Overcoming Barriers to Erythropoietic Therapy

ABSTRACT: Barriers to use of erythropoietic therapy in cancer patients include nonresponse in a sizable proportion, resultant lowering of cost-effectiveness, and inconvenience. Darbepoetin alfa represents the outcome of efforts to develop agents with improved erythropoietic potency. This agent has been shown to produce high dose-related response rates, reduce risk of transfusion, and produce dose-related rapidity of response in cancer patients; no loss in dose-efficiency is observed with once-every-2-week dosing compared with weekly dosing, and the feasibility of every-3-week dosing has been demonstrated. In addition, the characteristics of this agent may permit a treatment schedule consisting of frontloading with an optimal dose followed by low-dose maintenance, which may further improve dose-efficiency and cost-effectiveness of treatment. The characteristics of darbepoetin alfa suggest the ability to improve overall quality of erythropoietic therapy, which may increase its utilization in patients who would benefit from such treatment. [ONCOLOGY 16(Suppl 10):71-77, 2002]

It is clear thaterythropoietic therapy reduces risk for red bloodcell (RBC) transfusion and improves quality of life in cancer patients. There isaccumulating evidence that such intervention may also improve outcome oftreatment and prolong survival in cancer patients (see other Glaspy article,"The Potential for Anemia Treatment to Improve Survival in CancerPatients," elsewhere in this supplement). Despite its proven and potentialbenefits, most patients eligible for erythropoietic therapy on the basis ofhaving hemoglobin levels < 10 mg/dL during chemotherapy do not receivetreatment; it is estimated that only 20% to 30% of eligible patients in theUnited States and 10% of those in Europe receive erythropoietic treatment. Thisunderutilization can be attributed to a number of factors. The failure ofavailable erythropoietic treatment to induce response in a significantproportion of patients blunts enthusiasm for its use, with enthusiasm beingfurther blunted by the related effect on overall cost-effectiveness oftreatment. Indeed, cost of treatment is an issue, irrespective ofcost-effectiveness. In addition, quality of life is still conceived of as a"soft" endpoint, with many physicians desiring to see proof of benefitdemonstrated using physiologic correlates of correction of anemia. Finally,there is an issue with inconvenience related to need to administer an additionaltherapy in patients and practices already overburdened with chemotherapyschedules. Work has been ongoing to identify new agents with characteristicsthat might permit erythropoietic therapy to surmount these barriers to use. Thenovel agent darbepoetin alfa exhibits a number of desirable characteristics thatmay facilitate effective use of erythropoietic therapy.

Pharmacologic Considerations in Improving Erythropoietic Agents

With the discovery that recombinant human erythropoietin (rHuEPO) is composed of a number of different isoforms that differ in the amount of posttranslation glycosylation, investigations were undertaken to determine whether these isoforms differed in terms of activity. Administration of separated isoforms in animal studies showed that increasing potency in promoting erythropoiesis was related to increasing number of sialic acids present on the isoforms.[1] This increased potency results from longer half-life and greater area under the concentration-time curve (not from increased receptor affinity, since increased sialic acid content actually reduces receptor affinity). On the basis of these findings, a project was undertaken to develop new erythropoietin genes via site-directed mutagenesis that added glycosylation sites to the molecule without interfering with receptor binding, inducing the resultant protein to unfold, or resulting in immunogenicity. These attempts reached fruition in the development of darbepoetin alfa. This molecule, resulting from 5 amino acid substitutions in the rHuEPO gene, possesses two additional (5 vs 3) sialic acid-containing carbohydrates and up to eight additional sialic acids (maximum of 22 vs 14) and has a greater molecular weight (37,400 vs 30,400 D) compared with its predecessor, epoetin alfa.[2,3] As shown in initial animal studies, the hematopoietic potency of darbepoetin alfa was increased compared with that of epoetin alfa, with the potency of a candidate agent with four glycans being intermediate (Figure 1).[2] Initial pharmacokinetic studies in hemodialysis patients showed that darbepoetin alfa had a threefold increased half-life compared with epoetin alfa after intravenous administration.[4]

Effectiveness of Darbepoetin Alfa in Cancer Patients

In a pivotal phase III trial performed in Europe, patients with small-cell or non-small-cell lung cancer with at least 12 further weeks of cisplatin-containing chemotherapy scheduled were randomized to placebo or once-weekly subcutaneous (SC) injections of darbepoetin alfa, 2.25 mg/kg for 12 weeks. Study drug was withheld if hemoglobin level increased to > 15 g/dL for men or > 14 g/dL for women, and was reinstated at 50% of the previous dose if hemoglobin level decreased to ≤ 13 g/dL. As shown in Figure 2, darbepoetin alfa treatment was associated with a significant reduction in proportion of patients requiring RBC transfusion and a significant increase in the proportion of patients achieving hematopoietic response, defined as an increase in hemoglobin of ³ 2 g/dL or a level of ³ 12 g/dL without RBC transfusion in the previous 28 days.

Darbepoetin AlfaDose-Finding Studies

In the United States, studies were undertaken to define optimal darbepoetin alfa dose level and schedule in cancer patients. In a study of weekly dosing, patients were randomized (4:1, darbepoetin alfa:epoetin alfa) to darbepoetin alfa, 0.5, 1.0, 1.5, 2.25, 4.5, 6.0, or 8.0 µg/kg once weekly, or to epoetin alfa, 150 U/kg three times weekly for 12 weeks (Figure 3). Patients in the epoetin alfa group had their dose doubled at 8 weeks for inadequate hemoglobin response (< 1 g/dL increase from baseline). In a study of biweekly dosing, patients were randomized (1:1:1:1:1) to darbepoetin alfa, 3.0, 5.0, 7.0, or 9.0 µg/kg every 2 weeks, or epoetin alfa 40,000 U weekly for 12 weeks, with the epoetin alfa dose being increased to 60,000 U weekly for inadequate hemoglobin response at 6 weeks (Figure 3).

In both studies, darbepoetin alfa was withheld if hemoglobinlevels increased to ³15 mg/dL in men or ³ 14g/dL in women. Treatment was reinstated at the next lowest dose level or at 50%of the previous dose in the group receiving 0.5 µg/kgin the weekly dosing study and at 75% of the previous dose in the biweeklydosing study if hemoglobin subsequently decreased to ≤13 g/dL.

In the once-weekly dosing study, hemoglobin response was defined as an increase of at least 2 g/dL in the absence of RBC transfusion during the prior 28 days. The findings among the darbepoetin alfa dose groups indicated a dose-response effect, with peak response occurring at the 4.5 mg/kg dose. Mean changes in hemoglobin from baseline were 1.14 g/dL in the epoetin alfa group and 0.49, 0.62, 1.07, 1.31, 1.87, 1.85, and 2.17 in the darbepoetin alfa, 0.5, 1.0, 1.5, 2.25, 4.5, 6.0, and 8.0 µg/kg groups, respectively. Time to hemoglobin response was reduced in the darbepoetin alfa, 4.5 µg/kg group (approximately 8 weeks) compared with lower darbepoetin alfa doses and the epoetin alfa group (approximately 10 weeks). Findings in the once-weekly and once-every-2-weeks dosing studies were analyzed by comparing hematopoietic response (ie, hemoglobin increase of ³ 2 g/dL or hemoglobin level of ³ 12 g/dL in the absence of RBC transfusion within the prior 28 days) at matched total planned doses—ie, by comparing response at a dose of 1.5 µg/kg once weekly with response at a dose of 3.0 µg/kg biweekly.[5] This analysis showed that administration of a similar total dose every 2 weeks resulted in no loss of dose-efficiency compared with once-weekly dosing (Figure 4), indicating the absence of a need to increase the overall dose with biweekly dosing.

An additional study, performed in Europe, Asia, andAustralia, has examined the potential for every-3-week darbepoetin alfa dosingin patients receiving chemotherapy for solid tumors. In this study, patientswere randomized (1:4) to placebo or darbepoetin alfa, 4.5, 6.75, 9.0, 12.0,13.5, or 15.0 µg/kgevery 3 weeks for 12 weeks. Peak hemoglobin response appeared to occur at the12.0 to13.5 µg/kgdose levels, corresponding to a weekly dose of 4.0 to 4.5 µg/kg.Mean changes in hemoglobin from baseline were -0.02 g/dL in the placebo groupand 0.54, 0.86, 0.89, 1.63, 1.45, and 1.23 g/dL in the 4.5, 6.75, 9.0, 12.0,13.5, and 15.0 µg/kgevery-3-week darbepoetin alfa dose groups, respectively.

Overall, these findings indicate that darbepoetin alfaproduces high dose-related response rates and dose-related time to response incancer patients and may permit dosing intervals to be extended to as long as3 weeks. Such characteristics may have considerable impact on overalleffectiveness, overall cost and cost-effectiveness, and convenience oferythropoietic treatment. Darbepoetin alfa treatment in controlled trials wassafe, with adverse events being similar to those observed with placebo orepoetin alfa, and no neutralizing antibodies to the molecule have been reportedto date.

Potential for IncreasingDose-Efficiency

The traditional approach to erythropoietic treatment in cancer patients involves initial treatment at a dose that does not produce response in all patients who will eventually respond to treatment. Although dose increases after a designated period result in response in an additional group of patients, a sizable proportion of patients (approximately 30% overall) receive a full 12 to 16 weeks of treatment without response. It has been hypothesized that efficiency of treatment can be markedly improved by using the dose of an agent that produces peak response as a loading dose followed by reduced dose maintenance treatment (Figure 5).

The viability of such an approach with darbepoetin alfa wassuggested by findings in murine studies showing that bolus administration ofhigh doses was associated with maintenance of a dose-response effect, with nodose-response effect being observed with epoetin alfa. We have subsequentlyperformed a pilot study of the front loading/maintenance approach in cancerpatients. Patients were randomized to receive darbepoetin alfa, 4.5 µg/kgonce weekly, followed by (1) reduction to 1.5 µg/kgweekly if hemoglobin increased to ³ 12g/dL, (2) reduction to 2.25 µg/kgonce weekly after 4 weeks, or (3) reduction to 3.0 µg/kgevery 2 weeks after 4 weeks or to receive epoetin alfa, 40,000 U weekly,increased to 60,000 U weekly at week 6 if hemoglobin response was inadequate(< 1 g/dL increase).⁶Overall, hemoglobin response (increase of ³2 g/dL from baseline) was observed in 62% of all darbepoetin alfa patients andin 48% of epoetin alfa patients at 12 weeks. The predicted improvement intime to hemoglobin response was observed in darbepoetin alfa groups 1 and 2,with more than 50% of patients in both groups responding by 8 weeks. Quality oflife as assessed by the Functional Assessment of Cancer Therapy (FACT)-Fatiguesubscale score was markedly improved with darbepoetin alfa treatment comparedwith epoetin alfa treatment. The mean increase in scores among all darbepoetinalfa patients was 3.8 at week 4 and ranged from 5.8 to 7.5 thereafter.

Figure 6 shows data obtained from the once-weekly and once-every-2-weeks dosing studies of darbepoetin alfa at a dose of 3 µg/kg q2wk, which produced similar effectiveness to epoetin alfa, 40,000 to 60,000 U/wk.[5]

Timing of Erythropoietic Therapy and Chemotherapy

Available data indicate that there is an increase inendogenous erythropoietin levels on the days immediately followingadministration of chemotherapy, with this pattern being consistent over multiplechemotherapy cycles. The increase appears to be of relatively short duration, asconcentrations return to near-baseline levels prior to each subsequentchemotherapy cycle. Since this increase in erythropoietin concentration mayreflect dropout of responsive cells, the issue of whether erythropoietic therapyshould be administered during the period of increase needs to be addressed. Thisissue may be especially important in the context of potential biweekly orevery-3-week dosing schedules with darbepoetin alfa, since any potentialresistance to effect would occur during the period of maximum darbepoetin alfablood concentrations. A randomized synchrony study has been initiated to assesseffects of timing of darbepoetin alfa and chemotherapy dosing.

Conclusion

Barriers to use of erythropoietic therapy include issues ofeffectiveness, convenience, and cost-effectiveness. Darbepoetin alfa treatmenthas been shown to produce dose-related increases in hemoglobin level, reducerisk of RBC transfusion, and produce dose-related rapidity of response in cancerpatients. Treatment with this agent appears to allow flexible dosing on aweekly, biweekly, or every 3 weeks schedule; preliminary findings also suggestthat the agent may be suitable for use in a frontloading/maintenance therapyschedule that would further improve dosing efficiency. Together with itseffectiveness in correcting anemia, the flexibility in dosing with darbepoetinalfa may allow novel approaches to dosing and scheduling that could improveerythropoietic therapy overall and, thus, renew enthusiasm for its use inpatients who stand to benefit from such therapy.

References:

1. Egrie JC, Dwyer E, Lykos M, et al: Novel erythropoiesisstimulating protein (NESP) has a longer serum half-life and greater in vivobiological activity than recombinant human erythropoietin (abstract 243). Blood90(10):56a, 1997.

2. Elliot SG, Lorenzini T, Strickland T, et al: Rationaldesign of novel erythropoiesis stimulating protein (Aranesp): A super-sialatedmolecule with increased biological activity (abstract 352). Blood96(11):82a, 2000.

3. Egrie JC, Browne JK: Development and characterization ofnovel erythropoiesis stimulating protein (NESP). Br J Cancer84(suppl 1):3-10, 2001.

4. Macdougall IC, Gray SJ, Elston O, et al: Pharmacokineticsof novel erythropoiesis stimulating protein compared with epoetin alfa indialysis patients. J Am Soc Nephrol 10:2392-2395, 1999.

5. Glaspy J, Jadeja J, Justice G, et al: Darbepoetin alfaadministered every 1 or 2 weeks alleviates anemia (with no loss of doseefficiency) in patients with solid tumors (abstract 1256). Blood98(11):298a, 2001.

6. Glaspy J, Jadeja J, Justice G, et al: Optimizing the management of anemiain patients with cancer: A randomized, active-controlled study investigating thedosing of darbepoetin alfa (abstract 1446). Proc Am Soc Clin Oncol 21:362a,2002.