably efficacious; the median PFS in our study was 10.4 months (95% CI: months), and the 18-month survival rate was 77.2% (95% CI: %). ORR was 75.9% (out of 29 evaluable patients), with SD reported in an additional 17.2%, for a CBR of 93.1%. The ORR compares very favorably to the ORR achieved in previous trials using doublet combinations, either cbp? G (41.1%) 7 or cbp? B (36.9% in all the patients or 49.2% in the subgroup of patients with measurable disease at baseline) [8]. All participants in our trial had HER2-negative disease; response rates achieved in similar cohorts published previously were between 36.9% and 48.9% (as measured by the independent review facility) [8, 9]. The E-2100 study, had doubled previously reported ORR observed with cbp monotherapy, by adding B (21.2 vs. 36.9%, respectively); our confirmed ORR of 75.9% has greatly improved upon these previous trials [8, 9]. Although one cannot rely on cross-trial comparisons, the 27.6% CR and 48.3% PR observed in this trial seem to be exceptional. Another investigation using this triplet regimen is underway; a phase II study is recruiting MBC patients for treatment with nab-p, G, and B on an alternative schedule (day 1 and 8, q 21 days) [20]. Historically, the MBC patient population has been challenging to treat; therapeutic responses are fleeting, and the 5-year survival rate is very low. In addition, treatment options for patients with TN disease are greatly needed. A large percentage of the patients in this study were TN (44.8%). Within this patient subgroup, 38.4% (5/13) had CR as their best response, and the CBR was exceptionally high at 84.6%. Surprisingly, there was also no significant difference when comparing PFS (P = 0.707) and OS (P = 0.548) between TN patients and patients with hormone receptor-positive disease (Fig. 3). In a phase II study examining the combination of capecitabine and B, in a set of HER2-negative MBC patients, the ER-negative subgroup had a median TTP of 4.0 months (95% CI: ), while the ER-positive subgroup had a median of 8.9 months (95% CI: ) [21]. The greater treatment activity confirmed in the hormonal receptor-positive group is a common observation; in this respect, the response to our study in both subgroups is clinically relevant. An additional benefit of our patient demographic is our large proportion of often under-represented minority groups (Table 1). The unequal representation of minority adults in cancer clinical trials has been documented [22]. An analysis of trial enrollment across ethnic groups from 2000 to 2002 found that blacks and Hispanics were significantly less likely than Non-Hispanic whites to participate in NCI-sponsored cooperative group studies (P \ 0.001); in breast cancer trials specifically the estimated enrollment fractions (the number of trial enrollees divided by the estimated number of the U.S. cancer cases per subgroup) for white, Hispanic, Black, Asian/Pacific Islander, and American Indian were 3.3, 2.4, 2.5, 3, 1, and 4.5%, respectively [23]. The patient demographic at JMH and SCCC embodies a large number of minorities that are indicative of Miami s diverse population of inhabitants. Therefore, the patients included in our phase II trial provide an opportunity to analyze a novel regimen across the racial and cultural spectrum. The limitations of the study include the small patient population (29 evaluable patients) and its single-center study design. Of note, patients were accrued in two different hospitals (JMH and UM/SCCC). However, the promising results and convenient dose schedule from this single-center (albeit two hospitals) phase II study indicate that this novel triplet combination of cytotoxic and biologic agents (nab-p, B and G) should be further investigated in a larger, randomized controlled trial. Acknowledgments We appreciate the efforts of Emilio Weiss, the Research Pharmacist. We would like to thank Lilly USA, Genentech, Inc., and Abraxis BioScience for their financial support and drug supply. Conflict of interest Statement Stefan Glück received research funding from Lilly USA, Genentech, Inc., and Abraxis BioScience. References 1. American Cancer Society (2009) Breast cancer facts and figures American Cancer Society Inc, Atlanta 2. O Shaughnessy J (2005) Extending survival with chemotherapy in metastatic breast cancer. Oncologist 10(suppl 3): Mayer EL, Burstein HJ (2007) Chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am 21: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desia N, Bhar P et al (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23(31): Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas G, Clawson A et al (2009) Significantly longer progressionfree survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 27:

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