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
Pivotal U.S. Clinical Trialof Prophylactic G-CSF
Small Cell Lung Cancer receiving CAE
NR 6.5 13.3
0.0014077 Cumulative
0.0012857 Cycle 1
P valueFilgrastimPlacebo
Parameter
% of patients
Crawford J, et al. N Engl J Med. 1991;325:164–170.
(n = 102) (n = 92)
NR = not reported
Febrile neutropenia
Culture-confirmed infection
Pegylating filgrastim makes once-per-chemotherapy-cycle dosing possible
Daily dosing
One dose per cycle of chemotherapy
Filgrastim
Pegfilgrastim
Helicalbundle
Helicalbundle
Polyethylene glycol(PEG)
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)
Neulastim™ (pegfilgrastim) Summary of Product Characteristics.
Cycle 1* days
0 3 6 9 12 15 18 21
Mea
n s
eru
mco
nce
ntr
atio
n (g
/L)
0.01
0.1
1
10
102
103
Mea
n A
NC
( 1
09/L
)
0.01
0.1
1
10
102
103
Pegfilgrastim serum levelPegfilgrastim serum level
ANCANC
Holmes FA, et al. JCO. 2002 (using 100 100 g/kg)/kg)
Pegfilgrastim : PK and Pharmacodynamics
Cycle 1: Doxo + Docetaxel (Breast Ca)
Pegfilgrastim Is as Effective as Filgrastim
in All Cycles of ChemotherapyDoxo + Docetaxel (Breast Ca)
Pegfilgrastim 100 µg/kg Pegfilgrastim 100 µg/kg
Filgrastim 5 µg/kg/dFilgrastim 5 µg/kg/d
00 7 7 14 14 21 21 7 7 14 14 21 21 77 1414 21 21 7 7 14 14 21 21
100100
1010
1.01.0
0.10.1
0.010.01
Cycle 1Cycle 1 Cycle 2Cycle 2 Cycle 3Cycle 3 Cycle 4Cycle 4
Cycle dayCycle day
ANC ANC ((101099/L)/L)
Holmes FA, et al. Holmes FA, et al. JCO 2002JCO 2002
Data on file, Amgen.
Mean duration of severe neutropenia (ANC <0.5 x 109/L)
Rationale for 6 mg fixed dose of pegfilgrastim
Filgrastim5 µg/kg/d(n = 25)
5-7 mg(n = 29)
3-5 mg(n = 46)
7-9 mg(n = 22)
DS
N (
day
s)
0
0.5
1
1.5
2
2.5
Pegfilgrastim
Pegfilgrastim phase 3 pivotal trials in breast cancer: study design
Randomise* Chemotherapy:Doxorubicin (A) 60 mg/m2
Docetaxel (T) 75 mg/m2
Pegfilgrastim 100 µg/kg† or
6 mg fixed dose‡
then daily placebo
Filgrastim5 µg/kg/day§
Repeat forfour cycles
Day 1
Starting day 2
*Stratified by weight and prior chemotherapy§Daily to ANC 10 109/L or 14 doses
Pegfilgrastim 100 µg/kg (n = 154)†
6 mg (n = 80)‡
Filgrastim 5 µg/kg/day (n = 156)†
(n = 77)‡
†Holmes F, et al. J Clin Oncol. 2002;20:727-731.‡Green M, et al. Ann Oncol. In press.
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
Holmes F, et al. J Clin Oncol. 2002;20:727-731; Green M, et al. Ann Oncol. In press.
DSN was comparable for pegfilgrastim and filgrastim in both studies
DSN in cycle 1
Holmes F, et al. J Clin Oncol. 2002;20:727-731; Green M, et al. Ann Oncol. In press; Data on file, Amgen.
–0.15 to 0.63–0.36 to 0.3095% CI*
1.6
(n = 75)
Filgrastim5 µg/kg/day
1.8
(n = 77)
Pegfilgrastim6 mg fixed dose
1.71.8Mean DSN (days)
(n = 149)(n = 147)
Pegfilgrastim100 µg/kg
Filgrastim5 µg/kg/day
Holmes et al Green et al
*Confidence interval (CI) for difference of the means.
Pegfilgrastim and filgrastim provide comparable neutrophil recovery
Green M, et al. Ann Oncol. In press.
Median ANC levels and inter-quartile range
0.01
0.10
1.00
10.00
100.00
1000.00
Cycle day
1 2 3 4 5 6 7 8 99 10 11 12 13 14 15 16 17 18 19 20 21
AN
C (
x109 /
L)
Study drug
Chemo-therapy
Filgrastim, 5 µg/kg/day (n = 75)
Pegfilgrastim fixed, 6 mg (n = 77)
Pegfilgrastim 6 mg fixed dose is effective across a broad range of body weights
0
1
2
3
4
46–62 kg >71–80 kg>62–71 kg >80–132 kg
Mean DSN in cycle 1 by body weight group in quartiles
Adapted from Green M, et al. Ann Oncol. In press.
Pegfilgrastim 6 mg fixed dose
Filgrastim 5 µg/kg/day
Me
an
DS
N
± s
tan
da
rd e
rro
r (d
ays
)
Pegfilgrastim is comparable to filgrastim in all cycles of chemotherapy
Adapted from Green M, et al. Ann Oncol. In press.
0
1
2
3
4
Cycle 1 Cycle 3Cycle 2 Cycle 4
Me
an
DS
N
± s
tan
da
rd e
rro
r (d
ays
)
Pegfilgrastim 6 mg fixed dose
Filgrastim 5 µg/kg/day
Mean DSN by chemotherapy cycle
Incidence of febrile neutropenia across all cycles
20%
Filgrastim5 g/kg/d
13%
Pegfilgrastim6 mg fixed dose
9%18%Incidence of FN* across
allcycles
Pegfilgrastim100 g/kg
Filgrastim5 g/kg/d
Holmes et al (n = 296) Green et al (n = 152)
*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.
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
Siena S, et al. ESMO 2002.IV = intravenous
Results of combined analysis: pegfilgrastim led to a
lower incidence of FN than filgrastim
Adapted from ‡Siena S, et al. ESMO 2002;*Holmes F, et al. J Clin Oncol. 2002;20:727-731; †Green M, et al. Ann Oncol. In press
Pegfilgrastim*(100 µg/kg)
Pegfilgrastim†
(Fixed 6 mg dose)Combined analysis‡
25
20
15
10
5
0
9
13
1820
11
19
Pegfilgrastim
Filgrastim
Inci
den
ce o
f F
N (
%)
P <0.05 P = 0.029P = NS
19%*
38%†
11%*
0
10
20
30
40
Pegfilgrastim Filgrastim No G-CSF
Adapted from *Siena S, et al. ESMO 2002.†Misset J, et al. Ann Oncol. 1999;10:553-560.
42%
50%
71%
Inci
den
ce o
f F
N
(Per
cen
tag
e p
atie
nts
)Pegfilgrastim shows a 71% relative
reduction in FN incidence
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
Siena S, et al. ESMO 2002.
Pegfilgrastim Filgrastim
Adapted from Holmes F, et al. J Clin Oncol. 2002;20:727-731.
25%
75%
26%
74%
Patients reporting bone pain
Patients not reporting bone pain
Pegfilgrastim is as well tolerated as filgrastim
Filgrastim Vs. Pegfilgrastim
Safety
Efficacy
Course
Serum half-life
EquivalentEquivalent
EquivalentEquivalent
Once-per-chemotherapy cycle
Daily injections
~27 hours~3 hours
Pegfilgrastim
6 mg/cycleFilgrastim
5 µg/kg/day
Day
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
1 2
Pegfilgrastim 6 mg
Repeat every14 days
Younes, A. et al. (ASH 2005)
ABVDDoxorubicin 25 mg/m2 Bleomycin 10 units/m2 Vinblastine 6 mg/m2
Dacarbazine 375 mg/m2
0
10
20
30
40
50
60
ABVD cycle
ABVD + PegfilgrastimEfficacy: 100% full dose delivered 99% on time
0
5
10
15
20
25
Months after completion of ABVD
N=23
N=23
N=23
N=16N=12
Time of ANC measurement
Safety of ABVD + PegfilgrastimLong-Term Follow-Up
Phase 2 Study of RCHOP-14 + Pegfilgrastim in Subjects With NHL
Day
• Single-arm phase 2 trial in 34 patients with low-, intermediate-, orhigh-grade NHL– 29 subjects eligible for analysis
1 3
Repeat every14 days
2
Rituximab 375 mg/m2
Pegfilgrastim 6 mg
4
CHOPCyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d 5
Moore T, et al. Blood. 2003;102. Abstract 2365..
n = 14 n = 13 n = 13 n = 13 n = 12
Error bars represent interquartile range
0
5
10
15
20
25
1 2 3 4 5 6
n = 15
Cycle
Median WBC Counts
R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002
13/1413/13
12/13 12/13
12/12
Error bars represent standard error
15/15
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6
Cycle
Cycles of CHOP-R Delivered at Full Dose
R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002
Cycles of CHOP-R Delivered on Time
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6
Cycle
15/1513/14 12/13
10/1310/12
Error bars represent standard error
13/13
R-CHOP q14 + Pegfilgrastim
Moore et al ASH 2002
• 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
Repeat every14 days 6
Pegfilgrastim 6 mg single dose
Day 1 2
CHOPCyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d 5
orFilgrastim5 µg/kg/d
Lopez, A. et al. (ASH 2003).
Rituximab375mg/m2
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)
Pegfilgrastim or Filgrastim RCHOP-14 in NHL
Lopez, A. et al. (ASH 2003).
6975
81 81
0
20
40
60
80
100
Planned Dose on Time No Delay
Pegfilgrastim (n=32)Filgrastim (n=26)
Patients(%)
Lopez, A. et al. (ASH 2003).
n = 22n = 22 n = 21n = 21 n = 24n = 24 n = 21n = 21
Pegfilgrastim or Filgrastim RCHOP-14 in NHL
50
60
70
80
90
100
Planned Dose on Time
Pegfilgrastim (188 cycles given)
Filgrastim (145 cycles given)
Cy
cle
s (
%)
(n= 175 cycles) (n= 137 cycles)
93 94
Lopez, A. et al. (ASH 2003).
Pegfilgrastim or Filgrastim RCHOP-14 in NHL
Randomized Trial of ESHAP Plus GCSF or PegGCSFRelapsed Lymphoma
Paclitaxel/ Topotecan + Rituximab
Relapsed Aggressive B-Cell NHL
Paclitaxel 200 mg/m2(3 hr infusion)
G-CSF
1 2 3 4 5 6 - 16
Day
Topotecan 1mg/m2(30 min infusion)
Rituximab 375mg/m2
Paclitaxel + Topotecan + Rituximab (TTR)
Relapsed/Refractory Aggressive NHLMDACC Experience
Response Rate (%)
Primary
Clinical Trial N RefractoryRelapsed
Paclitaxel 44 15% 50%
Topotecan 40 12% 43%
Paclitaxel + Topotecan 63 31% (6% CR) 62% (18% CR)
Paclitaxel + Topo + Rituximab 45 55% (25% CR) 80% (60% CR)
TTR for Relapsed/Refractory Aggressive B-NHL
Survival by TTR Treatment Outcome
0 12 24 36 480
25
50
75
100
Month
PR/CR Transplant
PR/CR Observation
< PR
0 12 24 360
25
50
75
100
PR/CR
< PR
Month
TTR for Relapsed/Refractory Aggressive B-NHL
Event Free Survival (EFS)
(N=50)Median EFS = 21 mo
(N=21)EFS = 2 mo
P < 0.0001
0
5
10
15
20
Box PlotGrouping Variable(s): Category for ANC
ANC: Cycle#1
Taxol + Topo + PegGCSF Taxol + Topo + GCSFN = 7 N = 18
0
5
10
15
20
Box PlotGrouping Variable(s): Category for ANC
Neutropenic fever +/- infection
2/7 = 28.5 % 20/78 = 25.6%
Taxol + Topotecan + PegFilgrastim (Neulastim)
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
Holmes F et al, J Clin Oncol. 2002;20:727-731; Green M, et al. Ann Oncol. In press; Siena S, et al. ESMO 2002; Johnston E, et al. J Clin Oncol. 2000;18:2522-2528.
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