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Lyman_Reiner_Morrow_Crawford_annalsApril2015

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Lyman_Reiner_Morrow_Crawford_annalsApril2015

  1. 1. 1 © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. The Effect of Filgrastim or Pegfilgrastim on Survival Outcomes of Patients With Cancer Receiving Myelosuppressive Chemotherapy G. H. Lyman1,* , M. Reiner2 , P. K. Morrow3 , J. Crawford4 1 Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center and the Department of Medicine, University of Washington, Seattle, WA, USA 2 Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA 3 Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA 4 Department of Medicine, Duke University School of Medicine, and Duke Cancer Institute, Durham, NC, USA * Correspondence to: Dr. Gary H. Lyman, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3- B232, Seattle, WA 98109-1024, USA; phone: +1 206-667-6670; fax: +1 206-667-5977; email: glyman@fhcrc.org Annals of Oncology Advance Access published April 7, 2015
  2. 2. 2 ABSTRACT Background: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. Patients and methods: Three placebo-controlled and two noninferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. Median OS, 6- and 12-month survival rates, and hazard ratios (HRs; unadjusted Cox model with 95% confidence intervals [CIs]) were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. Results: In patients with lung cancer receiving filgrastim versus placebo, median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI, 0.48–1.35; P=0.412); in patients who crossed over to filgrastim from placebo after cycle 1, median OS was 16.9 months (HR, 0.75; 95% CI, 0.43–1.28; P=0.286). Median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-
  3. 3. 3 controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58–1.03). Conclusions: In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. Abstract word count: 287 (limit, 300) Clinical trial registration: NCT00035594, NCT00094809 Keywords: pegfilgrastim, filgrastim, G-CSF, overall survival, neutropenia Key message: In this analysis of registrational clinical trials of filgrastim and pegfilgrastim, patients with cancer receiving myelosuppressive chemotherapy with prophylactic G-CSF support had greater OS point estimates compared with placebo, and the hazard ratio for OS was <1 in a meta-analysis of the placebo-controlled studies in favor of G-CSF vs placebo. The results were not statistically significant.
  4. 4. 4 Introduction Severe neutropenia (SN) and febrile neutropenia (FN) are dose-limiting toxicities of myelosuppressive chemotherapy that may lead to chemotherapy dose delays or dose reductions [1-3]. Prophylactic granulocyte colony-stimulating factor (G-CSF) therapy has been shown to reduce the incidence of SN and FN in patients receiving chemotherapy for nonmyeloid malignancies and has been associated with increased chemotherapy relative dose intensity (RDI) compared with the absence of G-CSF support [4-9]. Retrospective analyses of randomized controlled trials (RCTs) have shown an association between higher chemotherapy RDI and improved outcomes in patients receiving cytotoxic chemotherapy [10, 11]. A recent meta-analysis of RCTs assessing G-CSF primary prophylaxis in patients receiving myelosuppressive chemotherapy demonstrated a reduction in all-cause mortality among patients receiving G-CSF support [12]; however, the effect of G-CSF primary prophylaxis on overall survival (OS) has not been well characterized in clinical trials. This retrospective analysis assessed the effect of G-CSF primary prophylaxis on OS in patients receiving myelosuppressive chemotherapy and filgrastim, pegfilgrastim, or placebo in five registrational RCTs for which outcome data were available [5-9]. Methods Studies and patients An overview of the five registrational RCTs is presented in Table 1. The placebo- controlled trials were a phase 3 trial of filgrastim in small cell lung cancer (SCLC) [5], a phase 3 trial of pegfilgrastim in breast cancer (NCT00035594) [6], and a phase 2 trial of
  5. 5. 5 pegfilgrastim in colorectal cancer (NCT00094809) [7]. Two phase 3 noninferiority trials compared pegfilgrastim with filgrastim in breast cancer (referred to as noninferiority study 1 [8] and noninferiority study 2 [9]). Calculation of summary statistics for exposure to pegfilgrastim/filgrastim was based on the total dose for each patient over four cycles of chemotherapy (pegfilgrastim dose = single dose × 4; filgrastim dose = single dose × days of dosing × 4). Similarly, the tabulation of the number of doses reflects the total number of doses received by a patient in four cycles. For patients who crossed over from placebo to G-CSF after cycle 1, summary statistics for exposure and the total number of doses were calculated based on a maximum of three cycles. Meta-analysis of OS from Cox proportional hazard (PH) models in the three placebo- controlled trials was performed using a fixed-effect model; no measurable heterogeneity was detected (I2 = 0%). Results of the meta-analysis at the level of individual patient data (IPD) with a stratified Cox PH model were identical. Data collection and analysis The original publications of the placebo-controlled registrational trials reported OS/deaths for the intent-to-treat (ITT) analysis set. In this analysis, the treatment arms for OS/deaths were determined by the treatment actually received (as-treated set). Exposure to pegfilgrastim/filgrastim and OS are reported separately for patients who crossed over from placebo to G-CSF according to study design. The meta-analysis of the three placebo-controlled trials used the as-treated analysis sets.
  6. 6. 6 Incidence of severe neutropenia and febrile neutropenia Severe neutropenia was defined as grade 3/4 neutropenia (absolute neutrophil count [ANC] <1.0 × 109 cells/L) or grade 4 neutropenia (ANC <0.5 × 109 cells/L). Febrile neutropenia was defined as a temperature ≥38.2ºC with ANC <1.0 × 109 cells/L [5, 7] or ANC <0.5 × 109 cells/L [6, 8, 9] on the same day [5-9] or the day after [6, 7] completion of chemotherapy. The incidence and duration of SN and FN were evaluated for the safety analysis set in the placebo-controlled studies. Differences between the G-CSF and placebo arms in the incidence of SN and FN were evaluated by calculating the relative risk (RR), where RR <1.0 indicated a lower event rate for the G-CSF arm versus the placebo arm; P values were calculated using the chi-square test. The incidence of SN and FN was assessed only in cycle 1 because patients randomized to placebo in the lung and breast cancer studies who developed FN could cross over after cycle 1 to receive open-label filgrastim or pegfilgrastim, respectively [5, 6]. Blood collection for the assessment of ANC was performed 3 days per week in the lung cancer study [5], allowing reliable estimates of the duration of neutropenia. Because blood was collected only once per week in the breast and colorectal cancer studies [6, 7], duration of neutropenia could not be assessed. Antibiotic use Differences in intravenous and oral antibiotic use for any cause between the G-CSF and placebo arms were evaluated by calculating RR, where RR <1.0 indicated a lower use rate for the G-CSF arm relative to the placebo arm; P values were based on the chi- square test. Deaths by extent of disease were summarized descriptively.
  7. 7. 7 Overall survival Kaplan-Meier estimates of OS (the time from study day 1 until death) and 6- and 12- month survival rates (where estimable) were compared between arms using an unadjusted log-rank test. Maximum follow-up time on the phase 3 breast cancer trial [6] was 159 days, insufficient to estimate 6- and 12-month survival. Median survival time was not reached for the two noninferiority trials. Unadjusted Cox PH models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A fixed-effect, study-level meta-analysis was performed to estimate OS among the three placebo- controlled trials. In the absence of heterogeneity, the results from the IPD analysis (stratified on study) were identical. Results Cycle 1 incidence of severe neutropenia and febrile neutropenia In the ITT analysis sets of the three placebo-controlled studies, the incidence of grade 3/4 neutropenia in cycle 1 was significantly lower among patients receiving G-CSF versus placebo (Table 2). The incidences of grade 3/4 and grade 4 neutropenia were significantly lower among patients in the lung cancer study receiving filgrastim versus placebo (P=0.0014 and P=0.0001, respectively), as was the incidence of FN (P<0.001). Likewise, the incidences of grade 3/4 and grade 4 neutropenia were significantly lower among patients in the breast cancer study receiving pegfilgrastim versus placebo (both P<0.0001), as was the incidence of FN (P<0.001). In the colorectal cancer study, the incidence of grade 3/4 neutropenia was significantly lower among patients receiving pegfilgrastim versus placebo (P=0.0027).
  8. 8. 8 Cycle 1 antibiotic use Oral and intravenous antibiotic use (any cause) in cycle 1 was significantly reduced among patients in the lung cancer study receiving filgrastim versus placebo (P=0.0048) and among patients in the breast cancer study receiving pegfilgrastim versus placebo (P=0.0007; Table 2). The difference in antibiotic use in the colorectal cancer study, however, was not statistically significant (P=0.580). Exposure to G-CSF and chemotherapy Across all studies, the median exposure (mg) to pegfilgrastim or filgrastim was similar (Table 3). In the two placebo-controlled trials, in which crossover from placebo to G- CSF was allowed by study design [5, 6], the median exposure (mg and number of doses) was similar and consistent among patients receiving G-CSF for a total of four cycles beginning in cycle 1 and patients who crossed over from placebo and received G- CSF for a total of three cycles beginning in cycle 2. In the noninferiority studies [8, 9], mean exposure was higher in pegfilgrastim treatment arms compared with filgrastim treatment arms. The studies included in this analysis reported limited information on chemotherapy RDI, with no information on dose reductions or delays reported in the placebo-controlled lung cancer study or the first noninferiority breast cancer study [5, 9]. In the placebo- controlled trial in colorectal cancer [7], a nonsignificant difference in the incidence of chemotherapy dose delays or reductions was observed between patients receiving pegfilgrastim versus placebo (33.4% vs 45%; P=0.06). In the placebo-controlled trial in breast cancer [6], 80% and 78% of patients in the pegfilgrastim and placebo groups, respectively, received their planned chemotherapy dose on time; these results were expected because patients who developed FN then crossed over to pegfilgrastim. The
  9. 9. 9 second noninferiority breast cancer study reported similar chemotherapy dose administration between the filgrastim and pegfilgrastim arms, with 90% of patients receiving chemotherapy according to the planned schedule [8]. Overall survival and 6- and 12-month survival There were generally fewer OS events among patients receiving G-CSF versus placebo in the placebo-controlled studies; there were generally fewer OS events among patients receiving pegfilgrastim versus filgrastim in the noninferiority studies (Table 4; Figure 1). In the lung cancer study, the point estimate for median OS was 3 months longer among patients receiving filgrastim only versus placebo only, but the difference was not statistically significant (P=0.412 for HR). Among patients in the placebo arm receiving open-label filgrastim after cycle 1 as a result of FN, the point estimate for median OS was almost 6 months longer versus placebo only, but the difference was not statistically significant (P=0.286 for HR). In the other studies, median OS could not be estimated because of the small number of OS events. To evaluate the relationship between G-CSF primary prophylaxis and survival, a fixed effect model meta-analysis of the placebo-controlled studies was performed. In the as- treated analysis sets comparing G-CSF primary prophylaxis with placebo, the HR (95% CI) for OS was 0.77 (0.58–1.03). In the placebo-controlled studies, where estimable, 6- and 12-month survival rates were generally higher among patients receiving G-CSF (beginning in cycle 1 or cycle 2) versus placebo (Table 4). In the noninferiority studies, 6- and 12-month survival rates, where estimable, were comparable among patients receiving pegfilgrastim versus filgrastim.
  10. 10. 10 Discussion Chemotherapy-induced FN can often result in chemotherapy dose delays or dose reductions, which may result in reduced chemotherapy RDI and compromised outcomes [13-16]. Meta-analyses and pooled analyses have provided some evidence of an association between G-CSF primary prophylaxis and improved survival in patients receiving myelosuppressive chemotherapy [4, 12, 17]. In this retrospective analysis of RCTs of filgrastim and pegfilgrastim [5-7], patients receiving G-CSF primary prophylaxis had greater median OS point estimates and greater 6- and 12-month survival rates versus placebo, but the benefits were not statistically significant. Similar nonsignificant increases in the median OS point estimate and 6- and 12-month survival rates were seen among patients with SCLC who were randomized to placebo but then crossed over to open-label filgrastim after experiencing FN during cycle 1. In the fixed-effect meta- analysis of the placebo-controlled studies (Cox PH model with no heterogeneity), the HR for OS was <1 in favor of G-CSF primary prophylaxis compared with placebo; although the result was not statistically significant, it may be considered hypothesis generating. In contrast with the original reports of the registrational studies [5-9], this analysis assessed OS data from patients in the as-treated analysis data set rather than the ITT data set to ensure that the OS estimate reflected the actual treatment received by patients. Results of our survival analysis are consistent with those in previous reports [4, 12, 17, 18]. In a meta-analysis of RCTs (N=59), patients receiving G-CSF primary prophylaxis with myelosuppressive chemotherapy had reduced mortality risk versus patients without G-CSF support (RR, 0.93; P<0.001) [12]. In an earlier meta-analysis of 17 RCTs, patients receiving primary prophylaxis with filgrastim, pegfilgrastim, or lenograstim had lower risk of infection-related mortality (RR, 0.55; P=0.018) and early mortality during chemotherapy treatment (RR, 0.60; P=0.002) versus patients without G-
  11. 11. 11 CSF support [4]. Evidence of improved survival has also been observed with G-CSF prophylaxis in patients receiving myelosuppressive chemotherapy for myeloid malignancies [17, 18]. Notably, a higher 5-year survival rate was observed with primary prophylaxis with filgrastim or lenograstim versus no prophylaxis in a subgroup of patients with acute lymphoblastic leukemia (44% versus 27%; P=0.03) [17]. Additionally, patients receiving filgrastim or pegfilgrastim prophylaxis during the first cycle (P=0.018) or any cycle (P=0.04) of chemotherapy for acute myeloid leukemia survived longer than patients who did not receive prophylaxis [18]. Collectively, our retrospective analysis and these studies provide evidence that G-CSF primary prophylaxis may improve OS in patients receiving myelosuppressive chemotherapy. In all three placebo-controlled studies, exposure to G-CSF was generally similar between active treatment arms, and the incidence of grade 3/4 neutropenia in cycle 1 was significantly lower among patients receiving G-CSF compared with those receiving placebo. The incidences of grade 4 neutropenia, FN, and antibiotic use in cycle 1 were also lower in the G-CSF arms of the placebo-controlled studies, but the differences were not statistically significant in the colorectal cancer study. The apparent treatment effect of G-CSF primary prophylaxis was likely reduced in the placebo-controlled SCLC [5] and breast cancer [6] studies, which allowed patients in the placebo arm to cross over to secondary prophylaxis with G-CSF after cycle 1 as a result of FN. This crossover design limited the ability to evaluate the impact of G-CSF on survival outcomes in these trials. This analysis had several limitations. First, the number of OS events was small, and the studies were neither designed nor powered to assess OS [5-9]. Second, patients who crossed over from the placebo arm to the G-CSF arm in cycle 2 did so after experiencing FN in cycle 1 and cannot be assumed to have the same risk of FN as patients who
  12. 12. 12 remained on the assigned therapy. In the lung cancer study, OS in the placebo-only arm may have been shortened by early deaths/withdrawals compared with the crossover arm in which patients survived to receive subsequent therapy. Third, follow-up time was not equivalent among the studies (60–240 days in the placebo-controlled breast cancer study and noninferiority study 1 versus 900–1000 days in the other studies). Fourth, the studies differed in the tumor types and chemotherapy regimens and in how and when neutropenia was assessed. Lastly, because of limited availability of data, we were not able to determine in this analysis if patients receiving G-CSF experienced fewer chemotherapy dose delays or higher RDIs that may have correlated with improved outcomes. Despite these limitations, many of which were likely to bias against the G- CSF-containing arm, point estimates for OS were greater among patients receiving G- CSF primary prophylaxis compared with placebo. However, the differences were not statistically significant. Current guidelines recommend initiating primary prophylaxis with G-CSF in patients at high risk for FN in the first chemotherapy cycle or when needed for the on-time delivery of full-dose chemotherapy [19-22]. Secondary prophylaxis is less desirable because many patients may experience neutropenic complications before receiving G-CSF support. Prospective assessment of the effects of G-CSF primary prophylaxis on long- term outcomes in patients with cancer receiving myelosuppressive chemotherapy is warranted.
  13. 13. 13 Acknowledgments The authors acknowledge James Balwit, MS, and Benjamin Scott, PhD, whose work was funded by Amgen Inc., for assistance in writing this manuscript. Funding This study was funded by Amgen Inc. There were no grants or applicable grant numbers for this study. Disclosures GHL is the primary investigator on a research grant from Amgen Inc. to the Fred Hutchinson Cancer Research Center. MR and PKM are employees of and own stock in Amgen Inc. JC has served as a consultant for and has received research funding from Amgen Inc.
  14. 14. 14 References 1. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol 2003; 21: 4524-4531. 2. Lyman GH, Dale DC, Friedberg J et al. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study. J Clin Oncol 2004; 22: 4302-4311. 3. Lyman GH. Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 2006; 20: 16-25. 4. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007; 25: 3158-3167. 5. 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: 164-170. 6. Vogel CL, Wojtukiewicz MZ, Carroll RR et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 2005; 23: 1178-1184. 7. Hecht JR, Pillai M, Gollard R et al. A randomized, placebo-controlled phase II study evaluating the reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving pegfilgrastim with every-2-week chemotherapy. Clin Colorectal Cancer 2010; 9: 95-101.
  15. 15. 15 8. Green MD, Koelbl H, Baselga J et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003; 14: 29-35. 9. 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: 727-731. 10. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 2009; 7: 99-108. 11. Lyman G, Poniewierski M, Wogu A et al. Association of survival with chemotherapy intensity, myelosuppression, and supportive care in patients with advanced solid tumors. J Clin Oncol 2013; 31: 6534. 12. Lyman GH, Dale DC, Culakova E et al. The impact of the granulocyte colony- stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol 2013; 24: 2475-2484. 13. Budman DR, Berry DA, Cirrincione CT et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998; 90: 1205-1211. 14. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 1990; 8: 963-977.
  16. 16. 16 15. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995; 332: 901-906. 16. Lepage E, Gisselbrecht C, Haioun C et al. Prognostic significance of received relative dose intensity in non-Hodgkin's lymphoma patients: application to LNH- 87 protocol. The GELA. (Groupe d'Etude des Lymphomes de l'Adulte). Ann Oncol 1993; 4: 651-656. 17. Giebel S, Thomas X, Hallbook H et al. The prophylactic use of granulocyte- colony stimulating factor during remission induction is associated with increased leukaemia-free survival of adults with acute lymphoblastic leukaemia: a joint analysis of five randomised trials on behalf of the EWALL. Eur J Cancer 2012; 48: 360-367. 18. Bradley AM, Deal AM, Buie LW, van Deventer H. Neutropenia-associated outcomes in adults with acute myeloid leukemia receiving cytarabine consolidation chemotherapy with or without granulocyte colony-stimulating factor. Pharmacotherapy 2012; 32: 1070-1077. 19. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187-3205. 20. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, version 2.2014. Available at: http://www.NCCN.org. Accessed February 2, 2015. 21. Crawford J, Caserta C, Roila F, Esmo Guidelines Working Group. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol 2010; 21: v248-v251.
  17. 17. 17 22. Aapro MS, Bohlius J, Cameron DA et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011; 47: 8-32.
  18. 18. 18 Figure Legend Figure 1. Kaplan-Meier curves for median overall survival in the safety analysis set for (A) the phase 3 small cell lung cancer study, (B) the phase 3 breast cancer study, (C) the phase 2 colorectal cancer study, (D) noninferiority study 1 (phase 3 breast cancer), and (E) noninferiority study 2 (phase 3 breast cancer). Patients randomized to placebo were allowed to cross over to receive open-label filgrastim (A) or pegfilgrastim (B) as a result of febrile neutropenia during cycle 1. Note: The duration of follow-up differs among the studies.
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  24. 24. Table 1. Overview of Study Designs in Registrational Trials of Filgrastim and Pegfilgrastim Study Design Primary Endpoint Chemotherapy Regimen G-CSF Dosing Phase 3 SCLC [5] (N=211) Double-blind, randomized, placebo- controlled FN (temperature ≥38.2°C with ANC <1.0 × 109 cells/L) Cyclophosphamide, doxorubicin, etoposide Filgrastim 230 μg/m2 daily up to 14 days per cycle Phase 3 breast [6] (N=928) Double-blind, randomized, placebo- controlled FN (temperature ≥38.2°C with ANC <0.5 × 109 cells/L on same day or 1 day after fever) Docetaxel Pegfilgrastim 6 mg once per cycle Phase 2 CRC [7] (N=252) Double-blind, randomized, placebo- controlled Incidence of grade 3/4 neutropenia (ANC <1.0 × 109 cells/L) FOLFOX4, FOLFIRI, or FOIL Pegfilgrastim 6 mg per cycle Noninferiority 1: phase 3 breast [8] (N=157) Double-blind, randomized, noninferiority Duration of grade 4 neutropenia (ANC <0.5 × 109 cells/L) in cycle 1 Doxorubicin, docetaxel Pegfilgrastim 6 mg/kg once per cycle or filgrastim 5 μg/kg daily Noninferiority 2: phase 3 breast [9] (N=310) Double-blind, randomized, noninferiority Duration of grade 4 neutropenia (ANC <0.5 × 109 cells/L) in cycle 1 Doxorubicin, docetaxel Pegfilgrastim 100 μg/kg once per cycle or filgrastim 5 μg/kg daily ANC=absolute neutrophil count; CRC=colorectal cancer; FN=febrile neutropenia; FOIL=5-fluorouracil (5-FU), oxaliplatin, irinotecan, leucovorin; FOLFIRI=5-FU, leucovorin, irinotecan; FOLFOX4=5-FU, leucovorin, oxaliplatin; G-CSF=granulocyte colony-stimulating factor; SCLC=small cell lung cancer.
  25. 25. Table 2. Incidence of Neutropenia and Antibiotic Use in the Safety Analysis Set During Cycle 1 (ITT Analysis) Study Grade 3/4 Neutropenia,a n/N (%) Grade 4 Neutropenia,b n/N (%) Febrile Neutropenia, n/N (%) Antibiotic Use,c n/N (%) Phase 3 SCLC [5] (N=211) Filgrastim Placebo 84/93 (90.3) 101/101 (100) RR, 0.90 (95% CI, 0.85–0.97) P=0.0014 78/93 (83.9) 100/101 (99.0) RR, 0.85 (95% CI, 0.77–0.93) P=0.0001 28/92 (30.4) 57/102 (55.9) RR, 0.54 (95% CI, 0.38–0.78) P<0.001 44/100 (44.0) 68/107 (63.6) RR,d 0.69 (95% CI, 0.53–0.90) P=0.0048e Phase 3 breast [6] (N=928) Pegfilgrastim Placebo 39/467 (8.4) 358/461 (77.7) RR, 0.11 (95% CI, 0.08–0.15) P<0.0001 24/467 (5.1) 260/461 (56.4) RR, 0.09 (95% CI, 0.06–0.14) P<0.0001 2/467 (<1) 52/461 (11.3) RR, 0.04 (95% CI, 0.01–0.15) P<0.001 56/467 (12.0) 93/461 (20.2) RR,d 0.59 (95% CI, 0.44–0.81) P=0.0007 Phase 2 CRC [7] (N=252) Pegfilgrastim Placebo 5/124 (4.0) 18/117 (15.4) RR, 0.26 (95% CI, 0.10–0.68) P=0.0027 4/124 (3.2) 6/117 (5.1) RR, 0.63 (95% CI, 0.18–2.17) P=0.4592 1/124 (<1) 2/117 (1.7) RR, 0.47 (95% CI, 0.04–5.13) P=0.552 16/124 (12.9) 18/117 (15.4) RR,d 0.84 (95% CI, 0.45–1.57) P=0.580 ANC=absolute neutrophil count; CI=confidence interval; CRC=colorectal cancer; G-CSF=granulocyte colony-stimulating factor; ITT=intent-to-treat; RR=relative risk; SCLC=small cell lung cancer. a Grade 3/4 = ANC <1000 cells/mm3 . b Grade 4 = ANC <500 cells/mm3 .
  26. 26. c Includes all intravenous and oral antibiotic use. d RR <1.0 indicates a lower event rate for the G-CSF arm relative to the placebo arm. e P value based on the chi-square test.
  27. 27. Table 3. Exposure to Pegfilgrastim/Filgrastim and Baseline Disease Characteristics in the Safety Analysis Set By Study Study Patients Treated, n Exposure to G-CSF, mg G-CSF Doses, n Baseline Disease Stage, % Phase 3 SCLC [5] Filgrastim only (n=100) 100 Median, 23.5 Range, 1.1–60.4 Median, 65 Range, 3.0–126 Limited: 27 Extensive: 73 Placebo then filgrastima (n=73) 73 Median, 18.6 Range, 3.0–26.1 Median, 50 Range, 11–71 Limited: 29 Extensive: 71 Placebo only (n=34) 34 NA NA Limited: 23 Extensive: 77 Phase 3 breast [6] Pegfilgrastim only (n=467) 467 Median, 24.0 Range, 6.0–36.0 Median, 4.0 Range, 1.0–4.0 Nonmetastatic: 19 Metastaticb : 81 Placebo then pegfilgrastima (n=89) 89 Median, 18.0 Range, 6.0–18.0 Median, 3.0 Range, 1.0–3.0 Nonmetastatic: 9 Metastatic: 91 Placebo only (n=465) 372 NA NA Nonmetastatic: 18 Metastaticb : 82 Phase 2 CRC [7] Pegfilgrastim (n=126) 124 Mean, 21.5 SD, 5.4 Median, 24.0 Range, 6.0–24.0 Stage 2: 0.8 Stage 3: 0.8 Stage 4: 95 Not assessed: 3
  28. 28. Placebo only (n=126) 117 NA NA Stage 2: 0 Stage 3: 1.6 Stage 4: 97 Not assessed: 1.6 Noninferiority 1: phase 3 breast [8] Pegfilgrastim (n=80) 79 Mean, 23.5 SD, 2.5 Mean, 3.9 SD, 0.4 Stage 2: 25 Stage 3: 27 Stage 4: 48 Filgrastim (n=77) 76 Mean, 15.0 SD, 4.1 Mean, 41.5 SD, 8.2 Stage 2: 31 Stage 3: 27 Stage 4: 43 Noninferiority 2: phase 3 breast [9] Pegfilgrastim (n=154) 150 Mean, 29.1 SD, 9.5 Mean, 3.8 SD, 0.7 Stage 2: 49 Stage 3: 26 Stage 4: 25 Filgrastim (n=156) 151 Mean, 15.5 SD, 4.4 Mean, 41.0 SD, 8.7 Stage 2: 56 Stage 3: 25 Stage 4: 19 CRC=colorectal cancer; G-CSF=granulocyte colony-stimulating factor; NA=not applicable; SCLC=small cell lung cancer; SD=standard deviation. a Patients randomized to placebo who crossed over to receive open-label filgrastim/pegfilgrastim as a result of febrile neutropenia during cycle 1. b Stages 3 and 4 combined.
  29. 29. Table 4. Kaplan-Meier Estimates of Overall Survival and 6- and 12-Month Survival Rates in the Safety Analysis Seta,b Study Events, n/N (%) Censored,c n/N (%) Median OS, mo (95% CI) 6-Month Survival, % (95% CI) 12-Month Survival, % (95% CI) Unadjusted HR (95% CI) Phase 3 SCLC [5] Filgrastim only 52/100 (52.0) 48/100 (48.0) 14.1 (10.6–NE) 87.0 (80.4–93.6) 55.0 (45.2–64.8) 0.81 (0.48–1.35) P=0.412 Placebo then filgrastimd 39/73 (53.4) 34/73 (46.6) 16.9 (13.0–NE) 91.8 (85.5–98.1) 67.1 (56.3–77.9) 0.75 (0.43–1.28) P=0.286 Placebo only 20/34 (58.8) 14/34 (41.2) 11.1 (9.0–NE) 76.5 (62.2–90.7) 44.1 (27.4–60.8) Reference Phase 3 breast [6] Pegfilgrastim only 5/467 (1.1) 462/467 (98.9) NE NE NE 0.40 (0.14–1.17) P=0.094 Placebo then pegfilgrastimd 4/89 (4.5) 85/89 (95.5) NE NE NE 1.62 (0.51–5.17) P=0.414 Placebo only 10/372 (2.7) 362/372 (97.3) NE NE NE Reference Phase 2 CRC [7] Pegfilgrastime 47/124 (37.9) 77/124 (62.1) NE (19.0–NE) 88.6 (82.8–94.5) 80.0 (72.5–87.5) 0.81 (0.54–1.20) P=0.292 Placebo 50/117 (42.7) 67/117 (57.3) 24.8 (19.0–NE) 85.7 (79.0–92.4) 72.0 (63.1–80.8) Reference Noninferiority 1: phase 3 breast [8] Pegfilgrastim 2/79 (2.5) 77/79 (97.5) NE 97.4 (93.8–100) NE NE P=0.608 Filgrastim 3/76 (3.9) 73/76 (96.1) NE 94.6 (88.2–100) NE Reference
  30. 30. Noninferiority 2: phase 3 breast [9] Pegfilgrastim 18/150 (12.0) 132/150 (88.0) NE 98.6 (96.8–100) 94.4 (90.7–98.2) NE P=0.092 Filgrastim 30/151 (19.9) 121/151 (80.1) 32.8 (NE–NE) 97.3 (94.7–99.9) 94.6 (90.9–98.2) Reference CI=confidence interval; CRC=colorectal cancer; HR=hazard ratio; NE=not estimable; OS=overall survival; SCLC=small cell lung cancer. a Median survival = NE because number of events insufficient to reach the median. b Estimates of 6- and 12- month survival = NE because of insufficient time on study. c Patients who had not died at the time of the analysis were censored at the date they were last known to be alive. d Patients randomized to placebo who crossed over to receive open-label filgrastim/pegfilgrastim after cycle 1 as a result of febrile neutropenia. e Includes three patients randomized to placebo who crossed over to receive open-label filgrastim/pegfilgrastim after cycle 1 as a result of febrile neutropenia.

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