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Pegfilgrastim (Neulastim TM ) Simplifying the management of chemotherapy-induced neutropenia

Pegfilgrastim (Neulastim TM ) 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.

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Pegfilgrastim (Neulastim TM ) Simplifying the management of chemotherapy-induced neutropenia

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  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 Trialof Prophylactic G-CSFSmall Cell Lung Cancer receiving CAE % of patients Placebo Filgrastim Parameter P value (n = 102) (n = 92) 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. 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)

  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) Neulastim™ (pegfilgrastim) Summary of Product Characteristics.

  5. Pegfilgrastim : PK and PharmacodynamicsCycle 1: Doxo + Docetaxel (Breast Ca) Pegfilgrastim serum level ANC 103 103 102 102 Mean ANC( 109/L) 10 10 Mean serumconcentration (g/L) 1 1 0.1 0.1 0.01 0.01 0 3 6 9 12 15 18 21 Cycle 1* days Holmes FA, et al. JCO. 2002 (using 100 g/kg)

  6. Pegfilgrastim Is as Effective as Filgrastimin All Cycles of ChemotherapyDoxo + 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 0 7 14 21 7 14 21 7 14 21 7 14 21 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) Filgrastim5µg/kg/d(n = 25) 5-7 mg (n = 29) 7-9 mg(n = 22) 3-5 mg(n = 46) Pegfilgrastim Data on file, Amgen.

  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/m2Docetaxel (T) 75 mg/m2 Repeat forfour cycles Randomise* Filgrastim5 µg/kg/day§ 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. *Stratified by weight and prior chemotherapy§Daily to ANC 10  109/L or 14 doses

  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 Holmes F, et al. J Clin Oncol. 2002;20:727-731; Green M, et al. Ann Oncol.In press.

  10. DSN was comparable for pegfilgrastim and filgrastim in both studies DSN in cycle 1 Green et al Holmes 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 95% CI* –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. *Confidence interval (CI) for difference of the means.

  11. 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) 100.00 10.00 ANC (x109/L) 1.00 Chemo- therapy Study drug 0.10 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) >62–71 kg 46–62 kg >71–80 kg >80–132 kg Adapted from Green M, et al. Ann Oncol. In press.

  13. 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) Cycle 2 Cycle 1 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 allcycles 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.

  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 IV = intravenous Siena S, et al. ESMO 2002.

  16. Results of combined analysis:pegfilgrastim led to a lower incidence of FN than filgrastim P = NS 25 20 15 10 5 0 Pegfilgrastim P <0.05 P = 0.029 Filgrastim 20 19 18 13 11 Incidence of FN (%) 9 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;20:727-731; †Green M, et al. Ann Oncol. In press

  17. Pegfilgrastim shows a 71% relative reduction in FN incidence † 40 38% 30 50% 71% Incidence of FN (Percentage patients) 19%* 20 42% 11%* 10 0 Pegfilgrastim Filgrastim No G-CSF Adapted from *Siena S, et al. ESMO 2002. †Misset J, et al. Ann Oncol. 1999;10:553-560.

  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 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% 75% 74% Adapted from Holmes F, et al. J Clin Oncol. 2002;20:727-731.

  20. Filgrastim Vs. Pegfilgrastim Filgrastim 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/m2Bleomycin 10 units/m2 Vinblastine 6 mg/m2 Dacarbazine 375 mg/m2 Pegfilgrastim 6 mg Repeat every14 days Day 1 2 Younes, A. et al. (ASH 2005)

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

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

  24. Single-arm phase 2 trial in 34 patients with low-, intermediate-, orhigh-grade NHL 29 subjects eligible for analysis 1 3 4 2 Phase 2 Study of RCHOP-14 + Pegfilgrastim in Subjects With NHL CHOP Cyclophosphamide 750 mg/m2 Doxorubicin 50 mg/m2 Vincristine 1.4 mg/m2 Prednisone 100 mg/d  5 Pegfilgrastim 6 mg Rituximab 375 mg/m2 Repeat every14 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 1 2 Day • 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 Rituximab375mg/m2 Pegfilgrastim 6 mg single dose CHOP Cyclophosphamide 750 mg/m2 Doxorubicin 50 mg/m2 Vincristine 1.4 mg/m2 Prednisone 100 mg/d  5 or Filgrastim5 µg/kg/d Repeat every14 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) 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 60 Patients(%) 40 20 0 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 NHL 94 93 Cycles (%) (n= 137 cycles) (n= 175 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) 1 2 3 4 5 6 - 16 Day

  34. 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)

  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) P < 0.0001 (N=50) Median EFS = 21 mo (N=21) EFS = 2 mo

  37. Taxol + Topotecan + PegFilgrastim (Neulastim) ANC: Cycle#1 Taxol + Topo + PegGCSFTaxol + Topo + GCSF N = 7 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 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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