Correction/Maintenance Dosing (Front Loading) of Darbepoetin alfa: Final Results from a Randomized Phase 3 Active Controlled Trial.

Prior research with darbepoetin alfa (DA; Aranesp^®) in patients with chemotherapy-induced anemia (CIA) has indicated the possibility of decreasing the time to response through the use of higher initial doses (4.5 mcg/kg once weekly [QW]) compared with standard dosing regimens (either of DA or epoetin alfa [Procrit^®]). Research has also shown that an every 3 week (Q3W) dosing schedule of DA is effective in alleviating the symptoms of CIA. Pilot studies using a correction/maintenance approach (‘front loading’) have combined these two potentially attractive clinical attributes. This active-controlled trial examined the efficacy of DA using a correction/maintenance dosing regimen in patients with nonmyeloid malignancies receiving chemotherapy. In this study, 727 anemic patients (hemoglobin [Hb] <11g/dL) were randomized 1:1 to receive a DA dose of either 2.25 mcg/kg QW for 16 weeks or 4.5 mcg/kg QW for weeks 1–4, followed by a Q3W maintenance regimen using the same dose (4.5 mcg/kg) for weeks 5–16. The primary endpoint was to demonstrate the non-inferiority of correction/maintenance dosing versus standard weekly dosing, with respect to the proportion of patients either requiring a transfusion or withdrawing from the study during the 16-week treatment period. The pre-specified, non-inferiority margin, based on the effect size observed in DA placebo-controlled trials, was 12.5%. The two treatment groups were well balanced for baseline characteristics: 32% had hematologic malignancies, 15% breast cancer and 13% lung cancer. Both groups had a mean (SD) baseline Hb of 9.6 (1.0) g/dL. Non-inferiority was demonstrated with respect to the primary endpoint with a mean (95% CL) difference between groups of 1% (−7, 9). No difference was observed for the proportion of patients receiving a RBC transfusion from week 5 to end of treatment [24% (19, 28) for the 2.25 mcg/kg QW group vs 25% (20, 30) for the correction/maintenance group]. Over the entire study period, 87% (83, 91) of patients in the DA 2.25 mcg/kg group achieved a hematopoietic response at the end of treatment compared with 68% (62, 73) in the correction/maintenance group, suggesting no additional benefit for correction/maintenance dosing compared with standard dosing. During the initial 7 weeks of study, no differences were observed between patients receiving 2.25 mcg/kg QW or 4.5 mcg/kg QW for any endpoint (eg, Hb change of 1.4 g/dL after 6 weeks in both groups); Q3W dosing at 4.5 mcg/kg was shown to be effective in maintaining Hb through the remainder of the treatment period. No difference in adverse events between the two groups was observed. DA 2.25 mcg/kg QW is highly effective with respect to the reduction of transfusion requirements and management of anemia symptoms in patients with CIA. In this study of anemic patients with nonmyeloid malignancies receiving chemotherapy, almost all patients in the 2.25 mcg/kg QW dose group achieved a hematopoietic response, offering little room for additional clinical benefit that may have been expected in the 4.5 mcg/kg QW group as a result of the increased dose. Q3W dosing with DA 4.5 mcg/kg was shown to effectively maintain Hb levels. The effectiveness of lower/less frequent doses cannot be determined from this trial.