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Gary H Lyman - One of the best experts on this subject based on the ideXlab platform.
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abstract ot1 05 01 the incidence of febrile neutropenia fn for chemotherapy patients receiving Pegfilgrastim by an on body injector Pegfilgrastim obi versus other fn prophylaxis strategies
Cancer Research, 2020Co-Authors: Reshma Mahtani, Jeffrey Crawford, Robert Rifkin, David C Dale, Alan Brookhart, Prasad L Gawade, Tatiana Lawrence, Rejesh Balani, Gary H LymanAbstract:For safety reasons, Pegfilgrastim should be administered the day after chemotherapy for prophylaxis of chemotherapy-induced FN (Lyman et al, Cancer. 2017;25:2619-2629). Because this is inconvenient, the Pegfilgrastim OBI was developed to reliably deliver Pegfilgrastim at 27 hours after its application. There are limited real-world data on whether this strategy improves patient persistence, compliance, and outcomes, and there are no published real-world data on FN risk among high-risk patients receiving other approaches to FN prophylaxis. For this reason, we are conducting a multicenter, prospective, observational cohort study at ~150 sites in the US to determine the risk of FN over the first 4 cycles of myelosuppressive chemotherapy among patients receiving Pegfilgrastim OBI or alternative choices for FN prophylaxis. Eligible patients are stratified into 2 groups, curative or palliative intent, and classified into subgroups of FN prophylaxis based on the first chemotherapy cycle: receiving Pegfilgrastim OBI vs other physician choice (ie, Pegfilgrastim prefilled syringe [PFS], Pegfilgrastim biosimilar PFS, daily filgrastim, or no G-CSF). Patients will be followed from screening/enrollment through completion of the 4th cycle of chemotherapy. Patients receiving Pegfilgrastim OBI with every chemotherapy cycle (≤ 4 cycles) are defined as “on-label Pegfilgrastim OBI”, a subset of the Pegfilgrastim OBI subgroup. Two interim analyses will be conducted after 1,000 and 2,000 patients have been enrolled and received study treatment; a steering committee will review the results. Eligible patients are ≥ 18 years old with non-Hodgkin lymphoma or breast, lung, or prostate cancer who are starting or have recently started (within 7 days) myelosuppressive chemotherapy in the neoadjuvant/adjuvant or first-line advanced/metastatic setting. Chemotherapy must be high (> 20%) or intermediate (10–20%) FN risk and administered once every 3 or 4 weeks with ≥ 4 cycles planned. Patients receiving intermediate risk regimens must also have ≥1 risk factor for FN. The primary endpoint is the overall incidence of FN (ANC 38°C, use of specific oral antibiotics, or use of IV antibiotics within 24 h of decreased ANC) over 4 cycles. Additional endpoints include incidence of FN among patients receiving chemotherapy with curative or palliative intent; persistence with G-CSF therapy; discontinuation, delay, or reduction in chemotherapy administration; incidence of adverse events; compliance with Pegfilgrastim therapy; and health-related quality of life (HRQoL). This is an estimation study. The planned sample size is 2,220 patients in each subgroup (Pegfilgrastim OBI and other physician choice) of the curative intent group; the final sample size is ≤5,440 patients (4,440 curative intent and ≤1,000 palliative intent). Expected FN incidence is 7.5% in the Pegfilgrastim OBI group and 10% in the other physician choice group. Standardized log binomial regression will be used to estimate the adjusted incidence of FN, and depending on the sample size, the adjusted relative risk of FN for Pegfilgrastim OBI vs other physician choice and for on-label Pegfilgrastim OBI vs other physician choice. G-CSF persistence and compliance as well as HRQoL (measured using the 12-item Short Form Health Survey [SF-12] HRQoL instrument) will be determined for the Pegfilgrastim OBI vs other physician choice groups. AEs will be graded according to NCI CTCAE Version 4.0. As of 25 June 2019, 1,048 patients have been enrolled. For study information, contact Tatiana Lawrence at tlawrenc@amgen.com. Citation Format: Reshma Mahtani, Jeffrey Crawford, Robert Rifkin, David Dale, Alan Brookhart, Prasad Gawade, Tatiana Lawrence, Rejesh Balani, Gary H Lyman. The incidence of febrile neutropenia (FN) for chemotherapy patients receiving Pegfilgrastim by an on-body injector (Pegfilgrastim OBI) versus other FN prophylaxis strategies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-05-01.
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use and effectiveness of Pegfilgrastim prophylaxis in us clinical practice a retrospective observational study
BMC Cancer, 2019Co-Authors: Derek Weycker, David Chandler, Mark Bensink, Robin Doroff, Ahuva Hanau, Charles Bowers, Rajesh Belani, Alexander Lonshteyn, Gary H LymanAbstract:Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy. Clinical practice guidelines recommend routine prophylactic coverage with granulocyte colony-stimulating factor (G-CSF)—such as Pegfilgrastim—for most patients receiving chemotherapy with an intermediate to high risk for FN. Patterns of Pegfilgrastim prophylaxis during the chemotherapy course and associated FN risks in US clinical practice have not been well characterized. A retrospective cohort design and data from two commercial healthcare claims repositories (01/2010–03/2016) and Medicare Claims Research Identifiable Files (01/2007–09/2015) were employed. Study population included patients who had non-metastatic breast cancer or non-Hodgkin’s lymphoma and received intermediate/high-risk regimens. Pegfilgrastim prophylaxis use and FN incidence were ascertained in each chemotherapy cycle, and all cycles were pooled for analyses. Adjusted odds ratios for FN were estimated for patients who did versus did not receive Pegfilgrastim prophylaxis in that cycle. Study population included 50,778 commercial patients who received 190,622 cycles of chemotherapy and 71,037 Medicare patients who received 271,944 cycles. In cycle 1, 33% of commercial patients and 28% of Medicare patients did not receive Pegfilgrastim prophylaxis, and adjusted odds of FN were 2.6 (95% CI 2.3–2.8) and 1.6 (1.5–1.7), respectively, versus those who received Pegfilgrastim prophylaxis. In cycle 2, 28% (commercial) and 26% (Medicare) did not receive Pegfilgrastim prophylaxis; corresponding adjusted FN odds were comparably elevated (1.9 [1.6–2.2] and 1.6 [1.5–1.8]). Results in subsequent cycles were similar. Across all cycles, 15% of commercial patients and 23% of Medicare patients did not receive Pegfilgrastim prophylaxis despite having FN in a prior cycle, and prior FN increased odds of subsequent FN by 2.1–2.4 times. Notwithstanding clinical practice guidelines, a large minority of patients did not receive G-CSF prophylaxis, and FN incidence was substantially higher among this subset of the population. Appropriate use of Pegfilgrastim prophylaxis may reduce patient exposure to this potentially fatal but largely preventable complication of myelosuppressive chemotherapy.
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the effect of filgrastim or Pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy
Annals of Oncology, 2015Co-Authors: Gary H Lyman, Phuong Khanh Morrow, Maureen Reiner, Jeffrey CrawfordAbstract: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 non-inferiority clinical trials of filgrastim and/or Pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The 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, the 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, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43–1.28; P = 0.286). The 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-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. Clinical trial registration NCT00035594, NCT00094809.
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primary vs secondary prophylaxis with Pegfilgrastim for the reduction of febrile neutropenia risk in patients receiving chemotherapy for non hodgkin s lymphoma cost effectiveness analyses
Journal of Medical Economics, 2014Co-Authors: Gregory Hill, Richard Barron, Kelly Fust, Michelle Skornicki, Douglas C A Taylor, Milton C Weinstein, Gary H LymanAbstract:AbstractObjective:Evaluate the cost-effectiveness of primary vs secondary prophylaxis (PP vs SP) with Pegfilgrastim to reduce the risk of febrile neutropenia (FN) in Non-Hodgkin’s Lymphoma (NHL) patients receiving myelosuppressive chemotherapy from a US payer perspective.Methods:A Markov model was used to compare PP vs SP with Pegfilgrastim in a cohort of patients receiving six cycles of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) or CHOP plus rituximab (CHOP-R) chemotherapy. Model inputs, including efficacy of Pegfilgrastim in reducing risk of FN and costs, were estimated from publicly available sources and peer-reviewed publications. Incremental cost-effectiveness was evaluated in terms of net cost per life-year saved (LYS), per quality-adjusted life-year (QALY) gained, and per FN event avoided over a lifetime horizon. Deterministic and probabilistic analyses were performed to assess sensitivity and robustness of results.Results:Lifetime costs for PP were $5000 greater than for SP;...
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cost effectiveness of Pegfilgrastim versus 6 day filgrastim primary prophylaxis in patients with non hodgkin s lymphoma receiving chop 21 in united states
Current Medical Research and Opinion, 2009Co-Authors: Gary H Lyman, Anjana Lalla, Richard Barron, Robert W DuboisAbstract:ABSTRACTObjectives: Prophylaxis with granulocyte-colony stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. Randomized clinical trials have shown that Pegfilgrastim, a 2nd-generation G-CSF, is at least as effective as the 1st-generation G-CSF filgrastim. In the meta-analysis of trials Pegfilgrastim performed better than filgrastim with respect to FN risk. The incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 and continuing in subsequent cycles of chemotherapy) with Pegfilgrastim versus filgrastim used for 6 days (as is often used in clinical practice) was estimated in patients with aggressive non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy in the United States.Methods: A decision-analytic model was constructed from a health insurer's perspective with a life-time study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due ...
Frankie A Holmes - One of the best experts on this subject based on the ideXlab platform.
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a combined analysis of two pivotal randomized trials of a single dose of Pegfilgrastim per chemotherapy cycle and daily filgrastim in patients with stage ii iv breast cancer
Oncology Reports, 2003Co-Authors: Salvatore Siena, Frankie A Holmes, John A Glaspy, James Hackett, Martine Piccart, Jennifer J RenwickAbstract:This combined, retrospective analysis compared once-per-chemotherapy-cycle Pegfilgrastim with daily Filgrastim in breast cancer patients undergoing myelosuppressive chemotherapy enrolled in two similarly designed, randomized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, a single subcutaneous (SC) injection of Pegfilgrastim [either 6 mg (n=77) or 100 microg/kg (n=149)] was administered, or daily Filgrastim SC injections (5 microg/kg/day; n=222) were initiated and continued until either absolute neutrophil count (ANC) > or =10 x 10(9)/l after the expected nadir or for up to 14 days, whichever occurred first. Individually, each of these trials demonstrated that a single Pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of Filgrastim. Clinical efficacy data from the two trials were combined for analysis (n=448). The risk of febrile neutropenia (FN; absolute neutrophil count or =38.2 degrees C) was significantly lower [11% vs 19%, respectively; relative risk = 0.56 (95% confidence interval: 0.35, 0.89)] in patients receiving Pegfilgrastim than for those receiving Filgrastim. Trends towards lower risks of hospitalization and intravenous anti-infective use were also observed. These observations were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. Pegfilgrastim may offer patients more effective protection against neutropenic complications of chemotherapy with fewer injections and less disruption to their lives.
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bone pain associated with once per cycle Pegfilgrastim is similar to daily filgrastim in patients with breast cancer
Clinical Breast Cancer, 2003Co-Authors: Ernst Kubista, Frankie A Holmes, John A Glaspy, Michael D Green, James Hackett, Theresa A NeumannAbstract:Bone pain is a common side effect of treatment with filgrastim. Pegfilgrastim is a pegylated long-acting analogue of filgrastim that is administered once per chemotherapy cycle. The profile of prospectively defined, patient-reported bone pain judged by the investigators as related to study drug was analyzed retrospectively for each drug using data from two comparable phase III trials. These multicenter, randomized, double-blind, noninferiority trials compared once-per-cycle Pegfilgrastim (6 mg, study 1 or 100 microg/kg, study 2) to daily filgrastim 5 microg/kg in patients with stage II-IV breast cancer undergoing multiple cycles of myelosuppressive chemotherapy (doxorubicin/docetaxel). Subcutaneous once-per-cycle Pegfilgrastim 6-mg and 100-microg/kg doses were administered to 76 and 150 patients, respectively; subcutaneous daily filgrastim 5 microg/kg was administered to a total of 227 patients. Because bone pain in study 1 was higher (P = 0.044) in every cycle compared with study 2, all analyses were performed separately for each study. No statistically significant differences in incidence, severity, or duration were observed between patients receiving either once-per-cycle Pegfilgrastim or daily filgrastim in either study. Bone pain incidence and severity were significantly greater (P 100 kg). No patients were withdrawn from either study for bone pain.
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comparable efficacy and safety profiles of once per cycle Pegfilgrastim and daily injection filgrastim in chemotherapy induced neutropenia a multicenter dose finding study in women with breast cancer
Annals of Oncology, 2002Co-Authors: Frankie A Holmes, S Jones, J Oshaughnessy, S Vukelja, T George, Michael Savin, Donald A Richards, John A Glaspy, L Meza, G CohenAbstract:Abstract Background Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support. Patients and methods Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received Pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (Pegfilgrastim 30, 60 or 100 µg/kg) or daily subcutaneous injections (filgrastim 5 µg/kg/day). Safety, efficacy and pharmacokinetics were analyzed. Results The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received Pegfilgrastim 30, 60 and 100 µg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7, 2 and 1.3 days for doses of Pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of Pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of Pegfilgrastim and filgrastim were similar. Conclusions A single subcutaneous injection of Pegfilgrastim 100 µg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.
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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
Journal of Clinical Oncology, 2002Co-Authors: Frankie A Holmes, Michael Savin, L Meza, Joyce Oshaughnessy, Svetislava J Vukelja, Stephen E Jones, J Shogan, J Glaspy, M Moore, I WiznitzerAbstract:PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of Pegfilgrastim (SD/01, sustained-duration filgrastim; 1...
Robert W Dubois - One of the best experts on this subject based on the ideXlab platform.
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cost effectiveness of Pegfilgrastim versus 6 day filgrastim primary prophylaxis in patients with non hodgkin s lymphoma receiving chop 21 in united states
Current Medical Research and Opinion, 2009Co-Authors: Gary H Lyman, Anjana Lalla, Richard Barron, Robert W DuboisAbstract:ABSTRACTObjectives: Prophylaxis with granulocyte-colony stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. Randomized clinical trials have shown that Pegfilgrastim, a 2nd-generation G-CSF, is at least as effective as the 1st-generation G-CSF filgrastim. In the meta-analysis of trials Pegfilgrastim performed better than filgrastim with respect to FN risk. The incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 and continuing in subsequent cycles of chemotherapy) with Pegfilgrastim versus filgrastim used for 6 days (as is often used in clinical practice) was estimated in patients with aggressive non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy in the United States.Methods: A decision-analytic model was constructed from a health insurer's perspective with a life-time study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due ...
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cost effectiveness of Pegfilgrastim versus filgrastim primary prophylaxis in women with early stage breast cancer receiving chemotherapy in the united states
Clinical Therapeutics, 2009Co-Authors: Gary H Lyman, Anjana Lalla, Richard Barron, Robert W DuboisAbstract:Abstract Background: Prophylaxis with granulocyte colony-stimulating factor reduces the risk for febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. Objective: We estimated the incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 of chemotherapy) with Pegfilgrastim versus filgrastim in women with early-stage breast cancer receiving myelosuppressive chemotherapy in the United States. Methods: A decision-analytic model was constructed from a health payer's perspective with a lifetime study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due to reduced FN-related mortality and on-time receipt of full-dose chemotherapy. Sensitivity analyses were conducted. Results: Pegfilgrastim was cost-saving and more effective (ie, dominant strategy) than 11-day filgrastim. The incremental cost-effectiveness ratio (ICER) for Pegfilgrastim versus 6-day filgrastim was $12,904 per FN episode avoided. Adding the survival benefit due to reduced FN mortality and receipt of optimal chemotherapy dose yielded an ICER of $31,511 per quality-adjusted life year (QALY) gained and $14,415 per QALY gained, respectively. The most influential factors included inpatient FN case-fatality rate, cost of Pegfilgrastim and filgrastim, baseline probability of FN, relative risk for FN between filgrastim and pegfil-grastim, and cost of administration of filgrastim. Conclusion: Pegfilgrastim was cost-saving compared with 11-day filgrastim and cost-effective compared with 6-day filgrastim from a health payer's perspective for the primary prophylaxis of FN in these women with early-stage breast cancer receiving myelosuppressive chemotherapy.
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comparison of Pegfilgrastim with filgrastim on febrile neutropenia grade iv neutropenia and bone pain a meta analysis of randomized controlled trials
Current Medical Research and Opinion, 2007Co-Authors: Lionel Pinto, Zhimei Liu, Quan Doan, Myriam Bernal, Robert W Dubois, Gary H LymanAbstract:ABSTRACTBackground and objective: While head-to-head clinical trials demonstrate Pegfilgrastim to be as efficacious as filgrastim in reducing chemotherapy-induced neutropenia, these studies lacked the statistical power to demonstrate better outcomes with one therapy compared to the other. Our objective was to obtain a pooled estimate of the effect of Pegfilgrastim compared with filgrastim on incidence of febrile neutropenia (FN), and related outcomes among patients with solid tumors and malignant lymphomas receiving myelosuppressive chemotherapy.Research design and methods: We searched PubMed and EMBASE for articles published from January 1, 1990 to August 31, 2006 reporting on randomized controlled trials (RCTs) that compared the efficacy and safety of Pegfilgrastim versus filgrastim. We only accepted studies in which filgrastim (5 µg/kg/day) and Pegfilgrastim (100 µg/kg or a fixed dose of 6 mg) were administered at approved doses indicated on the package insert. Pooled relative risk (RR) was estimated u...
Pere Gascon - One of the best experts on this subject based on the ideXlab platform.
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biosimilar Pegfilgrastim improving access and optimising practice to supportive care that enables cure
BioDrugs, 2020Co-Authors: Paul Cornes, Pere Gascon, Arnold G Vulto, Matti AaproAbstract:Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar Pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2–21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10–14 days, while Pegfilgrastim is administered once per cycle. When taken according to the guidelines, Pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (< 7 days) and has been shown to be inferior to Pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with Pegfilgrastim might also aid patient adherence. The introduction of biosimilar Pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar Pegfilgrastim offers countries using biosimilar filgrastim opportunities to improve adherence and thus cancer survival, whilst offering economic benefits for countries using reference Pegfilgrastim. These benefits can be realised in full if biosimilar Pegfilgrastim becomes part of routine clinical practice supported by drug and therapeutic committees implementing guidelines with multidisciplinary support in the hospital.
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pooled analysis of two randomized double blind trials comparing proposed biosimilar la ep2006 with reference Pegfilgrastim in breast cancer
Annals of Oncology, 2017Co-Authors: Kimberly L Blackwell, Pere Gascon, Allen Nixon, Roumen Nakov, C M Jones, Andriy Krendyukov, N HarbeckAbstract:ABSTRACT Background Following the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population. Patients and methods LA-EP2006 is a proposed biosimilar that has been developed for Pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference Pegfilgrastim with LA-EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor. Results A total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA-EP2006: n = 314; reference: n = 310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA-EP2006 and reference groups (1.05 ± 1.055 days versus 1.01 ± 0.958 days), with a treatment difference of − 0.04 days [95% confidence interval (CI): −0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of ±1 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference Pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference Pegfilgrastim, and there were no reports of neutralizing antibodies. Conclusions This pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar Pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference Pegfilgrastim in patients with breast cancer receiving TAC chemotherapy. Clinical trial numbers NCT01735175 and NCT01516736.
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proposed biosimilar Pegfilgrastim la ep2006 compared with reference Pegfilgrastim in asian patients with breast cancer an exploratory comparison from two phase iii trials
Future Oncology, 2017Co-Authors: N Harbeck, Pere Gascon, Allen Nixon, Roumen Nakov, C M Jones, Andriy Krendyukov, Kimberly L BlackwellAbstract:Aim: This is a pooled subgroup analysis of Asian patients enrolled in two Phase III confirmatory studies comparing proposed biosimilar LA-EP2006 with reference Pegfilgrastim in women receiving chemotherapy for breast cancer. Patients & methods: Women were randomized to LA-EP2006 (n = 90) or reference (n = 84) Pegfilgrastim (Neulasta®, Amgen, Inc., CA, USA) for ≤6 cycles of TAC chemotherapy. Primary end point was duration of severe neutropenia during Cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 109/l) with equivalence confirmed if 95% CIs were within a ±1-day margin. Results: Mean duration of severe neutropenia (days) in Cycle 1 was 1.36 ± 0.98 (LA-EP2006) versus 1.35 ± 1.06 (reference) (difference 0.01 days; 95% CI: -0.30–0.32, indicating equivalence). Conclusion: LA-EP2006 showed similar clinical efficacy and safety compared with reference Pegfilgrastim.
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a comparison of proposed biosimilar la ep2006 and reference Pegfilgrastim for the prevention of neutropenia in patients with early stage breast cancer receiving myelosuppressive adjuvant or neoadjuvant chemotherapy Pegfilgrastim randomized oncology s
Oncologist, 2016Co-Authors: Kimberly L Blackwell, Pere Gascon, Roman Donskih, Michael C Jones, Allen Nixon, Maria J Vidal, Roumen Nakov, P Singh, Gregor Schaffar, N HarbeckAbstract:Background. Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of Pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference Pegfilgrastim(Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy. Methods. A total of 308 patients were randomized to LA-EP2006 or reference Pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count, <0.5x10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin. Results. Baseline characteristics were well balanced. DSN was equivalent between groups at mean +/- SD 1.36 +/- 1.13 (LA-EP2006, n=155) and 1.19 +/- 0.98 (reference, n=153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI-0.36 to 0.04;95% CI-0.40 to 0.08), LA-EP2006 was equivalent to reference Pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against Pegfilgrastim, filgrastim, or polyethylene glycol were detected. Conclusion. LA-EP2006 and reference Pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC.
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a randomized double blind multicenter phase iii study of fixed dose single administration Pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy
Annals of Oncology, 2003Co-Authors: Michael D Green, Pere Gascon, H Koelbl, Jose Baselga, A Galid, V Guillem, Salvatore Siena, R I Lalisang, Hellmut Samonigg, M R ClemensAbstract:Background: We evaluated the efficacy of a single fixed 6 mg dose of Pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy, compared with daily administration of filgrastim, in the provision of neutrophil support. Patients and methods: Patients (n = 157) were randomized to receive either a single 6 mg subcutaneous (s.c.) injection of Pegfilgrastim or daily 5 mg/kg s.c. injections of filgrastim, after doxorubicin and docetaxel chemotherapy (60 mg/m 2 and 75 mg/m 2 , respectively). Duration of grade 4 neutropenia, depth of neutrophil nadir, incidence of febrile neutropenia, time to neutrophil recovery and safety information were recorded. Results: A single 6 mg injection of Pegfilgrastim was as effective as daily injections of filgrastim for all efficacy measures for all cycles. The mean duration of grade 4 neutropenia in cycle 1 was 1.8 and 1.6 days for the Pegfilgrastim and filgrastim groups, respectively. Results for all efficacy end points in cycles 2–4 were consistent with the results from cycle 1. A trend towards a lower incidence of febrile neutropenia was noted across all cycles with Pegfilgrastim compared with filgrastim (13% versus 20%, respectively). A single fixed dose of Pegfilgrastim was as safe and well tolerated as standard daily filgrastim. Conclusions: A single fixed dose of Pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelo
Bingbing Yang - One of the best experts on this subject based on the ideXlab platform.
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Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor
BioDrugs, 2015Co-Authors: Tara Arvedson, James O’kelly, Bingbing YangAbstract:Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as Pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and Pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate Pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.
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comparison of pharmacokinetics and safety of Pegfilgrastim administered by two delivery methods on body injector and manual injection with a prefilled syringe
Cancer Chemotherapy and Pharmacology, 2015Co-Authors: Bingbing Yang, Phuong Khanh Morrow, Michael Moxness, Desmond PadhiAbstract:For patients with clinically significant risk of febrile neutropenia, Pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may preclude patients from returning to the clinic the next day for Pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of Pegfilgrastim administered via an on-body injector applied to the subject’s skin versus manual injection using a prefilled syringe. Healthy subjects aged 18–50 years were randomized 1:1 to receive a single 6-mg subcutaneous Pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after Pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration (C max) and area under the concentration curve from time 0 to infinity (AUC0–inf). Secondary endpoints included safety, tolerability, and immunogenicity. Pegfilgrastim mean AUC0–inf values for the on-body injector (n = 125) and manual injection (n = 128) were 10,900 and 11,100 h ng/mL, respectively; mean C max values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for C max and 1.00 for AUC0–inf; the corresponding 90 % CIs were within the prespecified range (0.80–1.25), indicating comparable Pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No Pegfilgrastim-neutralizing antibodies were detected. Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.
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prevention of chemotherapy induced neutropenia with Pegfilgrastim pharmacokinetics and patient outcomes
Chemotherapy, 2012Co-Authors: Bingbing Yang, Michael A Savin, Michael D GreenAbstract:Patients receiving cytotoxic chemotherapy are at risk for developing chemotherapy-induced neutropenia (CIN). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF) that stimulates the proliferation, differentiation and function of neutrophils, is approved for the prevention of CIN. To eliminate the burden of daily filgrastim injection, Pegfilgrastim, a long-acting form of filgrastim, was developed by covalently attaching a 20-kDa polyethylene glycol molecule to filgrastim to increase molecular size and thus reduce renal elimination. Consequently, neutrophil-mediated clearance is the primary mechanism for Pegfilgrastim elimination. Therefore, after a single Pegfilgrastim injection following chemotherapy treatment, Pegfilgrastim concentration is sustained during neutropenia and decreases with neutrophil recovery. Pegfilgrastim has received marketing authorization approval from many regions to reduce the incidence of CIN based on the similar efficacy and safety of a single injection of 6 mg of Pegfilgrastim administered once per chemotherapy cycle and 10 to 11 daily injections of filgrastim at 5 µg/kg. The efficient self-regulating clearance of Pegfilgrastim allows administration once per chemotherapy cycle, thereby providing a more convenient treatment regimen than filgrastim.
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Pharmacokinetics and Pharmacodynamics of Pegfilgrastim
Clinical Pharmacokinetics, 2011Co-Authors: Bingbing Yang, Anna KidoAbstract:Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N -terminal methionine residue. Similar to filgrastim, Pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, Pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to Pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of Pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for Pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of Pegfilgrastim is significantly reduced and the concentration of Pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥1 × 10^9/L as a surrogate marker threshold for the clearance of Pegfilgrastim to subtherapeutic levels. After repeated administration of Pegfilgrastim, the peak concentrations of Pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of Pegfilgrastim; the analysis supported that 100 µg/kg was an adequate weight-based dose of Pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of Pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of Pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 µg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of Pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of Pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.
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serum Pegfilgrastim concentrations during recovery of absolute neutrophil count in patients with cancer receiving Pegfilgrastim after chemotherapy
Pharmacotherapy, 2007Co-Authors: Bingbing Yang, Anna Kido, Atsuko ShibataAbstract:Study Objective. To examine the serum concentrations of Pegfilgrastim during recovery of absolute neutrophil count (ANC) in patients with cancer who received Pegfilgrastim after chemotherapy. Design. Retrospective analysis. Data Source. Data were pooled from seven Pegfilgrastim registrational clinical trials: four open-label phase I or II studies and three randomized phase II or III studies. Patients. A total of 370 patients with non–small cell lung cancer, Hodgkin's lymphoma, non–Hodgkin's lymphoma, or breast cancer. Measurements and Main Results. Chemotherapy was given every 3 weeks, and Pegfilgrastim was given once/chemotherapy cycle, 24 hours after chemotherapy completion. Data were available from 187 patients for the serum Pegfilgrastim concentration analysis and from 319 patients for the ANC data analysis. Recovery of ANC to normal levels (≥ 1 × 103/mm3) correlated well with the decline of Pegfilgrastim concentrations to subtherapeutic levels; this inverse correlation was observed across different tumor types. By day 12 after Pegfilgrastim administration, all patients experienced ANC recovery to normal levels, and none had a serum Pegfilgrastim concentration above 2 ng/ml, considered the lowest concentration to elicit clinically meaningful granulopoiesis. After administration of Pegfilgrastim, a steady postnadir recovery of the ANC to normal levels was noted, and postnadir peaks of 30 × 103/mm3 or higher were observed in only three patients. Conclusion. Serum concentrations of Pegfilgrastim were consistently cleared to subtherapeutic levels by day 12 after Pegfilgrastim administration, and subtherapeutic Pegfilgrastim levels were predicted by ANC recovery to 1 × 103/mm3 or greater.