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1 Treating Anemia of Cancer with Every-4-Week Darbepoetin Alfa: Final Efficacy and Safety Results from a Phase II, Randomized, Double-Blind, Placebo-Controlled Study David Gordon, Gwen Nichols, Ali Ben-Jacob, Dianne Tomita, Tom Lillie and Carole Miller The Oncologist 2008, 13: doi: /theoncologist The online version of this article, along with updated information and services, is located on the World Wide Web at: Downloaded from by guest on March 3, 2014

2 The Oncologist Symptom Management and Supportive Care Treating Anemia of Cancer with Every-4-Week Darbepoetin Alfa: Final Efficacy and Safety Results from a Phase II, Randomized, Double-Blind, Placebo-Controlled Study DAVID GORDON, a GWEN NICHOLS, b ALI BEN-JACOB, c DIANNE TOMITA, d TOM LILLIE, d CAROLE MILLER e a Cancer Care Centers of South Texas and the U.S. Oncology Research Network, San Antonio, Texas, USA; b Columbia University Medical Center, New York, New York, USA; c Department of Internal Medicine, Cache Valley Cancer Treatment and Research Clinic Inc., Logan, Utah, USA; d Amgen Inc., Thousand Oaks, CA, USA; e Cancer Center, St. Agnes Hospital, Baltimore, Maryland, USA Key Words. Anemia of cancer Darbepoetin alfa Transfusions Erythropoiesis-stimulating agent Hemoglobin Disclosure: The article discusses darbepoetin alfa (Amgen). D.G., D.T. (employee), and T.L. (employee) own stock in Amgen. G.N. became an employee of Hoffmann-La Roche after this study was conducted. C.M. has acted as a consultant to Amgen (darbepoetin alfa). This study ( ) was supported by research funding from Amgen Inc. No other potential conflicts of interest were reported by the authors. ABSTRACT Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 g/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients. The Oncologist 2008;13: INTRODUCTION Anemia is common in oncology patients and is a debilitating condition that often results in increased transfusion requirements and reduced quality of life [1]. Cancer patients who are not receiving chemotherapy and/or radiation therapy can develop anemia that is caused by the cancer itself [1 4]. Patients with anemia of cancer (AoC) may have both depressed erythropoiesis and depressed production of en- Correspondence: David H. Gordon, M.D., Cancer Care Centers of South Texas, 540 Madison Oak Drive, Suite 200, San Antonio, Texas 78258, USA. Telephone: ; Fax: ; David.Gordon@usoncology.com Received December 10, 2007; accepted for publication May 5, AlphaMed Press /2008/$30.00/0 doi: /theoncologist The Oncologist 2008;13:

3 716 Darbepoetin Alfa for Treating Anemia of Cancer dogenous erythropoietin [5 7], possibly as a result of secretion of inflammatory cytokines that inhibit erythropoiesis. The underlying causes of AoC may also include metastases in the bone marrow, nutritional deficiencies, bleeding from tumors, and/or infection [6, 8 10]. Patients with AoC are often treated with RBC transfusions [3]. However, RBC transfusions can pose risks for the patient, including iron overload and disease transmission [7, 8, 11]. Erythropoiesis-stimulating agents (ESAs), such as epoetin alfa and darbepoetin alfa, are approved in the U.S. and Europe for the treatment of chemotherapy-induced anemia (CIA) [12, 13]. Previous studies suggested that both agents can also effectively treat patients with AoC. For example, epoetin alfa, administered at either 40,000 U weekly (QW) or 150 U/kg three times a week to patients with AoC increased hemoglobin levels [14 16] and improved patientreported quality-of-life scores [16]. Also, in a dose- and schedule-finding study in patients with AoC, darbepoetin alfa, administered once per week or at extended-dosing intervals (every three weeks [Q3W] and every 4 weeks [Q4W]), increased hemoglobin levels without any apparent safety concerns [17]. The goal of this phase II, randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of darbepoetin alfa administered Q4W for treating anemia in patients with AoC (administering darbepoetin alfa at extended dosing intervals may be advantageous for patients with AoC who may not visit a clinic frequently because they are not receiving chemotherapy or radiotherapy). The primary endpoint was the effect of darbepoetin alfa treatment on the percentage of patients achieving a hematopoietic response ( 2-g/dl rise in hemoglobin from baseline or achievement of a hemoglobin level 12 g/dl without RBC transfusions during the prior 28 days). Secondary endpoints included the impact of darbepoetin alfa treatment on hemoglobin levels, transfusion incidence, patient-reported fatigue, and safety parameters. METHODS Patients Approval of the study protocol was obtained from the institutional review board of each site before patients were recruited into the study. Written informed consent was obtained from each patient before any study-specific screening procedures were performed. Eligible patients were 18 years old with a nonmyeloid malignancy, anemia (hemoglobin 11 g/dl), an Eastern Cooperative Oncology Group (ECOG) performance status score 2, and adequate renal and liver function. Patients were excluded from the study if they had received, or planned to receive, cytotoxic chemotherapy or myelosuppressive radiotherapy during the study or within 30 days before screening, had anemia related to nutritional deficiencies or to diseases other than the nonmyeloid malignancy, and had a history of pure RBC aplasia. Patients were also excluded if they had uncontrolled hypertension, a cardiac condition (uncontrolled angina, congestive heart failure, or uncontrolled cardiac arrhythmia), iron deficiency, a positive HIV test, a known positive antibody response to any erythropoietic agent, and had received epoetin alfa or darbepoetin alfa within 30 days prior to screening. Patients who were pregnant, breast-feeding, or hypersensitive to mammalian-derived products were also excluded. Study Design This was a multicenter, randomized, double-blind, placebocontrolled, phase II study of darbepoetin alfa compared with placebo for treating AoC. All screening tests and procedures were performed within a maximum of 7 days before randomization. Patients were randomly allocated in a 3:1 ratio to receive darbepoetin alfa or placebo, respectively. Treatment-group assignment was obtained by calling into an interactive voice-response system. Randomization was stratified by screening hemoglobin categories of 10 g/dl and 10 g/dl. A patient s treatment assignment was unblinded only when knowledge of the treatment was essential for further management of the patient s care. Study visits occurred every 2 weeks, and darbepoetin alfa (6.75 g/kg) and placebo were administered s.c. Q4W for 13 weeks (four doses). All patients had an end-of-study visit at week 17 (or 4 weeks after the last dose of study product). If, after 8 weeks (two doses), the hemoglobin concentration was 10 g/dl or had declined below the baseline value, darbepoetin alfa could be escalated at the investigator s discretion to 10 g/kg Q4W. If the hemoglobin increased by 1 g/dl in a 2-week period, then the darbepoetin alfa dose was reduced by 25%, and if the hemoglobin exceeded 13 g/dl, darbepoetin alfa was withheld until it fell to 12 g/dl. Darbepoetin alfa was then reinstated at a dose 25% below the previous dose. Study Drug, Concomitant Medications, and Study Assessments Darbepoetin alfa was supplied as a clear, sterile protein solution of 500 g/ml in 1-ml vials with a polysorbate-containing solution as the vehicle. Placebo was supplied in containers identical to those for darbepoetin alfa. Investigators could prescribe concomitant medications or treatments necessary to provide adequate supportive

4 Gordon, Nichols, Ben-Jacob et al. 717 care. Nonmyelosuppressive radiation for local palliation was permitted. Patients could not receive investigational agents, erythropoietic agents (other than darbepoetin alfa as defined in the protocol), cytotoxic chemotherapy, or myelosuppressive radiotherapy. Iron status was evaluated Q4W, and iron supplementation was recommended in patients with serum iron 50 g/dl, ferritin 100 ng/dl, transferrin saturation 20%, or laboratory-defined iron deficiency. The dose, frequency, and route of administration of iron supplementation were at the discretion of the investigator. Hemoglobin was measured Q2W. RBC transfusions were recommended, but not required, for patients with a hemoglobin concentration 8 g/dl or for patients with a hemoglobin concentration 8 g/dl who displayed symptoms of anemia. Functional Assessment of Cancer Therapy Fatigue (FACT-F) questionnaires were completed at week 1 and weeks 5, 9, 13, and 17. Study Endpoints The primary endpoint was the percentage of patients who achieved a hematopoietic response by week 17 (after 13 weeks of treatment). Secondary endpoints included the change in hemoglobin concentration from baseline to week 17, incidence of RBC transfusions from week 5 to week 17, and change in FACT-F scores from baseline to week 17. Safety endpoints included the incidence and severity of adverse events (including those associated with hypothetical or known safety concerns regarding the use of ESAs) and the incidence of formation of neutralizing antibodies against darbepoetin alfa. Because this study was among the first double-blind, randomized, controlled trials of darbepoetin alfa in the AoC setting, additional exploratory endpoints were identified as clinical experience expanded. These endpoints included the incidence of transfusions from week 1 to week 17, the percentage of patients achieving the hemoglobin target (11 g/dl), and the mean hemoglobin concentration maintained after the target hemoglobin was reached (maintaining hemoglobin in the range of g/dl is in accordance with evidence-based guidelines that were in effect at the time of the study [18 20]). Statistical Analysis This study was designed to demonstrate benefit with respect to hematopoietic response in patients receiving darbepoetin alfa 6.75 g/kg Q4W compared with placebo Q4W. The assumptions used to determine the sample size for this study were 20% and 45% hematopoietic response rates for the placebo and darbepoetin alfa groups, respectively. To have 90% power to detect the difference between an underlying placebo proportion of 20% and a treated proportion of 45% (using a 2 test with a 0.05 two-sided significance level), the estimated sample size was 220 patients (darbepoetin alfa, 165; placebo, 55). Efficacy and safety analyses were performed on randomized patients who received at least one dose of study product. Quality-of-life analyses were performed on randomized patients who received at least one dose of study product and who completed both the baseline and at least one subsequent FACT-F questionnaire. For efficacy analyses, patients were analyzed as randomized; for safety analyses, patients were analyzed by treatment received. Statistical analyses were performed using SAS software (version 8.2; SAS Institute Inc., Cary, NC). Results were stratified by screening hemoglobin concentration category ( 10 g/dl and 10 g/dl). Categorical variables were summarized using frequency and percent, and continuous variables were summarized by the mean, standard deviation (SD), and 95% confidence intervals (CIs). For time-toevent endpoints, the median and CI were calculated. The percentages of patients who achieved a hematopoietic response, who achieved the target hemoglobin level, or who received a transfusion were estimated using the Kaplan Meier (KM) method with the 95% CI. For the KM method, the 95% CI was based on the normal approximation with the variance estimated using Greenwood s formula. The KM graph of the time to hematopoietic response was generated. Differences between the treatment groups for each endpoint were calculated. Based on the sample size, the weighted mean of the difference between the two treatment groups was assumed to follow a normal distribution, and a test of whether the difference between the two treatment groups was significantly different from zero was performed at the 0.05 level of significance. Hemoglobin data collected within 28 days after an RBC transfusion were excluded from the analysis of hemoglobin endpoints. Hemoglobin values were analyzed using two methods: in the last-value-carried-forward (LVCF) approach, missing hemoglobin values were imputed using the preceding hemoglobin value; in the available data approach, missing values were not imputed. Available data were used for FACT-F scores and were not adjusted for RBC transfusions. All adverse events were summarized by system organ class and preferred term within system organ class using the MedDRA dictionary, version 9.0 (PSI International Inc., Fairfax, VA). RESULTS Patient Characteristics and Disposition The study period was May 25, 2004 to December 17, In total, 220 patients at 60 centers were random-

5 718 Darbepoetin Alfa for Treating Anemia of Cancer Figure 1. Flow of patients through the study. In this study, 316 patients were screened and 220 patients were randomized. Two of the 164 patients randomized to the darbepoetin alfa arm did not receive darbepoetin alfa. Thus, the primary analysis set comprised 162 randomized patients who received darbepoetin alfa and 56 randomized patients who received placebo. ized (164 patients to darbepoetin alfa and 56 patients to placebo) (Fig. 1). Two patients in the darbepoetin alfa group were randomized but not treated with study drug (Fig. 1); therefore, the primary analysis set (randomized patients who received at least one dose of study drug) consisted of 162 patients in the darbepoetin group and 56 patients in the placebo group. During the study, two patients in the placebo group received darbepoetin alfa and were considered in the darbepoetin alfa group for safety analyses. Eleven patients had significant protocol deviations, including seven (4%) in the darbepoetin alfa group and four (7%) in the placebo group, the most common of which was failure to meet inclusion/exclusion criteria (2% in the darbepoetin alfa group and 4% in the placebo group). Similar percentages of patients in the two treatment groups completed the study (Fig. 1). In general, patients in both treatment groups had similar baseline characteristics (Table 1). The majority of patients were women, white, and 65 years of age. The most common primary tumor type was breast cancer. Similar percentages of patients in both groups had a screening hemoglobin level 10 g/dl (darbepoetin alfa, 35%; placebo, 34%). The darbepoetin alfa group had a higher mean baseline level of endogenous erythropoietin than the placebo group; however, the median endogenous erythropoietin levels were similar. The darbepoetin alfa group had a significantly higher (p.03) baseline FACT-F score than the placebo group, and a higher percentage of patients in the darbepoetin alfa group received prior chemotherapy. Other cancer treatments (nonmyelosuppressive) were received by 34% and 46% of patients in the darbepoetin alfa group and placebo group, respectively. The most common on-study cancer treatments were hormonal therapy and monoclonal antibodies. Effect of Darbepoetin Alfa Versus Placebo on Hematopoietic Response Four patients in the darbepoetin alfa group and two patients in the placebo group were not eligible for analysis of hematopoietic response because they received a RBC transfusion within 28 days prior to their baseline hemoglobin assessment. A significantly higher percentage of patients in the darbepoetin alfa versus placebo group achieved a hematopoietic response (69% versus 24%; p.001) (Fig. 2A). In both treatment groups, a slightly higher percentage of patients in the 10-g/dl hemoglobin stratum had a hematopoietic response than in the 10-g/dl stratum (Fig. 2A). The median time to a hematopoietic response was 7 weeks (95% CI, 7 11) in the darbepoetin alfa group but could not be estimated in the placebo group (Fig. 2B). Additional Hemoglobin Endpoints The KM percentage of patients who achieved the target hemoglobin concentration (11 g/dl) was statistically significantly higher in the darbepoetin alfa group than in the placebo group: 85% (95% CI, 79% 92%) versus 50% (95% CI, 34% 66%) (p 0.001) (Table 2). The difference between groups in the percentages of patients who achieved the target hemoglobin was 38% (95% CI, 22% 54%). The percentage of patients who achieved the target

6 Gordon, Nichols, Ben-Jacob et al. 719 Table 1. Demographics, disease state, and baseline characteristics Darbepoetin alfa n 162 Placebo n 56 Sex, n (%) Female 102 (63%) 38 (68%) Race, n (%) White 119 (73%) 39 (70%) Other 43 (27%) 17 (30%) Mean (SD) age, years 70 (12) 70 (12) Age group in years, n (%) (70%) 40 (71%) (42%) 23 (41%) Primary tumor type, n (%) Breast 45 (28%) 15 (27%) Hematologic a 36 (22%) 8 (14%) Genitourinary 22 (14%) 8 (14%) Gastrointestinal 20 (12%) 8 (14%) Lung 16 (10%) 6 (11%) Gynecologic 11 (7%) 6 (11%) Other b 12 (7%) 5 (9%) Disease stage, n (%) I II 40 (25%) 14 (25%) III IV 97 (60%) 29 (52%) Limited 5 (3%) 0 (0%) Extensive 1 (1%) 2 (4%) Unknown 19 (12%) 11 (20%) ECOG status score, n (%) (99%) 55 (98%) 2 0 (0%) 1 (2%) Missing 1 (1%) 0 (0%) Known metastases, n (%) 62 (38%) 25 (45%) Baseline eepo, mu/ml Mean (SD) 81 (221), n (53), n 53 Median (range) 37 (12 1,936), n (12 360), n 53 Baseline eepo category, n (%) 100 mu/ml 138 (85%) 49 (88%) 100 to 500 mu/ml 14 (9%) 4 (7%) 500 mu/ml 3 (2%) 0 (0%) Mean (SD) baseline Hb, g/dl 10.1 (0.8), n (0.8), n 54 Prior chemotherapy, n (%) 54 (33%) 16 (29%) Mean (SD) baseline FACT-F score 30 (12), n (13), n 50 a Hematologic cancers included acute and chronic lymphocytic leukemia, non-hodgkin s lymphoma, Hodgkin s disease, multiple myeloma, and other lymphoma. b Other cancers included bone sarcoma, soft tissue sarcoma, melanoma, head and neck (squamous cell) carcinoma, and other tumors. Abbreviations: ECOG, Eastern Cooperative Oncology Group; eepo, endogenous erythropoietin; FACT-F, Functional Assessment of Cancer Therapy Fatigue; Hb, hemoglobin; SD, standard deviation.

7 720 Darbepoetin Alfa for Treating Anemia of Cancer Transfusions There was no difference between the two treatment groups in the KM percentage of patients who received RBC transfusions from week 1 to end of study (11% in both groups) (Fig. 4A). Also, there was no significant difference in the KM percentage of patients who received transfusions from week 5 to end of study (difference [darbepoetin alfa minus placebo] 2%; 95% CI, 5 9) (Fig. 4B). However, in both treatment groups, a lower percentage of patients with screening hemoglobin 10 g/dl received transfusions (Fig. 4). Figure 2. Patients with a hematopoietic response. (A): Percentage of patients who achieved a hematopoietic response after 13 weeks of treatment. Error bars indicate the upper 95% CI limit. (B): KM graph of the percentage of patients who achieved a hematopoietic response during the study. Abbreviations: CI, confidence interval; DA, darbepoetin alfa; Hb, hemoglobin; KM, Kaplan-Meier. hemoglobin level was higher in the 10-g/dl hemoglobin stratum than in the 10-g/dl hemoglobin stratum in both treatment groups (Table 2). The median time to reach the target hemoglobin was 5 weeks (95% CI, 3 7) in the darbepoetin alfa group but could not be estimated in the placebo group. Once the target hemoglobin concentration of 11 g/dl was achieved, the majority of patients treated with darbepoetin alfa in both screeninghemoglobin strata then maintained hemoglobin concentrations within the recommended range of g/dl (Table 2) [18 20]. The mean (SD) change in hemoglobin from baseline to week 17 was 1.3 (1.4) g/dl in the darbepoetin alfa group and 0.2 (1.0) g/dl in the placebo group; this was consistent in both screening-hemoglobin strata (LVCF approach) (Fig. 3). Analyses using available data indicated that the mean (SD) change in hemoglobin from baseline to week 17 was 1.4 (1.3) g/dl in the darbepoetin alfa group and 0.4 (1.0) g/dl in the placebo group. Quality of Life The mean baseline FACT-F score was significantly higher (p 0.03) in the darbepoetin alfa group than in the placebo group (Table 1), and by week 17, both treatment groups had a similar mean increase in FACT-F score from baseline (darbepoetin, 4.8; placebo, 5.0) (online supplementary Figure 1). Interestingly, the mean change in FACT-F scores was higher in the darbepoetin alfa group when patients screening hemoglobin was 10 g/dl (1.5 versus 0.6), but both groups had similar increases when screening hemoglobin was 10 g/dl (darbepoetin, 6.6; placebo, 6.8) (online supplementary Figure 1). Safety Endpoints The mean (SD) weeks of dosing was 11.7 (3.1) weeks in the darbepoetin alfa group and 11.5 (3.4) weeks in the placebo group, and the mean (SD) weekly dose of darbepoetin alfa was (48.0) g/week. The percentages of patients who had one or more doses withheld because the hemoglobin threshold ( 13 g/dl) was reached were 30% in the darbepoetin alfa group (n 50) and 4% in the placebo group (n 2). The percentages of patients who had a dose increase were 28% and 57% in the darbepoetin alfa and placebo groups, respectively. A similar proportion of patients in both treatment groups experienced adverse events and serious adverse events (Table 3). The most common serious adverse events were: disease progression (darbepoetin alfa, 4%; placebo, 7%), pneumonia (darbepoetin alfa, 3%; placebo, 2%), dehydration (darbepoetin alfa, 3%; placebo, 2%), and anemia (darbepoetin alfa, 2%; placebo, 4%). Treatment-related adverse events were reported by five patients in the darbepoetin alfa group (myalgia, n 1; rash, n 1, pruritic rash, n 1; deep vein thrombosis, n 2) and one patient in the placebo group (fatigue). There were no serious treatmentrelated adverse events reported in the placebo group. However, serious treatment-related adverse events (deep vein thrombosis) were reported in two patients from the darbepoetin alfa group.

8 Gordon, Nichols, Ben-Jacob et al. 721 Table 2. Hemoglobin endpoints Darbepoetin alfa n 162 Placebo n 56 Patients eligible for target Hb analysis, n a KM% (95% CI) of patients who achieved target Hb 85% (79% 92%) 50% (34% 66%) Crude% (95% CI) of patients who achieved target Hb 81% (74% 87%) 43% (29% 57%) Mean (SD) Hb maintained after target Hb achieved, g/dl b 11.9 (0.8), n (0.8), n 28 Patients maintaining Hb after achieving target, n (%) b 11 g/dl 19 (14%) 8 (29%) g/dl 103 (77%) 18 (64%) 13 g/dl 11 (8%) 2 (7%) a Patients who had hemoglobin values 11 g/dl at baseline or had no hemoglobin data at baseline were not eligible for this analysis. Patients who had no hemoglobin data after baseline were counted as not having achieved the target hemoglobin level. b This analysis included patients who had hemoglobin values 11 g/dl at baseline or had achieved the target hemoglobin. Abbreviations: CI, confidence interval; Hb, hemoglobin; KM, Kaplan Meier; SD, standard deviation. Figure 3. Change in hemoglobin from baseline to the end of the study at week 17. Data from the LVCF analytical approach are shown. Error bars indicate the upper 95% CL. Abbreviations: CI, confidence interval; Hb, hemoglobin; LVCF, last-value-carried-forward. Within the category of adverse events that are associated with known or hypothetical safety concerns, there was a slightly higher incidence of cardiovascular and thromboembolic events in the darbepoetin alfa group (10%) than in the placebo group (7%), and one patient in the darbepoetin alfa group had hypertension (not considered related to study drug) (Table 3). Nineteen patients died during the study or within 30 days following the end-of-study visit: 13 (8.0%) in the darbepoetin alfa group (nine because of cancer, one as a result of sepsis, one as a result of respiratory failure/septic shock, one as a result of pleural effusion, and one of unknown cause) and six (11%) in the placebo group (five because of cancer, and one of unknown cause). During this study, none of the patients developed neutralizing antibodies to darbepoetin alfa. Figure 4. Incidence of transfusions. (A): Percentage of patients with transfusions from week 1 to EOS at week 17. (B): Percentage of patients with transfusions from week 5 to EOS at week 17. Error bars indicate the upper 95% CI limit. Abbreviations: CI, confidence interval; EOS, end of study; Hb, hemoglobin. DISCUSSION The results from this phase II trial demonstrated that, in these AoC study patients, a significantly higher percentage

9 722 Darbepoetin Alfa for Treating Anemia of Cancer Table 3. Patient safety of patients who received darbepoetin alfa achieved a hematopoietic response and achieved the target hemoglobin concentration compared with patients who received placebo. In addition, patients in the darbepoetin alfa group had a greater change in hemoglobin from baseline to the end of treatment than patients in the placebo group. Previous studies have yielded conflicting results on the effectiveness of ESAs in reducing transfusion requirements in patients with AoC. For example, in three open-label studies, ESAs reduced transfusion requirements [15, 16, 21]; however, in three placebo-controlled trials, only trends toward a lower transfusion incidence in the ESA-treated group than in the placebo group were observed [14, 17, 22]. Likewise, in the present study, although darbepoetin alfa increased hemoglobin levels above those attained with placebo, there was no significant difference in the incidence of transfusions between the two treatment groups. In contrast, studies in cancer patients with CIA have consistently shown that treatment with darbepoetin alfa results in a significantly lower incidence of transfusions than with placebo [23, 24]. The discrepancy between the AoC and CIA patient populations may be related to differences in baseline transfusion requirements. For example, patients with AoC have Darbepoetin alfa n 164 Placebo n 54 Adverse events, n (%) Patients with any adverse events 114 (70) 38 (70) Serious adverse events 46 (28) 15 (28) Patients with treatment-related adverse events 5 (3) 1 (2) Serious treatment-related adverse events 2 (1) 0 (0) Adverse events of interest or death on study or disease progression, n (%) Cardiovascular and thromboembolic events 16 (10) 4 (7) Arrhythmia 3 (2) 3 (6) Congestive heart failure 6 (4) 1 (2) Cerebrovascular accident 2 (1) 0 (0) Myocardial infarction/coronary artery disorders 3 (2) 0 (0) Embolism/thrombosis (arterial and venous) 4 (2) 0 (0) Seizure 0 (0) 1 (2) Hypertension 1 (1) 0 (0) Pure red cell aplasia 0 (0) 0 (0) Immune system disorder 0 (0) 0 (0) Neoplasms benign, malignant, and unspecified 17 (10) 7 (13) (including cysts and polyps) Deaths on study 11 (6.7) 5 (9.3) Disease progression a 33 (20.1) 8 (14.8) a This item includes all reported adverse events of disease progression. As noted in the text, 4% of the instances of disease progression in the darbepoetin alfa group and 7% in the placebo group were considered serious by the investigators. lower baseline transfusion rates than patients with CIA [15, 16]. It is of interest to note, however, that in the present AoC study, patients with a screening hemoglobin level 10 g/dl had a lower incidence of transfusions if they received darbepoetin alfa than if they received placebo. In addition, patients in both treatment groups who had a screening hemoglobin level 10 g/dl had a lower incidence of transfusions than those with a screening hemoglobin level 10 g/dl. There are also conflicting data on the effect of ESAs on the quality of life of patients with AoC. In a number of studies, quality-of-life measures were improved after treatment with ESAs [15, 17, 21, 25]; however, in a recently completed large, placebo-controlled study of darbepoetin alfa in patients with AoC, darbepoetin alfa did not improve FACT-F scores above those observed with placebo [26]. In the present study, both treatment groups had a clinically meaningful rise (three or more points) [27] in FACT-F score from baseline, but darbepoetin alfa did not improve FACT-F scores above those observed with placebo. Given that the darbepoetin alfa group had a significantly higher mean baseline FACT-F score than the placebo group, this observation is difficult to interpret. In patients with screen-

10 Gordon, Nichols, Ben-Jacob et al. 723 ing hemoglobin 10 g/dl, darbepoetin alfa did, however, improve the mean FACT-F scores. In the present study, both treatment groups had a similar incidence of adverse events, suggesting that darbepoetin alfa was well tolerated in these study patients. In addition, the incidence of thromboembolic events in patients who received darbepoetin alfa (4%) was similar to that reported in a comprehensive meta-analysis of the effects of ESAs in patients with cancer [7]. This is a recognized risk associated with ESA use that has remained consistent over time and is documented in the original product labeling. Since the completion of this trial, safety results from a phase III randomized, placebo-controlled, double-blind trial of darbepoetin alfa in the AoC setting (using the same dosing regimen as the present study) were reported [22]. That trial failed to meet its primary endpoint of reducing all occurrences of RBC transfusions, although when 75 patients who were not transfused according to the protocol guidelines were included in the analysis, significant benefit was observed. Significant improvement in hemoglobin endpoints was also observed. An unexpected safety finding was that more deaths occurred in the darbepoetin alfa group (26.8%, 138/515) than in the placebo group (20.4%, 96/ 470) during the 16-week treatment period, and overall survival was worse in the darbepoetin alfa group (hazard ratio [HR], 1.29; 95% CI, ). It is noteworthy that the phase III trial was not designed to measure survival and that imbalances in baseline prognostic factors may have influenced survival outcomes; the HR was 1.17 (95% CI, ) after adjusting for prognostic factors including baseline hemoglobin level, FACT-F score, ECOG performance status score, stage, and tumor type. These survival results are inconsistent with those seen in the present study and previous studies in similar populations. It is possible that differences in the patient populations contributed to these disparate outcomes: 82% of patients in the phase III trial had stage III/IV disease and all had active disease, whereas 57% of patients in the present study had stage III/IV disease and 20% were in complete remission. Concerns regarding a potential relationship between ESAs and an increased risk for mortality and/or tumor progression have also been raised in some clinical studies designed to explore the ability of higher hemoglobin targets to improve survival in patients with cancer receiving chemotherapy or radiotherapy. Overall, these signals have not been observed consistently across studies, and within the chemotherapy-treated population, study-level meta-analyses (including data on 8,000 patients) have not indicated a clear effect of ESAs on tumor progression or mortality. Given these inconsistent results, further research is required to directly assess the impact of ESAs on disease outcomes. The 2007 update to the joint guidelines of the American Society of Clinical Oncology/American Society of Hematology does not recommend the use of darbepoetin alfa in patients with solid or nonmyeloid hematologic malignancies who are not receiving chemotherapy or radiation [28]. In 2008, the product labels for ESAs were updated with a boxed warning highlighting potential safety risks [12, 13]. The darbepoetin alfa label advises that the product should be used only for the treatment of anemia resulting from concomitant myelosuppressive chemotherapy (not AoC). The label also recommends that physicians should use the lowest dose of darbepoetin alfa needed to avoid RBC transfusions and discontinue darbepoetin alfa therapy following completion of a course of chemotherapy. In conclusion, darbepoetin alfa administered Q4W significantly raised hemoglobin levels and appeared to be well tolerated in patients with AoC in this phase II trial. Although no differences in on-study survival were observed between the darbepoetin alfa and placebo groups in this study, the survival outcomes observed in the subsequent phase III trial suggest a potential safety concern regarding the use of darbepoetin alfa in the AoC setting. The explanation of such differences in survival outcome between studies is unclear and further research into the potential effects of ESAs on survival in oncology patients is ongoing, including patient-level pooled data analyses of existing studies and additional clinical studies. ACKNOWLEDGMENTS This study ( ) was supported by research funding from Amgen Inc. The ClinicalTrials.gov identifier for this study is NCT We wish to thank Hung Lam and Yong Mun, Ph.D., for their assistance with the statistical analyses. In addition to the authors of the present paper, the following investigators participated in this study: Barry Berman, John Eckardt, Patrick Flynn, Gregory Guzley, David Smith, Clarence Vaughn, James Weick, Raymond Vivacqua, Marc Saltzman, Herbert Duvivier, Birbal Bhaskar, Veena Charu, Robert Moss, Julio Hajdenberg, Nilesh Mehta, Frank Slovick, Madhavan Pillai, Sunil Gandhi, Isaac Esseesse, Mukesh Bhatt, Vinay Raja, Rao Moravineni, Jorge Ayub, Niraj Gupta, Billy Clowney, Hema Rao, John Hankins, Sitki Ergul, Thomas Jones, Young Lee, James Cook, James Carinder, Rudolph Navari, Roberto Arevalo Araujo, Muhammad-Ali Zaydan Thomas Anderson, Patrick Elwood, Leo Orr, Michael Kosmo, Paul Richards, Donald Richards, Thomas Cartwright, David Dong, Larry Frase, Ira Felman, Carlos Rubin de Celis, David Schrier, and Mark Keaton.

11 724 Darbepoetin Alfa for Treating Anemia of Cancer AUTHOR CONTRIBUTIONS Conception/design: Dianne Tomita, Tom Lillie Administrative support: Carole Miller Provision of study materials or patients: David Gordon, Gwen Nichols, Ali Ben-Jacob, Carole Miller Collection/assembly of data: David Gordon, Ali Ben-Jacob, Carole Miller Data analysis and interpretation: David Gordon, Ali Ben-Jacob, Dianne Tomita, Tom Lillie Manuscript writing: David Gordon, Dianne Tomita, Tom Lillie Final approval of manuscript: David Gordon, Gwen Nichols, Ali Ben-Jacob, Dianne Tomita, Tom Lillie, Carole Miller The authors take full responsibility for the content of the paper, but thank Linda Runft, Ph.D., and Kathryn Boorer, Ph.D., employees of Amgen Inc., for their assistance in compiling the directives of the authors into drafts for review, collating the review comments of the authors into subsequent drafts, editing the drafts, and coordinating compliance of the authors with journal requirements. 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