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The safety and efficacy of darbepoetin alfa (Aranesp) at 3.0 µg/kg administered every 2 weeks and recombinant human erythropoietin (rHuEPO) given as 40,000 U weekly or 150 U/kg three times weekly were evaluated by
ABSTRACT: The safety and efficacy of darbepoetin alfa (Aranesp) at 3.0 µg/kgadministered every 2 weeks and recombinant human erythropoietin (rHuEPO) givenas 40,000 U weekly or 150 U/kg three times weekly were evaluated by pooling datafrom three darbepoetin alfa clinical studies. All studies enrolled anemic(hemoglobin ≤ 11.0 g/dL) patients receiving multicycle chemotherapy. Open-labelstudy drug was administered by subcutaneous injection. Hemoglobinconcentrations, red blood cell transfusion requirements, and standard safetyparameters were evaluated. Of 260 patients who received darbepoetin alfa at 3.0µg/kg every 2 weeks and 115 patients who received rHuEPO three times weeklyor once weekly, hematopoietic response (change in hemoglobin from baseline of ³2 g/dL or hemoglobin concentration of ³ 12 g/dL) was achieved in 71% (95%confidence interval [CI] = 65%-78%) of patients who received darbepoetin alfaevery 2 weeks, comparable to the response in patients who received rHuEPO (71%;95% CI = 61%-81%). The mean increase in hemoglobin concentration over13 weeks was also similar: 1.48 g/dL (95% CI = 1.28-1.68 g/dL) fordarbepoetin alfa and 1.31 g/dL (95% CI = 0.97-1.64 g/dL) for rHuEPO. Theproportion of patients in the darbepoetin alfa group requiring transfusions waslower (7%; 95% CI = 4%-11%) than that in the rHuEPO group (14%; 95% CI = 8%-22%).Darbepoetin alfa every 2 weeks was well tolerated with a safety profilecomparable to that of rHuEPO. In conclusion, darbepoetin alfa at a dose of 3.0µg/kg given every 2 weeks safely increases hemoglobin concentration to the sameextent as rHuEPO. [ONCOLOGY 16(Suppl 11):31-36, 2002]
It is increasingly recognized thatfatigue in cancer patientsprimarily caused by anemia resulting from chemotherapy or other aspects of thedisease processis associated with debilitating effects on quality of life andfunctioning.[1,2] Surveys performed by the multidisciplinary Fatigue Coalitionindicated that fatigue was the primary complaint in one-quarter of patientsafter chemotherapy (ahead of nausea at 13%), and that 61% of cancer patientsfelt their lives were affected more by fatigue than by pain associated withtheir disease. Cancer-related anemia has traditionally been treated with redblood cell transfusions; however, concerns over the safety of the blood supplyand potential adverse effects of transfusions in cancer patients have led to thedevelopment of erythropoietic agents as a safer alternative for increasinghemoglobin levels in these patients.
Improved understanding of the deleterious effects of anemia and theavailability of recombinant human erythropoietin (rHuEPO) have led to a greatdeal of active investigation of the benefits of erythropoietic therapy inpatients with chemotherapy-induced anemia. Most recently, with the developmentof darbepoetin alfa (Aranesp) and research into once-weekly therapy for rHuEPO (rHuEPOis licensed for this indication at a dose of 150 U/kg three times weekly),considerable efforts have been focused on reducing the need for frequentinjections. For patients with cancer (and their caregivers), each injection canbe a reminder of their disease; for those for whom self-injection is not anoption, each clinic visit is an interruption of normal life and may createsignificant logistic challenges relating to transportation, child care, or work.For clinic staff, administrative work and time are increased. A recent study ofpatients with chronic renal insufficiency reported that, on average, thesepatients spent 90 minutes traveling to/from the clinic and waiting to be seen,and 49% relied on someone else for transportation. It is likely that thesefindings would also be true for cancer patients. Thus, reducing the dosingfrequency of erythropoietic agents given to patients with chemotherapy-inducedanemia would be beneficial.
Weekly administration was shown to be effective in patients withchemotherapy-induced anemia in a large, open-label, uncontrolled study using asingle subcutaneous injection of 40,000 U of rHuEPO (this dose could beincreased to 60,000 U if a 1.0-g/dL hemoglobin increase had not been observedafter 4 weeks). With this regimen, 68% of patients achieved a hematopoieticresponse (a hemoglobin concentration ³ 12.0 g/dL and/or an increaseof ³ 2.0 g/dL without preceding transfusions) by the end of the 16-weektreatment period, which is comparable to the response observed withthree-times-weekly dosing.[5,6] However, this dose represents an increase ofapproximately 33% over the more routinely studied dose and schedule of 150 U/kgthree times weekly[7-9] or the dosing regimen of 10,000 U of rHuEPO three timesweekly, which has also been reported. Based on these results, weekly dosingis now accepted in clinical practice in the United States, although not in otherregions.
Darbepoetin alfa, a unique recombinant protein produced by modifying the genefor erythropoietin, is a more potent erythropoietic agent. Darbepoetin alfastimulates erythropoiesis through the same mechanism as endogenouserythropoietin and rHuEPO. However, darbepoetin alfa was engineered to haveadditional carbohydrate side chains (five total N-linked glycosylation sidechains with up to 22 sialic acid residues) compared with rHuEPO (three totalN-linked glycosylation side chains with up to 14 sialic acid residues).Sialic acid content is directly correlated with in vivo activity, possibly dueto the degree of clearance by the asialoglycoprotein receptor in the liver;the increased sialic acid content of darbepoetin alfa reduces its clearance andresults in an extended serum residence time.
Darbepoetin alfa was initially approved for use in patients with renalfailure. Pharmacokinetic studies in this indication showed that darbepoetin alfahad an approximately threefold longer terminal half-life than rHuEPO (25.3 vs8.5 hours). An extensive clinical development program has evaluated thepharmacokinetics, efficacy, and safety of various dose and schedule combinationsof darbepoetin alfa during cancer chemotherapy. Phase I and II studies exploreddosing intervals ranging from weekly to every-4-week administration.[14-21]These included an every-2-week dosing schedule, which appeared to be effectivein alleviating anemia in patients with solid tumors receivingchemotherapy.[14,19]
Comparisons between rHuEPO studies (or between rHuEPO studies and darbepoetinalfa studies) may be confounded due to differences in factors such as studydesign, populations, treatment duration, analytical methodologies, responsedefinitions, or the use of analysis sets other than the intent-to-treat set. Toobtain a more precise estimate of the effect of darbepoetin alfa administered at3.0 µg/kg every 2 weeks, and to evaluate the relative effect of this doseand schedule compared with rHuEPO, data from three clinical studies of similardesign have been pooled.[14-17,19,20] Unlike comparisons with historicalliterature, this approach eliminates differences in analytical methodologies,treatment duration, and other potentially confounding factors. This reportdescribes the results of this combined analysis.
The population evaluated and the design of each of the three studies includedin these analyses were similar. All study centers were in the United States.Eligible patients were men or women ³ 18 years of age who werereceiving multicycle chemotherapy and had anemia (hemoglobin concentration £ 11.0 g/dL). Patients were required to have adequate renal and hepaticfunction and could not be iron deficient (defined as both transferrin saturation< 15% and ferritin < 10 ng/mL). Patients with known cardiacdisease or hematologic disorders that could cause anemia were not eligible. Eachcenter’s independent ethics committee or central ethics committee approved theprotocol, and patients provided written informed consent before anystudy-specific procedures were done.
The principal difference between the eligibilty criteria in the three studieswas tumor type (solid tumors were specified in two studies and nonmyeloidmalignancies in the third). However, as most patients in both groups had solidtumors, and no difference has been noted between the effect of erythropoieticagents on patients with hematologic malignancies and those with solidtumors,[5,6] this is not thought to have an impact on the validity of theconclusions from this pooled analysis.
All three studies were multicenter and open-label in design. The dose ofrHuEPO could be increased in both studies contributing rHuEPO data (at week 8 orweek 6), and the dose of darbepoetin alfa could be increased in one of the twostudies contributing darbepoetin alfa data (at week 7). The requirement forwithholding drug due to reaching specified maximum hemoglobin concentrations(14 g/dL for women, 15 g/dL for men) was the same in all studies. Redblood cell transfusions were recommended if hemoglobin decreased to £ 8.0g/dL or patients had symptoms
Efficacy analyses were conducted on the intent-to-treat analysis set (ie, allpatients who received at least one dose of study drug). All analyses weredescriptive. Baseline demographic and clinical characteristics were summarizedby the mean (standard deviation) for continuous measures and number (percentage)for categorical measures (Table 2). The proportion of patients achieving ahematopoietic response during the treatment phase was estimated by subtractingthe Kaplan-Meier estimate of the survivor function from 1; 95% confidenceintervals (CI) were calculated by using Greenwood’s estimate of thevariance (Figure 1). Time to hematopoietic response was summarized by theKaplan-Meier estimate of the median.
Hemoglobin concentration over time was summarized by plotting the mean hemoglobin by study week (95% CI were plotted at weeks 1, 5, 9, and 13); patients missing a hemoglobin value at a particular week or who had a red blood cell transfusion within 28 days of a particular week were excluded from the mean at that week (Figure 2). In addition, the change in hemoglobin concentration after 4 weeks and at the end of treatment was summarized by the mean (95% CI); hemoglobin values that were missing or that occurred within 28 days of a transfusion were replaced with the last available value that was not within 28 days of a transfusion (Table 3). The proportion of patients with a transfusion was estimated with a crude proportion and an exact 95% CI (Table 4).
Patient Demographicsand Disposition
A total of 375 patients were included in this analysis260 darbepoetin alfaand 115 rHuEPO (Table 2). Baseline demographic characteristics weregenerally similar in the two groups; the mean baseline hemoglobin concentrationwas slightly lower for the rHuEPO group than the darbepoetin alfa group (9.89 vs10.23 g/dL, respectively), and the proportion of patients with stage IV diseaseslightly higher in the rHuEPO group than the darbepoetin alfa group (68% vs 56%,respectively). Demographic and baseline characteristics were similar across thethree individual studies, supporting the pooling of the data (data not shown).Patients with hematologic malignancies were enrolled in only one study (thestudy that allowed hematologic [nonmyeloid] tumors in addition to solid tumors).
Efficacy End Points
The effect on hemoglobin concentration during the studies was similar in thecombined rHuEPO and darbepoetin alfa groups. Hematopoietic response (a ³ 2.0-g/dL hemoglobin increase or hemoglobin value ³ 12.0 g/dLin the absence of transfusions) was similar in the two groups, with 71% (95% CI= 65%-78%) of patients in the darbepoetin alfa group and 71% (95% CI = 61%-81%)in the rHuEPO group meeting this definition of response (Figure1). The medianduration of time required to achieve a hematopoietic response was 9 weeks(95% CI = 8-11 weeks) for darbepoetin alfa and 9 weeks (95% CI= 7-11 weeks) for rHuEPO.
The mean change in hemoglobin concentration was calculated for all patientsafter 4 weeks and after 12 weeks of treatment. The results were comparablefor rHuEPO and darbepoetin alfa in each case (Table3). The mean change was 0.38g/dL (95% CI = 0.24 -0.52 g/dL) and 0.46 g/dL (95% CI = 0.20-0.72 g/dL)after 4 weeks, and was 1.48 g/dL (95% CI = 1.28-1.68 g/dL) and1.31 g/dL (95% CI = 0.97-1.64 g/dL) after 12 weeks for darbepoetin alfaand rHuEPO, respectively. The rise in hemoglobin concentration over time for thetwo groups followed a nearly superimposable course (Figure2).
Reports have indicated that red blood cell transfusion requirements may notbe affected until after 4 weeks of rHuEPO treatment,[8,9,23] so we evaluatedtransfusions from week 5 to the end of treatment (Table4). Seven percent (95%CI = 4%-11%) of darbepoetin alfa patients and 14% of rHuEPO patients (95% CI =8%-22%) required a transfusion during this period.
Adverse events were comparable between the darbepoetin alfa and rHuEPOpatients in the completed studies. The most frequently reported events werenausea, fatigue, vomiting, and diarrhea, consistent with a population ofpatients undergoing chemotherapy. Interim data from the ongoing study suggestedno important deviations from previous reports establishing the safety profile ofdarbepoetin alfa. Analysis of serum samples collected at various intervals hasrevealed no evidence of neutralizing antibodies to darbepoetin alfa.
Patients undergoing cancer chemotherapy are faced with frequentlyoverwhelming challenges in managing the debilitating effects of chemotherapy, aswell as the physical and psychological aspects of their disease. Among thefactors affecting the quality of life for these patients, fatigue resulting fromchemotherapy-induced anemia has been demonstrated to have a significant negativeimpact.[1-3] Even patients who are only mildly or moderately anemic have beenshown to benefit from treatment with rHuEPO in terms of improved energy andactivity levels and overall quality of life. However, the three-times-weeklydosing schedule indicated for rHuEPO can be burdensome to patients who mayrequire a clinic visit for each injection. A weekly dosing schedule, which iscommonly used in the United States, though not in other regions, offers someimprovement, but further decreases in dosing frequency would benefit patients,caregivers, and health-care providers alike.
Because of its longer serum residence time, darbepoetin alfa has allowedextended dosing in the renal disease setting, and has now been approved for usein patients with chemotherapy-induced anemia. Presented here are data from threestudies undertaken in the clinical development of darbepoetin alfa for thisindication. The data were combined to obtain a more robust analysis with largernumber of patients. Because the three studies enrolled a broadly similarpopulation (ie, one representative of the currently approved label fordarbepoetin alfa), were all conducted in the United States where medicalpractice is relatively consistent for this patient population, and had similartreatment durations/design characteristics, it was considered appropriate tocombine the data from these studies. Minor differences in eligibility criteriaare not expected to have had an effect on the conclusions from the analysis.
One study enrolled patients with nonmyeloid malignancies while the othersspecified solid tumors; however, results from the individual studies did notsuggest a difference in response, nor does the literature suggest a differentialresponse between patients with solid tumors or those with hematologicmalignancies.[5,6] One of the studies allowed a dose increase for inadequateearly hemoglobin increase in patients receiving darbepoetin alfa, whereas doseincreases were permitted in all rHuEPO groups; any effect on the results due tothis difference would be to rHuEPO’s advantage.
The combined analysis included a total of 375 patients withchemotherapy-induced anemia. The dose of 3.0 µg/kg darbepoetin alfa givenevery 2 weeks produced increases in hemoglobin concentration similar in bothmagnitude and time course to those obtained with rHuEPO. Hematopoietic response,which has become a commonly accepted measure of hemoglobin increase as reportedin the literature,[5,6] was achieved by 71% of darbepoetin alfa patients and 71%of rHuEPO patients, consistent with other reports for rHuEPO.[5,6] In terms ofclinical consequences of the increase in hemoglobin, only 7% (95% CI = 4%-11%)of darbepoetin alfa patients received red blood cell transfusions during thesecond and third months of treatment (ie, from week 5 onward), compared with 14%(95% CI = 8%-22%) of rHuEPO patients.
In a comprehensive clinical development program in cancer patients withchemotherapy-induced anemia, darbepoetin alfa demonstrated a tolerable level ofadverse eventsfew serious, treatment-related events, no unmanageable rapidincreases in hemoglobin, and no confirmed neutralizing antibodies.[14-21] Theresults from the three studies analyzed here are consistent with this safetyprofile.
The ability to restore normal hemoglobin levels with one dose of darbepoetinalfa every 2 weeks represents an important advance for patients undergoingchemotherapy. In all of the analyses performed, the impact of darbepoetin alfaat 3.0 µg/kg every 2 weeks was similar to that observed with rHuEPO eitherafter 12 weeks of treatment or evaluated over the treatment time course.The early and sustained erythropoietic effect obtained with darbepoetin alfagiven at 3.0 µg/kg every 2 weeks permits effective control of anemia withminimal disruption to patients’ daily lives.
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