Original Contribution
`
`Pegfilgrastim on the Same Day Versus Next Day of
`Chemotherapy in Patients With Breast Cancer, Non–Small-Cell
`Lung Cancer, Ovarian Cancer, and Non-Hodgkin’s Lymphoma:
`Results of Four Multicenter, Double-Blind, Randomized Phase
`II Studies
`
`By Howard A. Burris III, MD, FACP, Chandra P. Belani, MD, Peter A. Kaufman, MD, Alan N. Gordon, MD,
`Lee S. Schwartzberg, MD, Warren S. Paroly, MD, Seta Shahin, MS, Lyndah Dreiling, MD,
`and Alan Saven, MD
`
`Sarah Cannon Research Institute, Nashville; West Clinic, Memphis, TN; Penn State Cancer Institute, Hershey, PA; Norris
`Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH; M. D. Anderson Cancer Center at Orlando,
`Orlando, FL; North County Oncology Medical Clinic, Oceanside; Amgen, Thousand Oaks; and Ida M. and Cecil H. Green
`Cancer Center, Scripps Clinic, La Jolla, CA
`
`Abstract
`Purpose: To compare data on severe (grade 4) neutropenia
`duration and febrile neutropenia incidence in patients receiving
`chemotherapy with pegfilgrastim administered the same day or
`24 hours after chemotherapy.
`
`Patients and Methods: These were similar, randomized,
`double-blind phase II noninferiority studies of patients with lym-
`phoma or non–small-cell lung (NSCLC), breast, or ovarian can-
`cer. Each study was analyzed separately. The primary end point
`in each study was cycle-1 severe neutropenia duration. Approx-
`imately 90 patients per study were to be randomly assigned at a
`ratio of 1:1 to receive pegfilgrastim 6 mg once per cycle on the
`day of chemotherapy or the day after (with placebo on the alter-
`nate day).
`
`equate number of patients for analysis. However, in the NSCLC
`study, the neutropenic rate was lower than expected (only two
`patients per arm experienced grade 4 neutropenia). In the breast
`cancer study, the mean cycle-1 severe neutropenia duration was
`1.2 days (95% confidence limit [CL], 0.7 to 1.6) longer in the
`same-day compared with the next-day group (mean, 2.6 v 1.4
`days). In the lymphoma study, the mean cycle-1 severe neutro-
`penia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the
`same-day compared with the next-day group (mean, 2.1 v 1.2
`days). In the breast and lymphoma studies, the absolute neutro-
`phil count profile for same-day patients was earlier, deeper, and
`longer compared with that for next-day patients, although the
`results indicate that same-day administration was statistically
`noninferior to next-day administration according to neutropenia
`duration.
`
`Results:
`In four studies, 272 patients received chemotherapy
`and one or more doses of pegfilgrastim (133 same day, 139 next
`day). Three studies (breast, lymphoma, NSCLC) enrolled an ad-
`
`Conclusion: For patients receiving pegfilgrastim with chemo-
`therapy, pegfilgrastim administered 24 hours after chemother-
`apy completion is recommended.
`
`Introduction
`A major dose-limiting toxicity of chemotherapy is neutropenia.
`Infection resulting from neutropenia manifested as febrile neutro-
`penia (FN) can lead to hospitalization, morbidity, and mortality
`in as many as 10% of patients.1,2 Filgrastim is a recombinant
`growth factor that decreases the incidence, duration, and sever-
`ity of neutropenia and minimizes infection—as manifested by
`FN3,4— by stimulating the proliferation, differentiation, and
`activation of the neutrophil lineage, thereby reducing neutro-
`phil maturation time.5 Neulasta (pegfilgrastim; Amgen, Thou-
`sand Oaks, CA), produced by covalently binding a 20-kd
`polyethylene glycol molecule to the N-terminus of filgrastim,
`represents an improvement over filgrastim. Compared with fil-
`grastim, pegfilgrastim has a similar mechanism of action but a
`longer-acting effect, allowing patients to be injected only once
`per chemotherapy cycle compared with 10 to 11 days of filgras-
`tim.6,7 Pegfilgrastim is indicated to lower infection incidence, as
`manifested by FN, when administered once per cycle 24 hours
`after chemotherapy.8
`
`Although millions of patients have received these growth
`factors, it is recognized that eliminating an office visit the day
`after chemotherapy would be desirable for patients, their fam-
`ilies, and medical providers. Administration of filgrastim or
`pegfilgrastim within 24 hours before or after chemotherapy is
`not currently recommended because of the theoretical potential
`for increasing chemotherapy toxicity to myeloid progenitor
`cells after growth factor stimulation. Two studies observed a
`worsening in the incidence and/or duration of grade 4 neutro-
`penia in patients receiving 5 consecutive days of overlapping
`fluorouracil or topotecan with filgrastim.9,10 However, other
`studies have not reported increased myelosuppression when fil-
`grastim was administered the day preceding, or concurrent
`with, cell-cycle–specific chemotherapies.11-15 Interest in the
`same-day dosing schedule persists, highlighted recently in an
`article challenging the “24-hour mandate.”16
`To evaluate this dosing schedule, four tumor-specific studies
`were designed to assess the safety and efficacy of pegfilgrastim
`administered concurrently with chemotherapy. The malignan-
`cies chosen for evaluation— breast cancer, non-Hodgkin’s lym-
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`M A Y 2010
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`•
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`

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`
`
`Burris et alBurris et al
`
`Table 1. Key Study Information
`
`Characteristic
`
`Breast Cancer Study
`
`NHL Study
`
`NSCLC Study
`
`Ovarian Cancer Study
`
`Docetaxel 75 mg/m2;
`doxorubicin 50 mg/m2;
`cyclophosphamide 500
`mg/m2
`
`Stage II or III v stage IV
`
`Rituximab 375 mg/m2;
`cyclophosphamide 750 mg/m2;
`doxorubicin 50 mg/m2; vincristine
`1.4 mg/m2; prednisone 100 mg
`(days 1-5)
`
`Mantle-cell v diffuse large B-cell
`lymphoma
`
`14
`
`24
`
`None
`
`22
`
`Carboplatin AUC 6; docetaxel
`75 mg/m2
`
`Topotecan 1.5 mg/m2
`administered days 1-5 of
`each cycle
`
`One v two prior
`chemotherapy regimens for
`ovarian cancer
`
`10
`
`Histologically confirmed
`primary peritoneal,
`epithelial, or tubal ovarian
`cancer relapsed after, or
`refractory to, one or two
`prior regimens
`
`GOG 0 to 2
`
`No prior topotecan
`
`Chemotherapy
`
`Randomization
`stratification
`
`No. of sites
`
`Eligibility criteria
`
`Disease and stage
`
`Diagnostically confirmed
`stage IV or histologically
`confirmed stage II or III
`breast cancer
`
`Histologically proven mantle-cell
`lymphoma or diffuse large B-cell
`NHL (using REAL classification),
`Ann Arbor stage II, III, or IV
`
`Histologically or cytologically
`confirmed stage IIIb (with
`pleural effusion) or stage IV
`NSCLC
`
`Performance status
`
`ECOG 0 to 2
`
`ECOG 0 to 2
`
`Prior chemotherapy
`
`Stage II or III: untreated
`
`None allowed
`
`ECOG 0 to 2
`
`None allowed
`
`Stage IV: prior anthracycline
`ⱕ 300 mg/m2 and ⱖ 30
`days since anthracycline
`or herceptin
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; NSCLC, non–small-cell lung cancer; AUC, area under the curve; REAL, Revised European American Lymphoma
`Classification; ECOG, Eastern Cooperative Oncology Group; GOG, Gynecologic Oncology Group.
`
`phoma (NHL), non–small-cell lung cancer (NSCLC), and
`ovarian cancer— comprise 42% of cancer deaths.17
`
`Patients and Methods
`Patients
`The institutional review boards of participating centers ap-
`proved each protocol, and all patients gave written informed
`consent before any study-related procedures were performed.
`Study-specific eligibility criteria are summarized in Table 1.
`Patients were eligible to participate if they were age ⱖ 18 years,
`had adequate renal and liver function, and provided written
`informed consent. Patients were excluded if they had developed
`an active infection requiring treatment with systemic anti-in-
`fectives within 72 hours of chemotherapy.
`
`Study Drug
`Fixed-dose pegfilgrastim 6 mg and placebo were prepared as
`identical prefilled syringes for subcutaneous injection.
`
`Study Design
`These were randomized, double-blind studies exploring the
`safety and efficacy of administering pegfilgrastim on the same
`day of or day after chemotherapy. Each patient received an
`injection on day 1 within 4 hours after completion of chemo-
`therapy and again 24 hours (⫾ 2 hours) after chemotherapy on
`day 2. Each patient was randomly assigned to receive either
`pegfilgrastim on day 1 and placebo on day 2 or placebo on day
`1 and pegfilgrastim on day 2. Patients could receive up to six
`chemotherapy cycles every 3 weeks (Table 1).
`As recommended by the Infectious Disease Society of Amer-
`ica, anti-infective prophylaxis was not permitted because of
`emerging antibiotic resistance.18 A complete blood count was
`collected on the final day of actual and/or scheduled chemo-
`
`therapy and then weekly for each cycle. Additionally, for cycles
`1 and 3 (breast and ovarian studies) or cycles 1 and 4 (NHL and
`NSCLC studies), a complete blood count was obtained daily
`from day 5 (or day 7 for the ovarian study) until the absolute
`neutrophil count (ANC) was ⱖ 0.5 ⫻ 109/L. If the patient felt
`feverish, he or she recorded oral body temperature on a diary
`card. If the temperature was ⱖ 38.0°C, a complete blood count
`was scheduled. Oral temperature was collected daily by the
`patient until the temperature dropped below 38.0°C.
`For the breast cancer and lymphoma studies, which used
`more myelosuppressive regimens than the other studies, the
`original plan was to evaluate the feasibility of same-day admin-
`istration of pegfilgrastim in two phases. In the first phase, the
`safety data monitoring committee (SDMC) would evaluate the
`safety of 16 patients with advanced disease who had completed
`four chemotherapy cycles. After safety was established in these
`patients, the second phase would allow enrollment of patients
`with early-stage disease. However, in the breast study, because
`of the difficulty in accruing patients with advanced disease, the
`plan was amended to allow early-stage patients to enroll after
`the first seven patients with advanced disease were enrolled.
`Likewise, the lymphoma study was amended after the first three
`patients were enrolled, removing the requirement that only
`patients with mantle-cell lymphoma could be enrolled. This
`study closed early after enrolling 77 of the planned 90 patients
`with lymphoma as a result of additional enrollment problems.
`The ovarian study was closed early on the basis of internal
`evaluations supported by a gynecologic oncology advisory
`board and individual study investigators, including the princi-
`pal investigator. The major reason leading to study closure was
`a change in medical practice away from multiday topotecan
`(days 1 to 5, every 3 weeks) to once-per-week topotecan, which
`did not require pegfilgrastim use. Only 21 of 90 planned pa-
`tients were enrolled; therefore, analyses were limited to descrip-
`
`134
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`J O U R N A L O F O N C O L O G Y P R A C T I C E
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`• V O L. 6, I S S U E 3
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`Ex. 1078-0002
`
`

`
`
`
`Same-Day Administration of Pegfilgrastim and ChemotherapySame-Day Administration of Pegfilgrastim and Chemotherapy
`
`tive summaries, with no testing for noninferiority. All key end
`points were analyzed; however, the analyses were reduced in
`scope. Protocol amendments were not required for the NSCLC
`study.
`
`Objectives and End Points
`The primary objective in each study was to provide data on
`the safety and efficacy of pegfilgrastim administered on the
`same day versus on the day after chemotherapy, as measured
`by the duration of grade 4 neutropenia in cycle 1, which was
`the primary end point in each study. Secondary end points
`included cycle-1 neutropenia incidence and FN incidence
`(fever ⱖ 38.2°C and ANC ⬍ 0.5 ⫻ 109/L) in all cycles. The
`safety profile was measured by reports of adverse events and
`changes in laboratory values.
`
`Study Procedures
`In each study, patients received chemotherapy every 3 weeks for
`up to six cycles. All patients were randomly assigned in a
`blinded manner in a 1:1 ratio to receive pegfilgrastim on the last
`chemotherapy day (within 4 hours after the last dose) or ap-
`proximately 24 hours after the last dose. Those patients receiv-
`ing pegfilgrastim on the last chemotherapy day received a
`placebo injection approximately 24 hours later, and alterna-
`tively, those receiving pegfilgrastim approximately 24 hours af-
`ter the last chemotherapy dose received placebo on the last
`chemotherapy day. A health care provider administered the
`study drug injections. Patients, investigators, and site personnel
`were blinded to the day of pegfilgrastim treatment.
`For each study, an external SDMC reviewed partially
`blinded safety data (including hematology, adverse events, and
`chemotherapy dose reductions and delays) at the planned in-
`terim analysis and on a monthly basis. The SDMC recom-
`mended continuing enrollment both after the planned interim
`
`Table 2. Patient Disposition by Study
`
`analysis, conducted after 16 patients had the opportunity to
`complete three (or four) chemotherapy cycles, and during each
`regular by-study data review.
`
`Statistical Analyses
`Patients receiving at least one dose of study drug were included
`in the primary analysis set for the efficacy and safety analyses.
`Additionally, the primary end point was also evaluated using a
`per-protocol patient subset analysis, including all patients who
`met the entry criteria with postbaseline assessments.
`The clinical hypothesis that was tested in each of the studies
`was that the safety and efficacy of pegfilgrastim would not be
`altered by administering it on the same day of chemotherapy, as
`demonstrated by a similar duration of grade 4 neutropenia in
`cycle 1. To demonstrate noninferiority between the same-day
`and next-day groups, the upper bound of the two-sided 95%
`confidence limit (CL) of the difference (same day minus next
`day) in grade 4 neutropenia in cycle 1 was required to be less
`than 2 days. The 2-day margin was based on data from a pivotal
`filgrastim study.3 The difference in mean (placebo minus fil-
`grastim) was 2.95 days (two-sided 95% CL, 2.36 to 3.54). On
`the basis of the assumption of equivalent efficacy between peg-
`filgrastim and filgrastim and using the lower bound of the afore-
`mentioned 95% CL, a 2-day margin was selected. Although the
`2-day margin could be considered permissive given that the
`registrational pegfilgrastim trials mandated a 1-day noninferi-
`ority margin,6,7 it was felt that the 2-day margin was sufficient
`for a preliminary assessment in these phase II proof-of-concept
`studies. The planned sample size for each study was 90 patients.
`With a sample size of 45 patients in each group in cycle 1,
`assuming a one-sided ␣of 0.025 and standard deviation of 2.0
`days for duration of grade 4 neutropenia, there was a greater
`than 95% chance of concluding that the true difference in mean
`duration of grade 4 neutropenia was less than 2 days, if in fact
`
`Breast Cancer Study
`
`NHL Study
`
`NSCLC Study
`
`Ovarian Cancer Study
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Patient Characteristic
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No. screened
`
`Randomly assigned
`
`47
`
`98
`
`46
`
`37
`
`98
`
`40
`
`106
`
`45
`
`45
`
`10
`
`8
`
`21
`
`11
`
`11
`
`Received chemotherapy
`
`Received study drug
`
`Completed study
`
`Discontinued early
`
`46
`
`45
`
`33
`
`12
`
`45
`
`45
`
`37
`
`8
`
`36
`
`36
`
`26
`
`10
`
`39
`
`39
`
`31
`
`8
`
`44
`
`44
`
`19
`
`25
`
`44
`
`44
`
`20
`
`24
`
`43
`
`57
`
`79
`
`21
`
`72
`
`28
`
`82
`
`18
`
`73
`
`27
`
`8
`
`3
`
`5
`
`45
`
`55
`
`11
`
`1
`
`10
`
`4
`
`38
`
`62
`
`38
`
`9
`
`91
`
`36
`
`Disease progression
`
`Administrative decision
`
`Consent withdrawn
`
`1
`
`5
`
`0
`
`2
`
`11
`
`0
`
`0
`
`3
`
`1
`
`0
`
`7
`
`2
`
`0
`
`2
`
`4
`
`0
`
`6
`
`11
`
`0
`
`3
`
`0
`
`0
`
`8
`
`0
`
`11
`
`2
`
`2
`
`25
`
`5
`
`5
`
`12
`
`2
`
`1
`
`27
`
`5
`
`2
`
`7
`
`3
`
`0
`
`0
`
`2
`
`0
`
`0
`
`25
`
`1
`
`5
`
`0
`
`9
`
`45
`
`0
`
`Adverse event
`
`Death
`
`Other*
`
`1
`
`0
`
`5
`
`2
`
`0
`
`11
`
`0
`
`0
`
`4
`
`0
`
`0
`
`9
`
`2
`
`0
`
`2
`
`6
`
`0
`
`6
`
`2
`
`1
`
`2
`
`5
`
`3
`
`5
`
`4
`
`3
`
`3
`
`9
`
`7
`
`7
`
`3
`
`2
`
`4
`
`5
`
`10
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; NSCLC, non–small-cell lung cancer.
`* Other reasons for discontinuing the study early included protocol-specified deviation, protocol-specified criteria, and other.
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`M A Y 2010
`
`•
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`
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`Burris et alBurris et al
`
`the true duration were equal in the two groups. No inferential
`testing was performed for the external SDMC reviews; there-
`fore, no adjustments for multiplicity were made.
`The randomization for each study was stratified by high-
`risk and low-risk patients and generated using permuted
`blocks by a statistician not involved with the studies (Table 2).
`Site personnel called an interactive voice-response system to obtain
`numbers for patients, which the pharmacist used to assign appro-
`priate treatment.
`Secondary end points were summarized descriptively; no
`formal statistical testing was planned. All randomly assigned
`patients who received chemotherapy and at least one study drug
`dose were included in both the primary and per-protocol anal-
`ysis sets according to random assignment. All patients who
`received a study drug were included in the safety analyses ac-
`cording to the treatment actually received. Changes from base-
`line in laboratory values were summarized using descriptive
`statistics. Efficacy and safety analyses were also provided by the
`stratification factor in a descriptive manner.
`
`Results
`Patient Characteristics
`Across the four studies, 279 patients at 74 clinical sites in the
`United States were enrolled from February 2003 to August
`2005. Of these, 272 patients received chemotherapy and at least
`one study drug dose and were included in the primary analysis
`set (Table 2). Except for the ovarian study, more patients in the
`
`same-day treatment groups terminated participation in the
`studies early compared with the next-day groups (Table 2).
`Across the studies, baseline demographics and patient char-
`acteristics were generally well balanced between the same-day
`and next-day groups (Table 3). Baseline imbalances between
`the groups were only observed in the NSCLC study, in which
`there were slightly more patients with stage IV disease in the
`next-day group (91%) compared with the same-day group
`(77%) and slightly more patients with Eastern Cooperative
`Oncology Group performance status of 0 in the same-day
`group (55%) compared with the next-day group (30%). There
`were no notable protocol deviations affecting the analysis or
`interpretation of the results for the primary end point in any of
`the studies.
`
`Efficacy
`In cycle 1 of the breast study, grade 4 neutropenia was reported
`among 93% of same-day patients and 78% of next-day patients
`(Table 4, Fig 1A). More patients had severe neutropenia dura-
`tion of 3 days or longer in the same-day group (50%) than in
`the next-day group (18%). Mean severe neutropenia duration
`was 1.2 days (95% CL, 0.7 to 1.6) longer in the same-day group
`than in the next-day group (mean, 2.6 v 1.4 days). However, the
`results indicated the same-day group was statistically noninfe-
`rior to the next-day group with respect to duration of severe
`neutropenia (ie, the upper bound of the 95% CL [1.6] was less
`than the 2-day margin). Similar between-arm differences were
`observed for subgroups of patients with stage II to III or IV
`
`Table 3. Patient Demographics and Baseline Disease Characteristics by Study
`
`Breast Cancer Study
`
`NHL Study*
`
`NSCLC Study
`
`Ovarian Cancer Study
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Same Day
`
`Next Day
`
`Demographic or
`Characteristic
`
`No. of patients
`
`%
`
`No.
`
`45
`
`%
`
`No.
`
`45
`
`%
`
`No.
`
`36
`
`%
`
`No.
`
`39
`
`No.
`
`44
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`44
`
`18
`
`8
`
`8
`
`41
`
`27
`
`11
`
`11
`
`100
`
`100
`
`Female
`
`Age, years
`
`Median
`
`Range
`
`Race
`
`45
`
`100
`
`45
`
`100
`
`22
`
`61
`
`25
`
`64
`
`12
`
`53
`
`26
`
`68
`
`51
`
`31
`
`71
`
`60
`
`28
`
`83
`
`60
`
`26
`
`85
`
`64
`
`36
`
`80
`
`65
`
`40
`
`82
`
`58
`
`38
`
`81
`
`58
`
`36
`
`75
`
`35
`
`78
`
`27
`
`75
`
`29
`
`74
`
`35
`
`80
`
`41
`
`93
`
`7
`
`88
`
`9
`
`82
`
`White
`
`Black
`
`Other†
`
`Disease stage
`
`II
`
`40
`
`2
`
`3
`
`33
`
`89
`
`4
`
`7
`
`4
`
`6
`
`9
`
`13
`
`5
`
`4
`
`14
`
`11
`
`2
`
`8
`
`73
`
`25
`
`56
`
`11
`
`31
`
`10
`
`5
`
`21
`
`26
`
`7
`
`2
`
`16
`
`5
`
`3
`
`0
`
`7
`
`0
`
`0
`
`1
`
`0
`
`13
`
`1
`
`1
`
`9
`
`9
`
`—
`
`—
`
`§
`
`§
`
`—
`
`III‡
`
`IV
`Baseline ANC, ⫻ 109/L
`Mean
`
`SD
`
`5
`
`7
`
`11
`
`16
`
`11
`
`9
`
`24
`
`20
`
`13
`
`12
`
`36
`
`33
`
`16
`
`13
`
`41
`
`33
`
`10
`
`34
`
`23
`
`77
`
`4
`
`40
`
`9
`
`91
`
`8.6
`
`4.61
`
`9.1
`
`5.20
`
`5.5
`
`2.28
`
`6.2
`
`3.40
`
`12.9
`
`5.76
`
`13.0
`
`6.03
`
`—
`
`—
`
`4.4
`
`1.96
`
`—
`
`4.3
`
`1.12
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; NSCLC, non–small-cell lung cancer; ANC, absolute neutrophil count; SD, standard deviation.
`* Eight patients (same day, three; next day, five) enrolled with mantle-cell lymphoma; the remainder had diffuse large B-cell lymphoma.
`† Other races included Asian, Hispanic, Lebanese, and Filipino.
`‡ For the NSCLC study, disease stage III represents patients with disease stage IIIb and pleural effusion.
`§ Relapsed: same day, seven patients (88%); next day, six patients (55%).
`
`136
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`J O U R N A L O F O N C O L O G Y P R A C T I C E
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`• V O L. 6, I S S U E 3
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`Ex. 1078-0004
`
`

`
`
`
`Same-Day Administration of Pegfilgrastim and ChemotherapySame-Day Administration of Pegfilgrastim and Chemotherapy
`
`Table 4. Summary of Neutropenia by Study
`
`Characteristic
`
`No. of patients
`
`Grade 4 neutropenia*
`
`Cycle 1 incidence
`
`Duration, days
`
`0
`
`1
`
`Breast Cancer Study
`
`NHL Study
`
`NSCLC Study
`
`Ovarian Cancer Study
`
`Same
`Day
`
`Next
`Day
`
`Same
`Day
`
`Next
`Day
`
`Same
`Day
`
`Next
`Day
`
`Same
`Day
`
`Next
`Day
`
`No. %
`
`No. %
`
`No. %
`
`No. %
`
`No. %
`
`No. %
`
`No. % No. %
`
`45
`
`45
`
`36
`
`39
`
`44
`
`44
`
`8
`
`11
`
`42
`
`3
`
`3
`
`16
`
`93
`
`7
`
`7
`
`36
`
`35
`
`10
`
`16
`
`11
`
`78
`
`22
`
`36
`
`24
`
`31
`
`4
`
`7
`
`11
`
`86
`
`11
`
`19
`
`31
`
`25
`
`14
`
`10
`
`9
`
`64
`
`36
`
`26
`
`23
`
`2
`
`40
`
`2
`
`5
`
`91
`
`5
`
`2
`
`40
`
`2
`
`5
`
`91
`
`5
`
`6
`
`2
`
`2
`
`1
`
`75
`
`25
`
`25
`
`13
`
`6
`
`5
`
`1
`
`1
`
`55
`
`46
`
`9
`
`9
`
`2
`
`ⱖ 3
`
`Unknown
`
`23
`
`50
`
`8
`
`18
`
`13
`
`2
`
`36
`
`5†
`
`6
`
`2
`
`15
`
`5†
`
`3
`
`38
`
`4
`
`36
`
`Mean duration, days
`
`2.6
`
`1.4
`
`2.1
`
`1.2
`
`2.2 to 2.9
`
`1.1 to 1.7
`
`1.7 to 2.5
`
`0.8 to 1.6
`
`1.2
`
`0.7 to 1.6
`
`0.9
`
`0.29 to 1.42
`
`0.05
`0.05
`⫺0.02 to 0.1
`⫺0.02 to 0.1
`Not calculated
`
`1.9
`
`2.4
`
`0.4 to 3.3
`
`0.5 to 4.3
`
`Not calculated
`
`95% CL
`
`Mean difference‡
`
`95% CL
`Cycle 1 ANC nadir, ⫻ 109/L
`Geometric mean§
`
`95% CL
`Febrile neutropenia储
`Cycle 1
`
`Overall
`
`0.06
`
`1.8
`
`0.08
`
`0.30
`
`3.33
`
`3.23
`
`Not calculated
`
`0.04 to 0.09
`
`0.12 to 0.28
`
`0.05 to 0.12
`
`0.18 to 0.50
`
`2.52 to 4.39
`
`2.33 to 4.48
`
`10
`
`15
`
`22
`
`33
`
`3
`
`5
`
`7
`
`11
`
`4
`
`6
`
`11
`
`17
`
`1
`
`6
`
`3
`
`15
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`
`1
`
`13
`
`13
`
`2
`
`2
`
`18
`
`18
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; NSCLC, non–small-cell lung cancer; CL, confidence limit; ANC, absolute neutrophil count.
`* Grade 4 neutropenia is defined as ANC ⬍ 0.5 ⫻ 109/L.
`† Could not assess neutropenia duration because of inadequate ANC values.
`‡ Treatment difference ⫽ same day ⫺ next day.
`§ Because of the distribution of ANC nadir data, geometric mean is more representative than arithmetic mean for this comparison.
`储 Febrile neutropenia: temperature ⱖ 38.2°C and ANC ⬍ 0.5. ⫻ 109/L on same or next day.
`
`disease (data not shown). Across all cycles, the FN incidence
`was 33% for same-day patients and 11% for next-day patients,
`with most patients experiencing FN in cycle 1. Similar trends
`were observed in cycle 3 (data not shown).
`In cycle 1 of the lymphoma study, grade 4 neutropenia was
`reported among 86% of same-day patients and 64% of next-
`day patients (Table 4, Fig 1B). More patients had severe neu-
`tropenia duration of 3 days or longer in the same-day group
`(36%) than in the next-day group (15%). Mean severe neutro-
`penia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the
`same-day group than in the next-day group (mean, 2.1 v 1.2
`days). However, the results indicated the same-day group was
`statistically noninferior to the next-day group with respect to
`duration of severe neutropenia (ie, the upper bound of the 95%
`CL [1.4] was less than the 2-day margin). In cycle 1, FN was
`11% for the same-day patients and 3% for the next-day pa-
`tients, whereas across all cycles, FN incidence was 17% and
`15%, respectively. Similar trends were observed in cycle 3 (data
`not shown).
`In cycle 1 of the NSCLC study, only two patients (5%) in
`each group experienced grade 4 neutropenia for a duration of 1
`day each (Table 4, Fig 1C). Because more than 90% of patients
`did not experience grade 4 neutropenia, and there were no FN
`episodes in either group during the study, the difference in
`
`mean between the groups was not calculated. For the ovarian
`study, descriptive analyses are presented (Table 4, Fig 1D),
`although no conclusions could be drawn.
`
`Clinical Adverse Events
`In general, serious adverse events experienced by patients in
`each of these studies were those expected for patients with ma-
`lignancies receiving myelosuppressive chemotherapy. No pa-
`tient experienced bone pain that was considered serious in any
`study. In the breast, NSCLC, and ovarian studies, no serious
`adverse events were considered by the investigators to be study-
`drug related.
`In the breast study, 24% and 11% of patients in the same-
`day and next-day groups, respectively, reported serious adverse
`events. The most commonly reported serious adverse event was
`FN (same day, 18%; next day, 4%).
`In the lymphoma study, 33% of patients in both the same-
`day and next-day groups reported serious adverse events. More
`pyrexia and gastrointestinal disorders were experienced by pa-
`tients in the next-day group than in the same-day group. Four
`patients experienced serious adverse events that were reported as
`study-drug related, including one same-day patient (myocardial
`infarction and congestive cardiac failure in a 75-year-old man)
`and three next-day patients (allergic alveolitis, FN and pulmo-
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`M A Y 2010
`
`•
`
`jop.ascopubs.org
`
`137
`
`Ex. 1078-0005
`
`

`
`Same Day, n = 36
`Next Day, n = 39
`
`11 12 13 14 15 16 17 18 19 20 21
`1 2 3 4 5 6 7 8 9 10
`Cycle Day
`
`Same Day, n = 8
`Next Day, n = 11
`
`
`
`Burris et alBurris et al
`
`B
`1,000.00
`
`100.00
`
`10.00
`
`1.00
`
`0.10
`
`0.01
`
`ANC (x 109/L)
`
`D
`1,000.00
`
`100.00
`
`10.00
`
`1.00
`
`0.10
`
`0.01
`
`ANC (x 109/L)
`
`Same Day, n = 45
`Next Day, n = 45
`
`11 12 13 14 15 16 17 18 19 20 21
`1 2 3 4 5 6 7 8 9 10
`Cycle Day
`
`Same Day, n = 44
`Next Day, n = 44
`
`A
`1,000.00
`
`100.00
`
`10.00
`
`1.00
`
`0.10
`
`0.01
`
`ANC (x 109/L)
`
`C
`1,000.00
`
`100.00
`
`10.00
`
`1.00
`
`0.10
`
`0.01
`
`ANC (x 109/L)
`
`11 12 13 14 15 16 17 18 19 20 21
`1 2 3 4 5 6 7 8 9 10
`Cycle Day
`
`11 12 13 14 15 16 17 18 19 20 21
`1 2 3 4 5 6 7 8 9 10
`Cycle Day
`
`Figure 1. Median daily absolute neutrophil count (ANC) in cycle 1 by study: (A) breast cancer, (B) non-Hodgkin’s lymphoma, (C) non–small-cell lung
`cancer, (D) ovarian cancer. Horizontal reference line at ANC ⫽ 0.5 ⫻ 109/L. Bars indicate interquartile range.
`
`nary embolism, and FN in women ages 29, 74, and 54 years,
`respectively).
`In the NSCLC study, 44% and 33% of patients in the
`same-day and next-day groups reported serious adverse events,
`respectively. The most frequently reported serious adverse event
`was pneumonia, experienced by six (14%) and four (9%) pa-
`tients in the same-day and next-day groups, respectively.
`In the ovarian study, 38% and 46% of patients in the same-
`day and next-day groups, respectively, reported serious adverse
`events. The most frequently reported serious adverse events
`were pancytopenia (25% and 0%, respectively) and FN (13%
`and 18%, respectively).
`In each study, patients in both groups experienced similar
`postnadir hematologic recovery. No significant changes were
`observed in the mean ANC or platelet values on day 1 of each
`cycle in the breast and lymphoma studies (Figs 2A, 2B).
`
`Discussion
`To our knowledge, these are the only randomized double-
`blind studies comparing the safety and efficacy of pegfilgras-
`tim administration on the same day as chemotherapy with
`pegfilgrastim administration the day after chemotherapy
`completion (the recommended labeling). Other reports of
`same-day administration of growth factors and chemother-
`apy were not prospectively designed to address the question
`of same-day administration.9,10,15
`
`Full enrollment was reached in the NSCLC study; however,
`the neutropenic rate was lower than expected, and no definite
`conclusions could be drawn. The ovarian study was closed early
`because of a change in medical practice and was also inconclu-
`sive. The breast and lymphoma studies had sufficient enroll-
`ment and neutropenic rates to allow for evaluation of same-day
`pegfilgrastim administration compared with next-day adminis-
`tration. In both studies, the ANC profile for patients receiving
`same-day administration was earlier, deeper, and longer than
`that for patients receiving next-day administration. Mean du-
`ration of grade 4 neutropenia was clinically significantly longer,
`with nonoverlapping CLs, for patients receiving same-day ad-
`ministration than that for patients receiving next-day adminis-
`tration. Incidence of neutropenia was also higher for patients
`receiving same-day administration than that for patients receiv-
`ing next-day administration. FN incidence and FN hospitaliza-
`tions followed similar trends.
`In the breast study, risk of developing FN with same-day
`administration was approximately three times that with
`next-day administration. In the lymphoma study, FN rates
`seemed to be similar. However, in both studies, the same-day
`patients had approximately a 1-day increase in grade 4 neu-
`tropenia compared with the next-day group. This increase
`had clinical significance, because for each day of grade 4
`neutropenia, the likelihood of FN increases by approximately
`10% per day.19 Additionally, more patients experienced FN in the
`
`138
`
`J O U R N A L O F O N C O L O G Y P R A C T I C E
`
`• V O L. 6, I S S U E 3
`
`Copyright © 2010 by American Society of Clinical Oncology
`
`Ex. 1078-0006
`
`

`
`
`
`Same-Day Administration of Pegfilgrastim and ChemotherapySame-Day Administration of Pegfilgrastim and Chemotherapy
`
`Same Day
`Next Day
`
`Cycle 1
`n = 35, n = 39
`
`Cycle 2
`n = 29, n = 37
`
`Cycle 3
`n = 29, n = 37
`
`Cycle 4
`n = 29, n = 33
`
`Cycle 5
`n = 26, n = 32
`
`Cycle 6
`n = 26, n = 31
`
`Same Day
`Next Day
`
`Cycle 1
`n = 35, n = 37
`
`Cycle 2
`n = 28, n = 35
`
`Cycle 3
`n = 29, n = 35
`
`Cycle 4
`n = 27, n = 31
`
`Cycle 5
`n = 26, n = 30
`
`Cycle 6
`n = 26, n = 28
`
`20
`
`18
`
`16
`
`14
`
`12
`
`10
`
`8 6 4 2 0
`
`800
`
`700
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`B
`
`Mean ANC (109/dL)
`
`Mean Platelets (109/L)
`
`Same Day
`Next Day
`
`Cycle 1
`n = 44, n = 45
`
`Cycle 2
`n = 42, n = 42
`
`Cycle 3
`n = 39, n = 41
`
`Cycle 4
`n = 38, n = 41
`
`Cycle 5
`n = 33, n = 39
`
`Cycle 6
`n = 33, n = 38
`
`Same Day
`Next Day
`
`Cycle 1
`n = 44, n = 44
`
`Cycle 2
`n = 42, n = 41
`
`Cycle 3
`n = 39, n = 40
`
`Cycle 4
`n = 37, n = 40
`
`Cycle 5
`n = 32, n = 38
`
`Cycle 6
`n = 32, n = 37
`
`20
`
`18
`
`16
`
`14
`
`12
`
`10
`
`8 6 4 2 0
`
`800
`
`700
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`A
`
`Mean ANC (109/dL)
`
`Mean Platelets (109/L)
`
`Figure 2. Day 1 mean absolute neutrophil counts (ANCs) and platelet counts for the (A) breast cancer and (B) non-Hodgkin’s lymphoma studies. Error
`bars represent standard deviation.
`
`same-day than in the next-day group in cycle 1, when most FN
`events occur.20
`A possible biologic explanation for the increase in FN ob-
`served in the same-day arms may be that the initial stimulation
`of myeloid progenitor cells by pegfilgrastim renders these cells
`more sensitive to the effects of cytotoxic chemotherapy.5,9 This
`interpretation is consistent with median ANC curves (Fig 1), in
`which the measurable difference in neutrophil kinetics seems to
`occur before the nadir. Furthermore, although the magnitude
`varied by the degree of myelosuppression in each regimen, the
`effect was the same in every study.
`Although these are phase II proof-of-concept studies that can-
`not be considered definitive, collectively, these data are the highest
`level of clinical evidence pertaining to same-day dosing of pegfil-
`grastim. The randomized double-blind study designs reduced the
`potential bias of the study conclusions. The primary end point was
`based on objective hematologic results that were analyzed by a
`central laboratory. In the first cycle, complete blood counts were
`collected daily through ANC recovery. Each study was well con-
`ducted according to good clinical practice, with no important pro-
`
`tocol deviations. Health care professionals administered the study
`drug, ensuring high compliance. The results of the per-protocol
`patient subset analysis did not differ materially from those reported
`in this article. Furthermore, in the breast and lymphoma studies,
`the neutropenic event rates in the next-day dosing arms were con-
`sistent with other reported trials in which patients received next-
`day growth factor administration.20-23
`For patients receiving pegfilgrastim with chemotherapy,
`pegfilgrastim administered 24 hours after chemotherapy com-
`pletion according to the approved labeling is recommended. In
`light of these results, no additional studies are planned with a
`same-day dosing schedule.
`
`Accepted for publication on December 10, 2009.
`
`Acknowledgment
`We thank the patients who participated, the principal investigators and
`study coordinators, and Joan O’Byrne (paid consultant to Amgen) for
`medical writing support. Supported by Amgen. The breast cancer study
`was presented at the San Ant