Update on Pegfilgrastim (Neulasta)

Published: Monday, Sep 08, 2008
R&D INSIGHTS

Pegfilgrastim (Neulasta) is a covalent conjugateof recombinant methionyl human
granulocyte colony-stimulating factor(G-CSF; filgrastim) and monomethoxypolyethylene
glycol. Filgrastim is a water-soluble,175–amino acid protein with a molecular
weight of approximately 19 kD. Filgrastim isobtained from the bacterial fermentation of a
strain of Escherichia coli transformed with agenetically engineered plasmid containing the
human G-CSF gene. To produce pegfilgrastim,a 20-kD monomethoxypolyethylene glycol
molecule is covalently bound to the n-terminal methionyl residue of filgrastim. The average
molecular weight of pegfilgrastim is approximately 39 kD.

Pegfilgrastim is a longer-acting form of filgrastim(Neupogen), Amgen’s original leukocyte-
stimulating agent. Pegfilgrastim requires only one injection per chemotherapy cycle,
while filgrastim may require daily injections for up to 14 days following chemotherapy.

Both filgrastim and pegfilgrastim are colony stimulating factors that act on hematopoietic
cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation,
commitment, and end-cell functional activation. Studies on cellular proliferation, receptor
binding, and neutrophil function demonstrate that filgrastim and pegfilgrastim have
the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence
in vivo, compared with filgrastim.

Indication
Pegfilgrastim was approved by the U.S. Food and Drug Administration (FDA) and European
Medicines Agency (EMEA) in 2002 for reducing the incidence of infection, as manifested by febrile
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive
anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Pharmacology
Dr. Ziad Atassi, University of Ulm, Ulm, Germany and colleagues evaluated the pharmacokinetics,
safety, and efficacy of pegfilgrastim in 22 female patients with axillary metastatic breast cancer.
Subjects received dose-dense chemotherapy consisting of 3x4 sequential single-drug cycles of
epirubicin 90 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2 on a q15d schedule.
Pegfilgrastim was administered 24 hours after chemotherapy. Blood samples for pharmacokinetic
studies were taken on days 8, 10, and 12 of each cycle. The mean pegfilgrastim serum level on day
1 of each cycle was 2.88 ng/mL, 1.66 ng/mL, and 0.51 ng/mL on days 1, 10, and 12 of each cycle,
respectively. The minimum value was observed on day 12 of cycle 5. Pegfilgrastim remained bioavailable
until day 12 of each cycle with absent cumulative effects. Four patients presented with a single grade 3
neutropenia event, and no cases of febrile neutropenia were noted at any cycle. Nineevents of >grade 1
bone pain were noted. Considering the low adverse event rate, the investigators suggested that dose-dense
chemotherapy with primary pegfilgrastim prophylaxis is a safe option for high-risk breast cancer patients.

Pegfilgrastim for the Treatment of Chemotherapy-Associated Myelosuppression in
Pediatric Patients with Solid Tumors

Dr. Jessica A. Pollard and colleagues at theFred Hutchinson Cancer Research Center, Seattle,
Washington, reported their institutionalexperience with pegfilgrastim following doseintensive
chemotherapy for solid tumors. Thirty-nine pediatric patients were included
in this retrospective review. The median ageof patients evaluated was 12 years (range,
0.17–23 yr) and the median weight was 50 kg (range, 4–107 kg). Primary diagnoses included
osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, soft tissue sarcoma, neuroblastoma,
Hodgkin’s disease, and other solid tumors. A total of 141 chemotherapy courses with pegfilgrastim
support were administered (median, 4 courses per patient). No adverse events related
to pegfilgrastim were noted. Severe neutropenia occurred in 46% of courses. Overall, the median
duration of severe neutropenia was 0 days (range, 0-8 days). Febrile neutropenia occurred
in 28% of courses. Of particular interest were eight patients treated with interval-compressed
(every 14 days) sarcoma chemotherapy. Of 51 courses administered, the median course duration
was 15 days (range, 14–28 days). The investigators concluded that pegfilgrastim administration
following dose intensive chemotherapy for solid tumors is safe and feasible in children, including those
<45 kg. They noted that the frequency and duration of severe neutropenia, as well as the incidence of febrile
neutropenia, were similar to historic data on filgrastim.

GROC plus Pegfilgrastim in Relapsed AggressiveNon-Hodgkin’s Lymphoma
A more effective and less toxic salvage regimen for relapsed aggressive non-Hodgkin’s lymphoma
(NHL) is desirable for use before autologous stem cell transplant (ASCT). Gemcitabine
(Gemzar) and oxaliplatin (Eloxatin) are active single agents in NHL and have modest myelosuppressive
activity. Fernando Cabanillas, MD, Auxilio Mutuo Cancer Center, San Juan, Puerto Rico
and colleagues performed a study to evaluate the gemcitabine, rituximab (Rituxan), oxaliplatin
combination (GROC) administered every 14 days with pegfilgrastim support in patients with relapsed
aggressive NHL (N = 37). Twelve patients were refractory to first-line therapy and 14 had
partial response (PR) or progressive disease as best response to the preceding chemotherapy
regimen. Doses were: rituximab, 375 mg/m2 on day 1, gemcitabine, 1250 mg/m2 on day 2, oxaliplatin,
100 mg/m2 on day 2, and pegfilgrastim, 6 mg on day 3. Median age of patients was 59
years. Overall response to GROC was 81%, with 40.5% of patients achieving complete remission
and 40.5% achieving PR. At 2 years, overall survival (OS) was 33% and progression-free survival
(PFS) was 29%. Among patients who were not refractory to the preceding chemotherapy regimen,
the two-year PFS was 49% and 2-year OS was 52%. Despite the older age of patients receiving
GROC, its toxicity appeared to be lower and its overall response rate was either similar
or better. In 54% of patients, the response to GROC was better than to the preceding regimen.
The investigators also noted that in 16 cases, PFS was longer with GROC than with the preceding
regimen. The most common non-hematologic toxicities were reversible transaminitis, partially
reversible neuropathy, and diarrhea. In this prospective study, GROC was an effective, dosedense
salvage regimen even in patients with poor prognostic features such as older age. Furthermore,
GROC appeared to be as effective as DHAP (dexamethasone, cisplatin, cytarabine),
ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine, ICE [ifosfamide, carboplatin,
etoposide]), and RICE (rituximab, ICE), but with considerably less hematologic and nonhematologic
toxicity. Owing to the effectiveness and low toxicity profile of GROC, the investigators
recommended further evaluation as a first salvage option for relapsed aggressive NHL.

Risk of Hospitalization With PegfilgrastimVersus Filgrastim Prophylaxis
A retrospective cohort study was performed by Derek Weycker, PhD, Policy Analysis, Inc.,
Brookline, Massachusetts and colleagues using a U.S. health care claims database. The goal of
the study was to determine whether the risk of hospitalization for neutropenic complications
differs between pegfilgrastim and filgrastim in a real-world setting. The study population was
made up of patients with cancer who underwent a course of chemotherapy over a threeyear
period, and who also received pegfilgrastim or filgrastim during their first course.

For each patient, each unique cycle of chemotherapy was identified, as was each cycle in
which pegfilgrastim or filgrastim was administered by cycle day 5 (i.e., as prophylaxis). Risk
of hospitalization for neutropenia, fever, or infection (“neutropenic complications”) was then
examined on a cycle-specific basis, including all patient-cycles in which pegfilgrastim or filgrastim
was administered as prophylaxis. A total of 15,763 patient-cycles were identified
in which patients received prophylaxis either with pegfilgrastim (N = 14,570) or filgrastim
(N = 1193). The crude risk of hospitalization for neutropenic complications was 4.8% for filgrastim
and 3.1% for pegfilgrastim. The rates of all-cause hospitalization were 8.7% and 6.3%,
respectively. Unadjusted and adjusted odds of hospitalization were consistently lower (by
28% to 36%) with pegfilgrastim than with filgrastim.

The investigators concluded that the risk of hospitalization appears to be approximately
one-third lower with pegfilgrastim than with filgrastim prophylaxis in patients with
cancer receiving myelosuppressive chemotherapy in a real-world setting.

Summary
Presentations at this year’s ASCO meeting highlighted the advantages of pegfilgrastim
in reducing the incidence of febrile neutropenia in patients receiving chemotherapy for a
wide variety of solid tumors and hematologic malignancies, including osteosarcoma, Ewing’s
sarcoma, rhabdomyosarcoma, soft tissue sarcoma, neuroblastoma, Hodgkin’s disease,
NHL, and breast cancer. Outcomes investigations showed that non-Hodgkin's lymphoma patients
with cancer with a range of comorbid conditions who receive primary pegfilgrastim prophylaxis may
experience improved PFS and OS during chemotherapy. It also suggested that the risk of
hospitalization appears to be significantly lower with pegfilgrastim than with filgrastim
prophylaxis in patients with cancer receiving myelosuppressive chemotherapy.


Additional Information:
Impact of Pegfilgrastim on Early All-Cause Mortality in Patients Receiving Cancer Chemotherapy
Gary H. Lyman, MD, MPH, FRCP, Duke Universityand the Duke Comprehensive
Cancer Center,Durham, North Carolina, and colleaguesperformed a prospective observational
study of 4,458 consecutive adult patients receiving cancer chemotherapy
at 115 randomly selected U.S. practices to evaluate the effect of prophylactic colonystimulating
factors in cancer patients with multiple comorbid conditions. Pegfilgrastim was administered on
an individual basis to 1,209 patients (including 620 as primary prophylaxis) starting in cycle 1.
Patients receiving primary pegfilgrastim prophylaxis experienced better
PFS (P = 0.0109; HR = 0.65) and OS (P = 0.0079; HR= 0.41) than those without primary
pegfilgrastim prophylaxis.

In univariate analysis incorporating any use of pegfilgrastim as a time-dependent covariate, improvements
in both PFS (P < 0.0001; HR = 0.54) and OS (P < 0.0001; HR = 0.40) were observed.

In multivariate analysis, pegfilgrastim use was associated with improved PFS (P = 0.0070; HR
= 0.62) and OS (P = 0.0120; HR = 0.44) after adjustment for other significant covariates (including
Eastern Cooperative Oncology Group performance score, Charlson comorbidity
index, age, body-mass index, cancer type, stage of disease, and year on study. The investigators
concluded that cancer patients with a range of comorbid conditions who receive primary
pegfilgrastim prophylaxis may experience improved PFS and OS during chemotherapy.

Gary H. Lyman,
MD, MPH, FRCP
&ONCOLOGY
BIOTECH
NEWS
07/08.08 37



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