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.