Novel Erythropoiesis Stimulating Protein Reduces Need for Transfusions in Cancer Patients

September 1, 2001

SAN FRANCISCO-Novel erythropoiesis stimulating protein (NESP, darbepoetin-alfa, Aranesp) is an investigational recombinant erythropoietic protein that binds to the erythropoietin receptor and stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (epoetin alfa, Procrit, Epogen).

SAN FRANCISCO—Novel erythropoiesis stimulating protein (NESP, darbepoetin-alfa, Aranesp) is an investigational recombinant erythropoietic protein that binds to the erythropoietin receptor and stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (epoetin alfa, Procrit, Epogen).

NESP has a serum half-life of more than 40 hours in cancer patients receiving chemotherapy, approximately three times longer than epoetin. Thus, NESP can be given once a week or once every 2 weeks, compared with three times a week for epoetin alfa.

Poster presentations at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO) showed that NESP can correct disease-related and treatment-induced anemias in cancer patients, and can reduce the need for transfusions in lung cancer patients being treated with platinum-based regimens.

Preliminary studies also showed that NESP could increase hemoglobin levels in patients with lymphoproliferative malignancies, with solid tumors being treated with chemotherapy, and with non-myeloid malignancies being treated with chemotherapy.

Platinum Therapy in Lung Cancer

Robert Pirker, MD, reported a phase III, double-blind, placebo-controlled, randomized study of NESP in patients undergoing platinum treatment for lung cancer (abstract 1572). Dr. Pirker, of the University of Vienna Medical School, Vienna, Austria, reported the results on behalf of the NESP 980297 Study Group.

In this study, 320 anemic patients (hemoglobin 11 g/dL or less) were randomized to receive NESP 2.25 µg/kg or placebo. Study drug was administered subcutaneously once weekly for a maximum of 12 weeks and was withheld if hemoglobin concentrations were 14 g/dL (for women) or 15 g/dL (for men). The study dose was doubled if, at week 6, hemoglobin had not increased by at least 1 g/dL.

The primary study endpoint was the need for red blood cell transfusion after the first month of therapy (from week 5 to the end of the treatment phase).

Dr. Pirker reported that use of NESP reduced the proportion of patients who needed a blood transfusion from 51% with placebo to 21% (P < .001). NESP also significantly reduced the mean number of standard units of red blood cell transfusions needed over the entire course of treatment (P < .001), steadily increased hemoglobin concentrations from base-line, and reduced patient self-reported fatigue.

There was also a suggestion of improved median time to disease progression in patients with small-cell lung cancer. Dr. Pirker said that future studies would evaluate effects on time to progression and days of hospitalization.

In this, as in the other NESP studies, adverse effects were mainly those associated with chemotherapy and were similar to those in the placebo group.

Robert E. Smith, MD, on behalf of the NESP 990111 Study Group, reported that NESP improved hemoglobin levels in patients with chronic anemia of cancer who were not receiving chemotherapy (abstract 1574). Dr. Smith is with South Carolina Oncology Associates, Columbia, South Carolina.

This open-label, dose-finding study included anemic patients (hemoglobin 11 or less g/dL) with nonmyeloid malignancies who were not receiving chemotherapy or planned radiotherapy and were not iron deficient.

Patients were assigned sequentially to one of the following NESP doses: 1, 2.25, or 4.5 µg/kg/wk for a maximum of 12 weeks. Hemoglobin response and correction were defined as an increase of 2 g/dL or more from baseline and hemoglobin 12 g/dL or more, respectively, in the absence of a red blood cell transfusion during the preceding 28 days.

Dr. Smith reported data on 96 patients. The most common tumors were breast and prostate.

The lowest clinically effective dose was 1 µg/kg/wk. More than half of patients at all dose levels had hemoglobin increases of at least 2 g/dL, and fewer than 20% at all dose levels had dose-limiting toxicities. The percent of patients who achieved a hemoglobin response ranged from 66% to 92% with the mean change in hemoglobin level increasing with an increased NESP dose (1.66 to 2.91 g/dL for the 1 and 4.5 µg/kg groups, respectively). This study is continuing with dosing once every 3 weeks and once every 4 weeks.

Lymphoproliferative Malignancies

Michael Hedenus, MD, of Sundsvall Hospital, Sweden, reported on behalf of the NESP 990114 Study Group that NESP is more effective than placebo at increasing hemoglobin levels in patients with lymphoproliferative malignancies (abstract 1569).

This randomized, blinded, placebo-controlled, phase II study included 66 patients with lymphoproliferative malignancies and anemia (hemoglobin 11 g/dL or less). Patients were randomized to receive one of three planned doses of NESP (1, 2.25, or 4.5 µg/kg) or a placebo injection.

Study drug was administered subcutaneously once weekly for a maximum of 12 weeks.

Patients had either lymphoma (73%) or myeloma (27%). Hemoglobin response was defined as an increase of 2 g/dL or more from baseline, and hemoglobin correction was defined as 12 g/dL or higher, in the absence of a red blood cell transfusion in the preceding 4 weeks.

NESP administered once weekly increased hemoglobin levels and was associated with a lower incidence of red blood cell transfusions, compared with placebo (15% at the highest NESP dose vs 45% for placebo, from week 5 to the end of treatment). NESP was well tolerated, and no anti-NESP antibodies were detected.

Every-2-Week Dosing

A similar dose-escalation study of weekly and biweekly NESP in patients with solid tumors showed that NESP was similar to epoetin in ability to increase hemoglobin levels and that the time to hemoglobin response appeared to decrease with higher NESP doses (abstract 1546).

John A. Glaspy, MD, professor of medicine, UCLA, reported that in part A of this study, 269 patients were randomized to receive either epoetin (150 IU/kg three times a week, with the dose doubled at week 8 if hemoglobin increase was less than 1 g/dL) or NESP (sequential doses: 0.5, 1, 1.5, 2.25, 4.5, 6, and 8 µg/kg/wk).

In part B, 160 patients were randomized to receive either epoetin (40,000 U/wk, with the dose increased to 60,000 U/wk at week 6 if hemoglobin increase was less than 1 g/dL) or NESP (3, 5, 7, and 9 µg/kg every 2 weeks). Hemoglobin response and correction were defined, respectively, as a red blood cell increase of at least 2 g/dL from baseline and a hemoglobin of at least 12 g/dL.

Dr. Glaspy said that more than 54% of patients at all the NESP dosing levels in the every-2-week dosing schedule (part B) achieved a hemoglobin response and that increasing hemoglobin concentrations were associated with decreases in fatigue. The researchers concluded that reducing NESP dosing frequency from once weekly to once every 2 weeks resulted in no apparent loss of efficacy.

Pharmacokinetics

Anne Heatherington, MD, of Amgen Inc., Thousand Oaks, California, reported that NESP pharmacokinetic variables are stable and predictable when the drug is given just once every 3 weeks in non-myeloid cancer patients receiving cyclic chemotherapy (abstract 471).

A 1-compartment pharmacokinetic model, used to describe the serum concentration-time profiles for various NESP doses given on a weekly dosing schedule, was shown to predict the pharmacokinetic properties of NESP given once every 3 weeks. Observed mean values after 10 weeks of therapy were within one standard deviation of those predicted.

"These findings support the hypotheses that the pharmacokinetic properties of NESP in this population are dose- and time-linear, and are predictable," Dr. Heatherington said.