epoetin and darbepoetin

Current Controversies and Recent Clinical Guidelines for

use of Epoetin and Darbepoetin

Lukas Wartman, M.D.

November 2, 2007

Background of Erythropoiesis Stimulating Agents (ESAs):

The recombinant human erythropoetin, epoetin alfa, was approved by the FDA in 1993 for the treatment of anemia associated with chemotherapy. It is a 165-amino acid hormone with three N-glycosylation sites (at N24, N38, and N83) and one O-glycosylation site (at S126). It is produced from a CHO cell line.

Epoetin alfa is manufactured by Amgen, Inc., but is marketed as Procrit by Ortho Biotech, L.P., a subsidiary of Johnson & Johnson.

Darbepoetin, or Aranesp, was created by site-directed mutagenesis and differs from epoetin at five amino acid positions (A30N, H32T, P87V, Y88N and P90T). This results in two additional N-linked oligosaccharide attachments at N30 and N88.

Darbepoetin is manufactured and marketed by Amgen, Inc. and was approved by the FDA for the treatment of anemia associated with chemotherapy in July of 2002.

Rudimentary Economics of the ESAs:

In 2006, Amgen alone took in nearly $7 billion of revenue from epoetin and darbepoetin (Andrew Pollack, NY Times, May 11, 2007). Total U.S. sales of the agents were $10 billion in 2006.

In 2004, Medicare payments for these drugs in patients with cancer totaled $1.51 billion (20% of total Medicare part B spending in 2004).

The current Medicare reimbursement rate for Part B medications is 106% of the average sales price--this does take rebates/discounts into account (Robert Steinbrook, N ENGL J MED 2007; 356: 2448-2450).

BJC pays average wholesale price of $1735.50 per dose of darbepoetin (300 mcg) and $621 per dose of epoetin alfa (40,000 units). The pharmacy will not disclose overall amount spent on ESAs or amount of rebates/discounts.

Overview of ESA Efficacy and Safety: Treatment with an ESA significantly reduced the RR of blood

transfusion by 0.64; 95% CI 0.60 to 0.68, n=6,510. On average, patients treated with ESA received one less unit of blood than the control group.

Relative risk for thromboembolic complications was 1.67; 95% CI 1.35 to 2.06, n=6,769.

Overall survival HR was 1.08; 95% CI 0.99 to 1.18, n=8,167. “Suggestive evidence” that treatment with ESAs improves quality of

life. All data from Bohlius et al. from the Cochrane Database of

Systematic Reviews 2006, Issue 3 which is a review of 57 trials with 9,353 cancer patients.

Recent ESA Trials Reporting Adverse Outcomes: Henke et al. published the ENHANCE study of epoetin beta in head

and neck cancer patients in the Lancet in 2003. RTOG 99-03 (published in abstract form in 2004 by Machtay et al. in

the Int J Radiat Oncol Biol Phys) in head and neck cancer patients. Results for OS: HR 1.57, p=NS, n=148.

Leyland-Jones et al. published the BEST study of epoetin alfa in patients with metastatic breast cancer in the JCO in 2005.

Wright et al. published a trial of epoetin alfa in NSCLC patients with cancer-associated anemia in the JCO in 2007.

The Anemia of Cancer Study (Study 20010103) has not yet been published and was a trial of darbepoetin in patients with anemia of cancer (with Hgb<11) not receiving chemotherapy. Results for OS: HR 1.30, p=0.008, n=989.

The Lymphoid Cancers Anemia Study (Study 20000161) has not yet been published and was a trial of darbepoetin in anemic patients (with Hgb<11) with lymphoproliferative disorders receiving chemotherapy. Results for OS: HR 1.37, p=0.037, n=344.

The ENHANCE Trial: Henke et al. Lancet 2003; 362:1255-60.

A multi-center, double-blind, randomized, placebo-controlled trial supported by F Hoffmann-La Roche of 351 patients with squamous cell carcinoma of the head and neck with a primary endpoint of locoregional progression-free survival.

To be eligible, patients had to have Hgb < 12.0 g/dL (for women) or < 13.0 g/dL (for men) at study entry.

Patients received XRT of 60 Gy for R0 or R1 resected disease or 70 Gy for R2 resected disease or definitive treatment.

Patients assigned to SQ placebo (n=171) or epoetin beta, 300 IU/kg TIW, (n=180). Treatment began 10-14 days before XRT and continued throughout XRT course.

82% of patients achieved a Hgb > 14.0 (for women) or >15.0 (for men) in the epoetin arm versus only 15% in the placebo arm. At this point, treatment was held until Hgb fell below these target values. Treatment was also held if the Hgb increased by > 2 g/dL over a 1 week period.

ENHANCE Trial Results: Locoregional Progression-free Survival

R=0

R=1 or 2 1º XRT

ENHANCE Trial Results: Patients treated with epoetin had decreased overall survival with RR

of death of 1.39 by intention to treat analysis (p=0.02). In subgroup analysis, epoetin was associated with a poor outcome

only in patients < 60 yrs old, patients with initial Hgb > 11.0 g/dL, and advanced disease (including hypopharynx).

No difference in rates of thromboembolic events was reported between treatment and placebo groups.

Follow-up Analysis of Epo Receptors on Cancer Cells of ENHANCE Trial Patients:

Henke et al. published a follow-up report in the J Clin Oncology (24:4708-4713, 2006) to determine if expression of erythropoetin receptors on cancer cells of patients in the ENHANCE trials was associated with progression-free survival by Cox proportional hazards regression model.

The C-20 polyclonal rabbit antihuman EpoR antibody was used (Santa Cruz Biotechnologies, Santa Cruz, Ca).

154 of 157 patients’ samples were analyzed; 104 tested positive and 50 were negative.

Locoregional progression-free survival was poorer in patients with EpoR + tumors treated with epoetin beta than with placebo (adjusted RR 2.07, p<0.01) but PFS was not affected if patients with EpoR - tumors were treated with epoetin beta (adjusted RR 0.94, p=0.86). The difference in treatment-related relative risks was borderline significant (p=0.08).

Amgen scientists have previously reported that the C-20 Ab is non-specific in other tumor cell lines (Elliot et al. Blood 107: 1892-1895, 2006).

The BEST Trial: Leyland-Jones et al. J Clin

Oncol 23:5960-5972, 2005. A multi-center, double-blind, randomized, placebo-controlled trial supported

by Johnson & Johnson conducted at 139 sites in 20 countries of 939 patients with metastatic breast cancer receiving first-line chemotherapy (prior hormonal therapy or adjuvant chemotherapy was allowed) with a primary endpoint of 12-month overall survival.

Patients were assigned within 5 days of 1st chemotherapy cycle to receive epoetin alfa 40,000 U SQ qweek or placebo for 12 months. Therapy was initiated when Hgb < 13 g/dL and was tailored to maintain a Hgb of 12-14.

The study was stopped early (enrollment complete) because of higher mortality in the epoetin alfa arm.

From the final analysis, the 12-month overall survival was 70% in the epoetin alfa arm and 76% in the placebo arm (p=0.01).

The rates of thromboembolic events was similar in the 2 arms: 16% in the treatment arm and 14% in the placebo arm, but 6 patients in the treatment arm died (5 PE and1 MI) as a result whereas only 2 placebo patient died.

Copyright © American Society of Clinical Oncology

Leyland-Jones, B. et al. J Clin Oncol; 23:5960-5972 2005

Fig 1. Epoetin alfa dose adjustments



Fig 2. Patient disposition (intent-to-treat [ITT] population, N = 939)



Fig 3. Kaplan-Meier estimate of long-term survival, with convergence of lines about 19 months after randomization (as of January 4, 2003; intent-to-treat [ITT] population, N = 939)



Fig 4. Mean hemoglobin level (95% CI) over time overall and by 12-month survival status (intent-to-treat [ITT] population, N = 939)



Fig 5. Time to disease progression (intent-to-treat population, N = 939)

The EPO-CAN-20 Trial: Wright et al. J Clin Oncol 25:1027-1032, 2007.

A multi-center, double-blind, randomized, placebo-controlled trial sponsored by Ortho Biotech (Johnson & Johnson) of NSCLC patients who were unsuitable for curative therapy and had a baseline Hgb < 12.1 g/dL with a primary outcome of difference in the change of Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks.

Initially, trial excluded all patients who had been treated with chemotherapy in the preceding 2 months but due to slow accruement the eligibility criteria were relaxed to exclude only patients treated with platinum-based chemotherapy. Palliative XRT was allowed.

Patients were randomly assigned to either 12 weeks of Epoetin alfa 40,000 U SQ qweek or placebo. Trial accrued from 2/2001 to 11/2003.

After reports of adverse events in other ESA trials, an unplanned safety analysis halted the trial after 70 patients had been randomly assigned (33 to the treatment arm and 37 to the placebo arm).

Rates of thromboembolic events were low in both arms (1 event in the treatment arm and 2 in the placebo arm).


Wright, J. R. et al. J Clin Oncol; 25:1027-1032 2007

Fig 1. Consort flow chart


Wright, J. R. et al. J Clin Oncol; 25:1027-1032 2007

Fig 2. Overall survival curve from time of random assignment

Ongoing Trials EPO-ANE 3010 is a trial of metastatic breast cancer patients with

Hgb <11 randomized to epoetin alfa or placebo with endpoint of PFS.

DE20020015 is a trial of breast cancer patients on adjuvant chemotherapy with Hgb <13 randomized to darbepoetin or placebo with endpoint of EFS.

PREPARE is a multi-arm trial of breast cancer patients comparing dose-intensive versus standard chemotherapy with or without darbepoetin.

20010145 is a trial of patients with untreated SCLC with baseline Hgb 9-13 undergoing chemotherapy randomized to darbepoetin.

Clinicaltrials.gov lists 17 trials involving cancer patients and darpopoetin and 13 trials with cancer patients and epoetin alfa.

Overview of ASH/ASCO 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin. Adapted from Rizzo et al. prepublished online as Blood First Edition paper, October 23, 2007; DOI 10.1182/blood-2007-08-109488.

1. General Recommendation: Consider other correctable causes of anemia. “Consideration should be given to minimize use of ESAs in patients with high risk of thromboembolic events…”

2. Special commentary on the comparative effectiveness of epoetin and darbepoetin: They are considered equivalent.

3. Chemotherapy-induced anemia and threshold for initiating ESA therapy, Hgb concentration approaching or < 10 g/dL: Epoetin and darbepoetin are treatment options. RBC transfusion is another option. For initiation threshold, Hgb >10 g/dL but <12 g/dL: The decision to use ESA or wait depends on clinical circumstances.

4. Thromboembolic risk: RCTs and systematic reviews demonstrate an increased risk. There are no data using anticoagulants or aspirin to modulate this risk.

Guidelines Continued:

5. Starting and escalating doses: The FDA-approved starting dose of epoetin is 150 U/kg TIW or 40,000 U weekly SQ. The FDA-approved starting dose of darbepoetin is 2.25 mcg/kg weekly or 500 mcg q3weeks SQ. Dose escalation should follow FDA recommendations.

6. Discontinuing therapy for no response: Discontinue therapy if after 6-8 weeks there is no response (<1-2 g/dL rise in Hgb or no diminution of transfusion requirements).

7. Hemoglobin target: 12 g/dL. Dose reductions are recommended when Hgb rise exceeds 1 g/dL in any 2 wk period or when Hgb exceeds 11 g/dL.

8. Iron monitoring and supplementation: Baseline and periodic monitioring of iron studies is recommended.

Guidelines Continued:

9. Anemia in patients not receiving chemotherapy: “There is evidence that supports the use of epoetin and darbepoetin in patients with anemia associated with low-risk myelodysplasia. There are no published high-quality studies to support its exclusive use in anemic myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukemia patients in the absence of concurrent chemotherapy.” Also consistent with FDA black-box warning: “Use of ESAs increased the risk of death when administered to a target hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated in this population.”

10. Treatment of anemia in patients with non-myeloid hematological malignancies who are receiving concurrent chemotherapy: In patients with myeloma, non-Hodgkin’s lymphoma, and CLL, treat with chemotherapy and/or corticosteroids and await response prior to considering an ESA (remember to assess thromboembolic risk if an ESA is considered).

New CMS Guidelines in 7/2007:

Covered Indications for ESAs: Anemia secondary to myelosuppressive anticancer therapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia (MDS per local carrier)

Non-covered uses include any anemia in cancer patients due to folate, B-12 def., hemolysis, bleeding or bone marrow fibrosis; anemia associated with myelogenous leukemias or erythroid cancers; the anemia of cancer not related to cancer treatment; any anemia associated with radiotherapy; prophylactic use to prevent chemotherapy-induced anemia and prophylactic use to reduce tumor hypoxia.

CMS Guidelines Continued:

Initiate only if Hgb < 10 g/dL (or Hct < 30%) Starting doses are the FDA-approved doses. Maintenance doses begin 4 wks after the initial dose

and is given at initial dose if Hgb < 10 g/dL and the rise in Hgb > 1 g/dL (may increase dose by 25% if not increased by 1 g/dL but must discontinue if no response by 8 weeks).

Dose reduction by 25% if Hgb increases > 1 g/dL after 2 weeks but Hgb still <10 g/dL.

Treatment duration may not extend beyond 8 weeks after final dose of chemotherapy.

Hgb or Hct testing before all doses.

Summary:

Numerous trials have called the safety of ESAs into question. Subsequently, the use of ESAs has been limited by a recent CMS reimbursement policy change that may be motivated, at least in part, by financial incentives for CMS.

Well-designed trials are needed to clearly delineate the role of ESAs in oncology supportive care.

epoetin and darbepoetin

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