Transcript 20 Younes Neulastim

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 Trial
of Prophylactic G-CSF
Small Cell Lung Cancer receiving CAE
% of patients
Placebo
(n = 102)
Filgrastim
(n = 92)
P value
Cycle 1
57
28
0.001
Cumulative
77
40
0.001
13.3
6.5
NR
Parameter
Febrile neutropenia
Culture-confirmed
infection
NR = not reported
Crawford J, et al. N Engl J Med. 1991;325:164–170.
Pegylating filgrastim
makes once-per-chemotherapy-cycle dosing possible
Filgrastim
Daily dosing
Helical
bundle
Pegfilgrastim
One dose per cycle of
chemotherapy
Helical
bundle
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.
Pegfilgrastim : PK and Pharmacodynamics
Cycle 1: Doxo + Docetaxel (Breast Ca)
Pegfilgrastim serum level
ANC
Mean serum
concentration (g/L)
103
103
102
102
10
10
1
1
0.1
0.1
0.01
0.01
0
3
6
9
12
Cycle 1* days
Holmes FA, et al. JCO. 2002 (using 100 g/kg)
15
18
21
Pegfilgrastim Is as Effective as Filgrastim
in All Cycles of Chemotherapy
Doxo + Docetaxel (Breast Ca)
100
Cycle 1
Cycle 2
Cycle 3
Cycle 4
10
ANC
9
(10 /L)
1.0
Pegfilgrastim 100 µg/kg
Filgrastim 5 µg/kg/d
0.1
0.01
0
21
7
14
Holmes FA, et al. JCO 2002
21
7
14
21
Cycle day
7
14
21
7
14
Rationale for 6 mg fixed dose of pegfilgrastim
Mean duration of severe neutropenia (ANC <0.5 x 109/L)
2.5
DSN (days)
2
1.5
1
0.5
0
Filgrastim
5 µg/kg/d
(n = 25)
3-5 mg
(n = 46)
5-7 mg
(n = 29)
Pegfilgrastim
7-9 mg
(n = 22)
Data on file, Amgen.
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
Randomise*
Chemotherapy:
Doxorubicin (A) 60 mg/m2
Docetaxel (T) 75 mg/m2
Repeat for
four cycles
(n = 154)†
(n = 80)‡
Filgrastim
5 µg/kg/day§
Pegfilgrastim
100 µg/kg
6 mg
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;20:727-731.
‡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
Green et al
Holmes et al
Mean DSN
(days)
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)
1.8
1.7
1.6
1.8
95% CI*
*Confidence interval (CI) for
difference of the means.
–0.36 to 0.30
–0.15 to 0.63
Holmes F, et al. J Clin Oncol. 2002;20:727-731;
Green M, et al. Ann Oncol. In press; Data on file, Amgen.
Pegfilgrastim and filgrastim provide
comparable neutrophil recovery
Median ANC levels and inter-quartile range
1000.00
Filgrastim, 5 µg/kg/day (n = 75)
Pegfilgrastim fixed, 6 mg (n = 77)
ANC (x109/L)
100.00
10.00
1.00
0.10
Chemo- Study
therapy 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.
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
Mean DSN
± standard error (days)
4
Pegfilgrastim 6 mg fixed dose
Filgrastim 5 µg/kg/day
3
2
1
0
46–62 kg
>62–71 kg
>71–80 kg >80–132 kg
Adapted from Green M, et al. Ann Oncol. In press.
Pegfilgrastim is comparable to filgrastim
in all cycles of chemotherapy
4
Mean DSN
± standard error (days)
Mean DSN by chemotherapy cycle
Pegfilgrastim 6 mg fixed dose
3
Filgrastim 5 µg/kg/day
2
1
0
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Adapted from Green M, et al. Ann Oncol. In press.
Incidence of febrile neutropenia
across all cycles
Holmes et al (n = 296)
Incidence of
FN* across
all
cycles
Green et al (n = 152)
Filgrastim
5 g/kg/d
Pegfilgrastim
100 g/kg
Filgrastim
5 g/kg/d
Pegfilgrastim
6 mg fixed dose
18%
9%
20%
13%
*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 highrisk subgroups
• Endpoints examined in the combined analysis
were:
– incidence of febrile neutropenia
– hospitalisation
– IV anti-infective use
IV = intravenous
Siena S, et al. ESMO 2002.
Results of combined analysis:
pegfilgrastim led to a
lower incidence of FN than filgrastim
Incidence of FN (%)
25
P <0.05
Pegfilgrastim
Filgrastim
P = 0.029
19
20
P = NS
20
18
15
13
11
9
10
5
0
Combined
analysis‡
Pegfilgrastim* Pegfilgrastim†
(100 µg/kg) (Fixed 6 mg dose)
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 shows a 71% relative
reduction in FN incidence
†
Incidence of FN
(Percentage patients)
40
38%
30
50%
71%
20
11%*
19%*
42%
10
0
Pegfilgrastim
Filgrastim
No G-CSF
Adapted from *Siena S, et al. ESMO 2002.
J, et al. Ann Oncol. 1999;10:553-560.
†Misset
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
Siena S, et al. ESMO 2002.
serum levels
Pegfilgrastim is as well tolerated as filgrastim
Patients reporting bone pain
Patients not reporting bone pain
Pegfilgrastim
25%
Filgrastim
26%
75%
74%
Adapted from Holmes F, et al. J Clin Oncol. 2002;20:727-731.
Filgrastim Vs. Pegfilgrastim
Filgrastim
5 µg/kg/day
Pegfilgrastim
6 mg/cycle
Serum half-life
~3 hours
~27 hours
Course
Daily
injections
Once-perchemotherapy cycle
Efficacy
Equivalent
Equivalent
Safety
Equivalent
Equivalent
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
Pegfilgrastim
6 mg
Repeat every
14 days
Day
1
Younes, A. et al. (ASH 2005)
2
ABVD + Pegfilgrastim
Efficacy: 100% full dose delivered 99% on time
Safety of ABVD + Pegfilgrastim
Long-Term Follow-Up
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
Rituximab
375 mg/m2
Cyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d  5
Pegfilgrastim
6 mg
Repeat every
14 days
Day
1
2
Moore T, et al. Blood. 2003;102. Abstract 2365.
3
4
R-CHOP q14 + Pegfilgrastim
Median WBC Counts
25
20
15
10
5
0
n = 15
n = 14
n = 13
n = 13
n = 13
n = 12
1
2
3
4
5
6
Error bars represent interquartile range
Cycle
Moore et al ASH 2002
R-CHOP q14 + Pegfilgrastim
Cycles of CHOP-R Delivered at Full Dose
100%
13/13
15/15
12/12
13/14
12/13
12/13
80%
60%
40%
20%
0%
1
2
3
4
5
6
Cycle
Error bars represent standard error
Moore et al ASH 2002
R-CHOP q14 + Pegfilgrastim
Cycles of CHOP-R Delivered on Time
100%
15/15
13/13
13/14
12/13
10/12
10/13
80%
60%
40%
20%
0%
1
2
Error bars represent standard error
3
4
5
6
Cycle
Moore et al ASH 2002
Pegfilgrastim or Filgrastim
RCHOP-14 in NHL
• Randomized open-label phase 2 study of 14-day CHOPR for 6 cycles supported with pegfilgrastim or Filgrastim
in subjects with aggressive B-cell NHL
Rituximab
375mg/m2
CHOP
Cyclophosphamide 750 mg/m2
Doxorubicin 50 mg/m2
Vincristine 1.4 mg/m2
Prednisone 100 mg/d  5
Pegfilgrastim
6 mg single dose
or
Filgrastim
5 µg/kg/d
Repeat every
14 days  6
Day 1
Lopez, A. et al. (ASH 2003).
2
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)
Lopez, A. et al. (ASH 2003).
Pegfilgrastim or Filgrastim
RCHOP-14 in NHL
Pegfilgrastim (n=32)
Filgrastim (n=26)
100
81
80
69
75
81
Patients 60
(%)
40
20
0
n = 22
n = 21
Planned Dose on Time
Lopez, A. et al. (ASH 2003).
n = 24 n = 21
No Delay
Pegfilgrastim or Filgrastim
RCHOP-14 in NHL
100
93
94
90
Pegfilgrastim (188 cycles given)
Filgrastim (145 cycles given)
80
70
60
50
Planned Dose on Time
(n= 175 cycles)
Lopez, A. et al. (ASH 2003).
(n= 137 cycles)
Randomized Trial of ESHAP Plus GCSF or PegGCSF
Relapsed Lymphoma
Paclitaxel/ Topotecan + Rituximab
Relapsed Aggressive B-Cell NHL
Rituximab 375mg/m2
Paclitaxel 200 mg/m2
(3 hr infusion)
Topotecan 1mg/m2
(30 min infusion)
G-CSF
12345
6 - 16
Day
Paclitaxel + Topotecan + Rituximab (TTR)
Relapsed/Refractory Aggressive NHL
MDACC Experience
Response Rate (%)
Primary
Clinical Trial
N
Refractory
Relapsed
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
TTR for Relapsed/Refractory Aggressive B-NHL
Event Free Survival (EFS)
P < 0.0001
(N=50)
Median EFS = 21 mo
(N=21)
EFS = 2 mo
Taxol + Topotecan + PegFilgrastim (Neulastim)
ANC: Cycle#1
Taxol + Topo + PegGCSF
N=7
Taxol + Topo + GCSF
N = 18
Box Plot
Grouping Variable( s) : Categoryf or ANC
Box Plot
Grouping Variable( s) : Category for ANC
20
20
15
ANC
10
10
5
5
Neutropenic fever +/- infection
2/7 = 28.5 %
20/78 = 25.6%
Day 19-22
Day 13-14
Day 11-12
Day 9-10
Day 7-8
Day 5-6
Day 3-4
Day 21
Day 14
Day 12
Day 10
Day 8
Day 5
Day 3
0
Baseline
0
Day 1
ANC
15
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.