1. Pegfilgrastim (NeulastimTM) Simplifying the management of chemotherapy-induced neutropenia
Anas Younes, M.D.
Director, Clinical & Translational Research
Professor of Medicine
Dept of Lymphoma/Myeloma
M. D. Anderson Cancer Center

2. Pivotal U.S. Clinical Trial of Prophylactic G-CSF Small Cell Lung Cancer receiving CAE
% of patients
Placebo
Filgrastim
Parameter
(n = 102)
(n = 92)
P value
Febrile neutropenia
Cycle 1 57 28
0.001
Cumulative 77 40
0.001
13.3
6.5 NR
Culture-confirmed infection
NR = not reported
Crawford J, et al. N Engl J Med. 1991;325:164–170.

3. One dose per cycle of chemotherapy
Pegylating filgrastim makes once-per-chemotherapy-cycle dosing possible
Filgrastim
Daily dosing
Helical
bundle
Key points
Pegfilgrastim is a novel, long-acting, pegylated form of filgrastim that increases circulating neutrophils in the same way as filgrastim and endogenous G-CSF. Like filgrastim, pegfilgrastim binds to specific cell surface receptors on neutrophils and their precursors, thereby stimulating proliferation, differentiation, commitment and end cell functional activation.
Pegfilgrastim provides effective prophylaxis of neutropenia without the need for daily injections. In pivotal trials, one injection of pegfilgrastim was required per chemotherapy cycle compared with a median of 11 days of filgrastim injections [Green et al. In press, Holmes et al, 2002].
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002;13:
Pegfilgrastim
One dose per cycle of chemotherapy
Helical
bundle
Polyethylene glycol (PEG)

4. Pegfilgrastim: Therapeutic indication
Pegfilgrastim is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes)
Key points
Pegfilgrastim is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).
Reference
Neulastim™ (pegfilgrastim) Summary of Product Characteristics. Amgen (Europe) AG, The Netherlands
Neulastim™ (pegfilgrastim) Summary of Product Characteristics.

5. Pegfilgrastim serum level Mean serum concentration (g/L)
Pegfilgrastim : PK and Pharmacodynamics Cycle 1: Doxo + Docetaxel (Breast Ca)
Pegfilgrastim serum level
ANC
103
103
102
102
Mean ANC ( 109/L) 10 10
Mean serum concentration (g/L) 1 1
0.1
0.1
0.01
0.01 3 6 9 12 15 18 21
Cycle 1* days
Holmes FA, et al. JCO (using 100 g/kg)

6. Pegfilgrastim Is as Effective as Filgrastim in All Cycles of Chemotherapy Doxo + Docetaxel (Breast Ca)
100 10
1.0
0.1
0.01
Cycle 1 Cycle 2 Cycle 3 Cycle 4
ANC (109/L)
Pegfilgrastim 100 µg/kg
Filgrastim 5 µg/kg/d
Cycle day
Holmes FA, et al. JCO 2002

7. Rationale for 6 mg fixed dose of pegfilgrastim
Mean duration of severe neutropenia (ANC <0.5 x 109/L)
DSN (days)
Key points
An analysis was conducted of DSN vs total mg dose of pegfilgrastim received in the dose ranging phase 2 study conducted in breast cancer patients [Holmes et al, 2002]
Patients were grouped into those receiving approximately 4, 6 or 8 mg (± 1 mg), irrespective of weight-adjusted dose received (ie, 30, 60 or 100 µg/kg).
As shown in the figure, mean ± SE DSN values were: filgrastim: 1.60 ± 0.25 days; pegfilgrastim 3-5 mg: 2.04 ± 0.18 days; pegfilgrastim 5-7 mg: 1.72 ± 0.19 days; pegfilgrastim 7-9 mg: 1.23 ± 0.22 days [Data on file, Amgen].
6 mg was selected as the fixed dose to take forward for confirmation in phase 3, since the patients who received 5-7 mg of pegfilgrastim had a mean DSN that most closely resembled that of the patients in the filgrastim control group.
Pharmacokinetic and pharmacodynamic mathematical modeling also suggested that the fixed dose might provide adequate serum levels and efficacy for patients, regardless of body weight [Yang et al, 2000].
References
Data on file, Amgen.
Holmes FA, Jones SE, O'Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection Filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002: in press.
Yang BB, Lum PK, Renwick J, et al. Pharmacokinetic rationale for a fixed-dose regimen of a sustained duration form of Filgrastim in cancer patients. Blood. 2000;96:157b. Abstract 4384.
Filgrastim 5 µg/kg/d (n = 25)
3-5 mg (n = 46)
5-7 mg
(n = 29)
7-9 mg (n = 22)
Data on file, Amgen.
Pegfilgrastim

8. Pegfilgrastim phase 3 pivotal trials in breast cancer: study design
Starting day 2
Pegfilgrastim 100 µg/kg† or 6 mg fixed dose‡ then daily placebo
Day 1
Chemotherapy: Doxorubicin (A) 60 mg/m2 Docetaxel (T) 75 mg/m2
Randomise*
Repeat for four cycles
Key points
A single dose of pegfilgrastim (100 µg/kg or a fixed 6 mg dose) per chemotherapy cycle was compared with daily injections of filgrastim (5 µg/kg/day) in two pivotal, phase 3, randomised trials of patients receiving four cycles of AT chemotherapy for stage II–IV breast cancer.
The two trials were of similar design with the only appreciable difference being the dose of pegfilgrastim: Green et al, investigated a fixed dose (6 mg) while Holmes et al, investigated a by-weight dose (100 µg/kg). Both trials were appropriately powered for the primary efficacy endpoint. More subjects were enrolled in the US trial in order to provide additional safety experience.
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Filgrastim 5 µg/kg/day§
Pegfilgrastim 100 µg/kg (n = 154)†
6 mg (n = 80)‡
Filgrastim 5 µg/kg/day (n = 156)†
(n = 77)‡
*Stratified by weight and prior chemotherapy §Daily to ANC 10  109/L or 14 doses
†Holmes F, et al. J Clin Oncol. 2002;20: ‡Green M, et al. Ann Oncol. In press.

9. Pegfilgrastim phase 3 pivotal trials in breast cancer: study end points
Primary end point
DSN (grade 4) in cycle 1
Secondary end points and analyses
DSN in cycles 2–4
incidence of FN
ANC nadir
ANC recovery
safety
Key points
The primary endpoint of both phase 3 trials was the DSN (grade 4) in the first cycle of chemotherapy.
Secondary endpoints included the DSN in cycles 2 to 4, the depth of the ANC nadir in these cycles, incidence of FN, time to neutrophil recovery (ANC 2.0 x 109/L) and safety (incidence of adverse events).
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Holmes F, et al. J Clin Oncol. 2002;20: ; Green M, et al. Ann Oncol. In press.

10. DSN was comparable for pegfilgrastim and filgrastim in both studies
DSN in cycle 1
Holmes et al
Green et al
Filgrastim
5 µg/kg/day
Pegfilgrastim
100 µg/kg
Filgrastim
5 µg/kg/day
Pegfilgrastim
6 mg fixed dose
(n = 147)
(n = 149)
(n = 75)
(n = 77)
Mean DSN (days)
1.8
1.7
1.6
1.8
Key points
In phase 3, randomised, placebo-controlled trials, pegfilgrastim (100 µg/kg or a fixed 6 mg dose) once per cycle reduced DSN as effectively as daily filgrastim in patients receiving AT chemotherapy for stage II–IV breast cancer.
The trials were of a non-inferiority design. Pegfilgrastim and filgrastim were prospectively defined as being equivalent if the number of days of severe neutropenia did not differ by more than 1 day. All confidence intervals spanned zero, indicating that there was no difference statistically between pegfilgrastim and filgrastim.
In the by-weight dose study, the mean DSN was 1.7 days compared with 1.8 days for patients given pegfilgrastim (100 µg/kg) or daily filgrastim, respectively [Holmes et al, 2002]. In the fixed dose study, the mean DSN was 1.8 days compared with 1.6 days for patients given pegfilgrastim (6 mg) or daily filgrastim, respectively [Green et al. In press].
In comparison, if G-CSF is not used, the AT chemotherapy regimen results in a DSN of 5 to 7 days [Misset et al, 1999] and an incidence of FN of approximately 40% [Lembersky et al, 2000; Misset et al, 1999] indicating that primary prophylaxis with growth factors is warranted [Ozer et al, 2000].
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Lembersky BC, Anderson S, Smith R, et al. Phase II trial of doxorubicin and docetaxel for locally advanced and metastatic breast cancer: preliminary results from NSABP BP-57. Proc Am Soc Clin Oncol 2000;19:104a. Abstract 403.
Misset JL, Dieras V, Gruia G, et al. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol. 1999;10:
Ozer H, Armitage JO, Bennett CL, et al update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000;18:
95% CI*
–0.36 to 0.30
–0.15 to 0.63
*Confidence interval (CI) for difference of the means.
Holmes F, et al. J Clin Oncol. 2002;20: ; Green M, et al. Ann Oncol. In press; Data on file, Amgen.

11. Pegfilgrastim and filgrastim provide comparable neutrophil recovery
Median ANC levels and inter-quartile range
Filgrastim, 5 µg/kg/day (n = 75)
Pegfilgrastim fixed, 6 mg (n = 77)
100.00
10.00
ANC (x109/L)
Key points
The ANC nadir and recovery following the administration of chemotherapy are comparable following a once-per-cycle, fixed 6 mg dose of pegfilgrastim and daily filgrastim (5 µg/kg).
The ‘self-regulating’, neutrophil-mediated clearance of pegfilgrastim results in its elimination from the circulation as neutrophil levels recover, and provides a smooth recovery of the neutrophil count back to baseline levels.
Pegfilgrastim remains at an effective serum level for as long as it takes to achieve neutrophil recovery, providing protection tailored to individual patients.
Reference
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
1.00
0.10
Chemo-
therapy
Study
drug
0.01 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Cycle day
Green M, et al. Ann Oncol. In press.

12. Pegfilgrastim 6 mg fixed dose is effective across a broad range of body weights
Mean DSN in cycle 1 by body weight group in quartiles
Pegfilgrastim 6 mg fixed dose
Filgrastim 5 µg/kg/day
Mean DSN ± standard error (days)
Key points
In a randomised, double-blind, multicentre phase 3 study, a 6 mg fixed dose of pegfilgrastim delivered once per chemotherapy cycle was compared to daily 5 µg/kg filgrastim in patients receiving AT chemotherapy [Green et al. In press].
In patients receiving pegfilgrastim, there was no relationship between body weight and efficacy across all chemotherapy cycles [Green et al. In press].
A single, fixed dose of pegfilgrastim given once per chemotherapy cycle offers simple protection from neutropenia for all patients, and is effective over a broad range of body weights.
Reference
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
46–62 kg
>62–71 kg
>71–80 kg
>80–132 kg
Adapted from Green M, et al. Ann Oncol. In press.

13. Mean DSN by chemotherapy cycle Mean DSN ± standard error (days)
Pegfilgrastim is comparable to filgrastim in all cycles of chemotherapy
Mean DSN by chemotherapy cycle
Pegfilgrastim 6 mg fixed dose
Filgrastim 5 µg/kg/day
Mean DSN ± standard error (days)
Key points
In a randomised, double-blind, multicentre, phase 3 study of patients receiving AT chemotherapy for stage II–IV breast cancer, a once-per-cycle, fixed dose (6 mg) of pegfilgrastim reduced the DSN across all chemotherapy cycles [Green et al. In press] and was comparable in this respect to daily filgrastim dosed by weight (5 µg/kg).
Prophylactic administration of pegfilgrastim across all cycles resulted in a lower mean incidence and shorter mean DSN in later cycles when compared with cycle 1. This may be due to a ‘priming’ effect of G-CSF on neutrophil recovery by enhancing cell differentiation of the postmitotic pool [Crawford et al, 1997].
Pegfilgrastim therefore provides a simple, powerful solution when first-cycle G-CSF protection from neutropenia is needed, and provides a cumulative benefit when administered once per cycle over all cycles of chemotherapy.
Reference
Crawford J, Kreisman, H, Garewal H, et al. The impact of filgrastim schedule variation on hematopoietic recovery post-chemotherapy. Ann Oncol. 1997;8:
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Adapted from Green M, et al. Ann Oncol. In press.

14. Incidence of febrile neutropenia across all cycles
Holmes et al (n = 296)
Green et al (n = 152)
Filgrastim
5 g/kg/d
Pegfilgrastim
100 g/kg
Filgrastim
5 g/kg/d
Pegfilgrastim
6 mg fixed dose
Incidence of FN* across all cycles
18% 9%
20%
13%
Key points
The rates of febrile neutropenia across all chemotherapy cycles in both studies ranged from approximately 10 to 20% [Holmes et al, 2002; Green et al, In press].
The apparently lower overall rate of febrile neutropenia in patients receiving pegfilgrastim compared with those treated with filgrastim reached significance (P <0.05) in the larger of the two trials [Holmes et al, 2002]. There was a similar observed difference between treatment groups in the fixed dose study; however this did not reach statistical significance (P >0.05).
In patients who received a similar myelosuppressive regimen but did not receive any growth factor, the rate of febrile neutropenia was 38% [Misset et al, 1999].
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O’Shaughnessy, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Misset JL, Dieras V, Gruia G, et al. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol. 1999;10:
*Febrile neutropenia defined as ANC < 500 (0.5  109/L) and fever ( 38.2°C).
Holmes FA, et al. J Clin Oncol. 2002;20:727–731; Green M, et al. Ann Oncol. In press.

15. Combined analysis of pegfilgrastim phase 3 pivotal trials
No statistically significant differences in treatment effects were observed in the two individual phase 3 trials
Data from the two phase 3 trials were pooled to enable more robust comparisons including high- risk subgroups
Endpoints examined in the combined analysis were:
incidence of febrile neutropenia
hospitalisation
IV anti-infective use
Key points
No statistically significant or otherwise meaningful differences in treatment effects were observed over the range of body weights in the two individual, phase 3 clinical trials. Therefore, data were pooled to enable more robust comparisons, including those between high-risk subgroups [Siena et al, 2002].
The efficacy endpoints examined in the combined analysis were the incidence of FN (ANC <0.5 x 109/L with a temperature 38.2°C), hospitalisation (except hospitalisations resulting from a protocol specified procedure) and the use of IV anti-infectives.
Reference
Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick J. A single dose of pegfilgrastim per chemotherapy cycle reduces the incidence and duration of febrile neutropenia (FN) compared with daily filgrastim: a meta-analysis of two phase 3 randomised trials in patients with stage II-IV breast cancer. Abstract presented at the 27th Meeting of the European Society of Medical Oncology (ESMO) October 2002; Nice, France.
IV = intravenous
Siena S, et al. ESMO 2002.

16. Results of combined analysis: pegfilgrastim led to a lower incidence of FN than filgrastim25 20 15 10 5
Pegfilgrastim
P = NS
P <0.05
Filgrastim
P = 0.029 20 19 18 13
Incidence of FN (%) 11 9
Key points
In the pivotal phase 3 trial reported by Holmes et al (2002) patients were randomised to receive a single 100 µg/kg injection of pegfilgrastim per cycle or daily 5 µg/kg injections of filgrastim. Over four cycles of chemotherapy, 9% of patients receiving pegfilgrastim developed FN compared with 18% of patients receiving filgrastim. This difference was statistically significant (P = 0.029) [Holmes et al, 2002].
In the pivotal phase 3 trial reported by Green et al, patients were randomised to pegfilgrastim administered as a single fixed 6 mg dose per cycle, or to filgrastim administered on a daily basis (5 µg/kg). The incidence of FN was 13% in the patients receiving pegfilgrastim and 20% in the patients receiving filgrastim (NS) [Green et al, In press].
Although these trials were not powered to detect a significant difference between treatment groups with respect to incidence of FN, the analysis of FN (a clinically relevant endpoint) was prospectively defined in both trials. In the fixed dose trial, assuming the 7% difference observed between treatment groups would be maintained, the reduction in FN would have reached statistical significance, if the sample size had been the same as the by-weight dose trial.
Combined analysis of the data from both pivotal phase 3 randomised trials found that the incidence of FN was 11% in patients receiving once-per-cycle pegfilgrastim and 19% in those receiving daily filgrastim, a difference which was statistically significant (P <0.05) [Siena et al, 2002].
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick J. A single dose of pegfilgrastim per chemotherapy cycle reduces the incidence and duration of febrile neutropenia (FN) compared with daily filgrastim: a meta-analysis of two phase 3 randomised trials in patients with stage II-IV breast cancer. Abstract presented at the 27th Meeting of the European Society of Medical Oncology (ESMO) October 2002; Nice, France.
Combined analysis‡
Pegfilgrastim*
(100 µg/kg)
Pegfilgrastim†
(Fixed 6 mg dose)
Adapted from ‡Siena S, et al. ESMO 2002; *Holmes F, et al. J Clin Oncol. 2002;20: ; †Green M, et al. Ann Oncol. In press

17. Pegfilgrastim shows a 71% relative reduction in FN incidence† 40
38% 30
50%
71%
(Percentage patients)
Incidence of FN
19%* 20
Key points
In the combined analysis of the two pivotal trials, the observed decrease in incidence of FN (11% vs 19% for pegfilgrastim vs filgrastim, respectively) represents a 42% relative decrease in incidence of FN for pegfilgrastim compared to filgrastim [Siena et al, 2002]. This is similar to that seen in the original pivotal trial of filgrastim vs placebo in patients undergoing chemotherapy for small cell lung cancer [Crawford et al, 1991].
The relative difference in incidence of FN between filgrastim and no cytokine support [Misset et al, 1999] is 50% (19% vs 38%, respectively).
Therefore, the reduction seen here with the use of pegfilgrastim suggests a relative 71% overall reduction in FN incidence compared with no treatment (note that a direct comparison has not been done).
References
Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991;325:
Misset JL, Dieras V, Gruia G, et al. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol.1999;10:
Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick J. A single dose of pegfilgrastim per chemotherapy cycle reduces the incidence and duration of febrile neutropenia (FN) compared with daily filgrastim: a meta-analysis of two phase 3 randomised trials in patients with stage II-IV breast cancer. Abstract presented at the 27th Meeting of the European Society of Medical Oncology (ESMO) October 2002; Nice, France.
42%
11%* 10
Pegfilgrastim
Filgrastim
No G-CSF
Adapted from *Siena S, et al. ESMO 2002.
†Misset J, et al. Ann Oncol. 1999;10:

18. Combined analysis suggests additional benefits for pegfilgrastim
The risk of FN was significantly lower with a single administration of pegfilgrastim compared with daily filgrastim (P <0.05)
The incidence of FN was 42% less in patients receiving once-per-cycle pegfilgrastim compared with patients receiving daily filgrastim (P <0.05)
A trend towards a lower risk of hospitalisation and IV anti-infective use was evident in patients receiving pegfilgrastim compared with filgrastim
The rationale for the superior efficacy observed requires further investigation. Pegfilgrastim may be more effective than filgrastim due to its sustained serum levels
Key points
Combined analysis of data from two phase 3 studies found that patients given once-per-cycle pegfilgrastim had a significantly lower risk of developing FN compared with those given daily filgrastim [Siena et al. 2002]. The observed decrease in the incidence of FN (11% vs 19% for pegfilgrastim patients and filgrastim patients, respectively) represents a 42% relative decrease in the incidence of FN.
A trend towards a lower risk of hospitalisation and reduced need for IV anti-infective use was observed in patients receiving pegfilgrastim compared with filgrastim.
A single injection of pegfilgrastim, therefore, leads to a lower observed incidence of FN than that with daily filgrastim.
These findings may confer important clinical benefits for patients, and the rationale for the observed superior efficacy requires further investigation. Although pegfilgrastim and filgrastim have the same mechanism of action, pegfilgrastim may be more effective due to its sustained serum levels. In other words, increased serum residence time may be the primary determinant of efficacy.
Reference
Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick J. A single dose of pegfilgrastim per chemotherapy cycle reduces the incidence and duration of febrile neutropenia (FN) compared with daily filgrastim: a meta-analysis of two phase 3 randomised trials in patients with stage II-IV breast cancer. Abstract presented at the 27th Meeting of the European Society of Medical Oncology (ESMO) October 2002; Nice, France.
Siena S, et al. ESMO 2002.

19. Pegfilgrastim is as well tolerated as filgrastim
Patients reporting bone pain
Patients not reporting bone pain
Pegfilgrastim
Filgrastim
25%
26%
Key points
In randomised clinical trials in patients with cancer receiving pegfilgrastim after cytotoxic chemotherapy, most adverse events were caused by the malignancy or cytotoxic chemotherapy. The side effects of pegfilgrastim, mainly mild-to-moderate bone pain, are similar to those experienced during daily filgrastim administration [Green et al, In Press; Holmes et al, 2002].
In patients with breast cancer:
The incidence of bone pain was comparable between pegfilgrastim and filgrastim groups (25% vs 26%, respectively) [Holmes et al, 2002].
No relationship was observed between body weight and incidence of adverse events, including incidence or severity of bone pain [Green et al. In press].
In clinical trials to date, there has been no laboratory or clinical evidence for neutralising antibodies in patients receiving pegfilgrastim [Green et al. In press; Holmes et al, 2002a; Johnston et al, 2000; Crawford et al, 2000; Vose et al, 2001; George et al, 2001; Holmes et al, 2002b].
References
Crawford J, Garst J, Lee M, et al. A phase II multicycle trial of pegfilgrastim compared to filgrastim after myelosuppressive chemotherapy. In: 9th World Conference on Lung Cancer; 2000; Tokyo, Japan; 2000.
George S, Yunus F, Yang B-B, Hacket J, Neumann T, Liang B. Pharmacokinetic profiles of fixed dose single pegfilgrastim administration in patients with non-Hodgkin's lymphoma. Blood. 2001;98:27b. Abstract 3700.
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002a;20:
Holmes FA, Jones SE, O’Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002b;13:
Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol. 2000;18:
Vose JM, Crum M, Lazarus H, et al. Single dose pegfilgrastim (SD/01) is as effective as daily Filgrastim following ESHAP chemotherapy for subjects with non-Hodgkin's lymphoma or Hodgkin's disease. Blood. 2001;98:799a. Abstract 3322.
75%
74%
Adapted from Holmes F, et al. J Clin Oncol. 2002;20:

20. Filgrastim Vs. Pegfilgrastim
5 µg/kg/day
Pegfilgrastim
6 mg/cycle
Serum half-life
~3 hours
~27 hours
Daily injections
Once-per-chemotherapy cycle
Course
Efficacy
Equivalent
Equivalent
Safety
Equivalent
Equivalent

21. Phase II Study of ABVD + Pegfilgrastim in Hodgkin Lymphoma
Single-arm phase 2 trial in 23 newly diagnosed patients with classical Hodgkin lymphoma
23 evaluable patients enrolled
ABVD
Doxorubicin 25 mg/m2 Bleomycin 10 units/m2
Vinblastine 6 mg/m2
Dacarbazine 375 mg/m2
Key Points
Preliminary data from a phase 2 study of ABVD + pegfilgrastim were presented in 2003 at ASH.1
The primary objective is to determine the incidence of grade 3 and 4 neutropenia on day 14 that may require dose delays and/or reductions after at least one cycle of chemotherapy.1
Secondary end points are delivered dose intensity, hematologic and nonhematologic toxicity.1
Background
Single-arm single-center trial of ABVD chemotherapy in 24 chemotherapy-naive patients with Hodgkin’s disease.
24 patients given ABVD chemotherapy every 14 days, with the number of cycles determined by the physician. (Study complete with 24 patients)
Individual patients treated with 3 to 6 cycles of ABVD.
Pegfilgrastim given in all cycles, starting 24 hours after the last dose of chemotherapy.1
Younes A, Fayad L, Romaguera J, Pro B, Dang NH, Wang M. Efficacy of single administration of a fixed dose pegfilgrastim (Neulasta) in inducing neutrophil count recovery after 170 consecutive doses of ABVD chemotherapy in patients with Hodgkin lymphoma: safety of pegfilgrastim with Q14-day chemotherapy regimens. Blood. 2003;102. Abstract 2352.
Pegfilgrastim 6 mg
Repeat every 14 days
Day 1 2
Younes, A. et al. (ASH 2005)

22. Efficacy: 100% full dose delivered 99% on time
ABVD + Pegfilgrastim
Efficacy: 100% full dose delivered 99% on time

23. Safety of ABVD + Pegfilgrastim
Long-Term Follow-Up

24. Phase 2 Study of RCHOP-14 + Pegfilgrastim in Subjects With NHL
Single-arm phase 2 trial in 34 patients with low-, intermediate-, or high-grade NHL
29 subjects eligible for analysis
CHOP
Cyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d  5
Key Points
Single-arm phase 2 trial of 14-day CHOP-R in 34 patients with low-, intermediate-, or high-grade NHL.1
Primary end point is the proportion of patients given the planned dose of chemotherapy on time.1
Secondary end points are the incidence of grade 4 neutropenia and febrile neutropenia, hematologic and nonhematologic toxicity, delivered dose intensity, and response rates.1
Background
21-day CHOP with rituximab has been shown to improve the outcomes in patients with aggressive NHL1
Growth factors typically are administered with regimens like CHOP-R to help deliver the full regimen1
All patients have completed the study. Of 34 patients, 29 are assessable (5 patients were excluded)1
Moore TD, Patel T, Segal ML, et al. A single pegfilgrastim dose per cycle supports dose-dense (Q14D) CHOP-R in patients with non-Hodgkin's lymphoma. Poster presented at: Annual Meeting of the American Society of Hematology; December 6, 2003; San Diego, California.
Rituximab 375 mg/m2
Pegfilgrastim 6 mg 1 2 3 4
Repeat every 14 days
Day
Moore T, et al. Blood. 2003;102. Abstract 2365.

25. R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002

26. R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002

27. R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002

28. Pegfilgrastim or Filgrastim RCHOP-14 in NHL
Randomized open-label phase 2 study of 14-day CHOP-R for 6 cycles supported with pegfilgrastim or Filgrastim in subjects with aggressive B-cell NHL
Rituximab 375mg/m2
Pegfilgrastim 6 mg single dose
Key Points
Randomized open-label phase 2 study of 14-day CHOP-R for up to 6 cycles supported by a single dose of pegfilgrastim 6 mg or Filgrastim 5 µg/kg/day (days 2-13 or until ANC > 10 x 109/L post nadir) in patients with aggressive B-cell NHL.1
The end point was the number of patients given the full dose on time in all cycles.
Lopéz A, Data on file.
CHOP
Cyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d  5 or
Filgrastim 5 µg/kg/d
Day 1 2
Repeat every 14 days  6
Lopez, A. et al. (ASH 2003).

29. Pegfilgrastim or Filgrastim RCHOP-14 in NHL
Analysis of 60 randomized subjects:
58 given study drug (32 pegfilgrastim, 26 Filgrastim)
52 given all 6 cycles of chemotherapy (30 pegfilgrastim, 22 Filgrastim)
Reasons for discontinuation in the pegfilgrastim group:
2 Protocol specified criteria (Cycles 3 and 5)
Reasons for discontinuation in the Filgrastim group:
1 Other (Cycle 3)
2 Protocol specified criteria (Cycles 2 and 5)
1 Ineligibility determined (Cycle 3)
Background
Analysis of 60 randomized subjects
58 were given the study drug (32 pegfilgrastim, 26 Filgrastim )
52 were given all 6 cycles of the chemotherapy (30 pegfilgrastim, 22 Filgrastim)
The treatment groups are generally well balanced, but patients given Filgrastim were younger (mean, 47 vs 54 years), weighed less (mean, 67 vs 73 kg), and had higher pretreatment ANC and platelet counts than the patients given pegfilgrastim.
Lopéz A, Data on file.
Lopez, A. et al. (ASH 2003).

30. Pegfilgrastim or Filgrastim RCHOP-14 in NHL
Pegfilgrastim (n=32)
Filgrastim (n=26)
100 81 81 75 80 69
Patients (%) 60
Key Points
The primary endpoint in this study, the delivery of full chemotherapy dose on schedule, was defined very stringently and a patient who experienced a dose delay in even one cycle did not meet the primary endpoint.
22/32 (69%) (95%CI:50,84) of patients given pegfilgrastim and 21/26 (81%) (95%CI: 61,93)of those given Filgrastim were given the full dose of the chemotherapy on schedule
24/32 (75%) of patients given pegfilgrastim and 21/26 (81%) of those given Filgrastim were given all cycles of the chemotherapy without a delay of more than 3 days
Planned Dose on Time (PDOT) defined as >75% of the protocol specified dose (cyclophosphamide and doxorubicin) of chemotherapy administered within 17 days of Day 1 of the previous cycle.
Delay was defined as > 3 days delay in chemotherapy administration.
Lopéz A, Data on file. 40 20
n = 22
n = 21
n = 24
n = 21
Planned Dose on Time
No Delay
Lopez, A. et al. (ASH 2003).

31. Pegfilgrastim or Filgrastim RCHOP-14 in NHL94 93
Cycles (%)
Background:
In total, 145 cycles of chemotherapy were administered to subjects randomized to receive Filgrastim. Of these, 137 cycles (94%) (95% CI: 89,98) were delivered at planned dose on time. For those subjects randomized to receive pegfilgrastim, a total of 188 cycles were administered and of these, 175 (93%) (95% CI: 88,96) were delivered at planned dose on time.
Planned Dose on Time (PDOT) defined as >75% of the protocol specified dose (cyclophosphamide and doxorubicin) of chemotherapy administered within 17 days of Day 1 of the previous cycle.
Delay was defined as > 3 days delay in chemotherapy administration.
(n= 175 cycles)
(n= 137 cycles)
Lopez, A. et al. (ASH 2003).

32. Randomized Trial of ESHAP Plus GCSF or PegGCSF
Relapsed Lymphoma

33. Paclitaxel/ Topotecan + Rituximab Relapsed Aggressive B-Cell NHL
Rituximab 375mg/m2
Paclitaxel 200 mg/m2
(3 hr infusion)
G-CSF
Topotecan 1mg/m2
(30 min infusion)
Day

34. Paclitaxel + Topotecan + Rituximab (TTR)
Relapsed/Refractory Aggressive NHL
MDACC Experience
Response Rate (%)
Primary
Clinical Trial N Refractory Relapsed
Paclitaxel % 50%
Topotecan % 43%
Paclitaxel + Topotecan % (6% CR) 62% (18% CR)
Paclitaxel + Topo + Rituximab 45 55% (25% CR) 80% (60% CR)

35. TTR for Relapsed/Refractory Aggressive B-NHL
Survival by TTR Treatment Outcome

36. TTR for Relapsed/Refractory Aggressive B-NHL Event Free Survival (EFS)
Median EFS = 21 mo
(N=21)
EFS = 2 mo

37. Taxol + Topotecan + PegFilgrastim (Neulastim)
ANC: Cycle#1
Taxol + Topo + PegGCSF Taxol + Topo + GCSF
N = N = 18
Neutropenic fever +/- infection
2/7 = 28.5 % 20/78 = 25.6%

38. Summary Pegfilgrastim offers:
Simple 6 mg fixed dose once-per-cycle administration
Protection from neutropenia for adult patients, across a broad range of body weight
Self-regulating, neutrophil-mediated clearance
Freedom from daily injections
Comparable tolerability profile to daily filgrastim
Key points
Pegfilgrastim offers many benefits to healthcare professionals and patients. A single, once-per-chemotherapy-cycle injection of pegfilgrastim is more effective than daily injections of filgrastim at reducing the overall incidence of FN in patients receiving myelosuppressive chemotherapy [Siena et al, 2002]. Furthermore, once-per-cycle pegfilgrastim reduces the DSN as effectively as daily filgrastim [Holmes et al, 2002; Green et al. In press].
A once-per-cycle dosing schedule using a fixed dose of 6 mg pegfilgrastim offers simple protection from neutropenia for all patients, across a broad range of body weights [Green et al. In press].
The serum concentration of pegfilgrastim remains at an effective level for as long as it takes to achieve neutrophil recovery, providing tailored protection for individual patients due to the ‘self-regulating’, neutrophil-mediated clearance of pegfilgrastim [Johnston et al, 2000].
The convenience of once-per-cycle dosing of pegfilgrastim offers greater freedom for patients, caregivers and healthcare professionals by eliminating the burden of daily G-CSF. Furthermore, patient compliance may be improved, minimising the risk of missed doses.
Finally, the adverse event profile of pegfilgrastim is similar to that of filgrastim, with mild-to-moderate bone pain being the most commonly experienced study drug-related adverse event.
References
Green MD, Koelbl H, Baselga J, et al. A randomized, double-blind, phase 3 study of fixed-dose, single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. In press.
Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20:
Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol. 2000;18:
Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick J. A single dose of pegfilgrastim per chemotherapy cycle reduces the incidence and duration of febrile neutropenia (FN) compared with daily filgrastim: a meta-analysis of two phase 3 randomised trials in patients with stage II-IV breast cancer. Abstract presented at the 27th Meeting of the European Society of Medical Oncology (ESMO) October 2002; Nice, France.
Holmes F et al, J Clin Oncol. 2002;20: ; Green M, et al. Ann Oncol. In press; Siena S, et al. ESMO 2002; Johnston E, et al. J Clin Oncol. 2000;18: