Efficacy and Safety of Filgrastim and Its Biosimilars to Prevent Febrile Neutropenia in Cancer Patients: A Prospective Study and Meta-Analysis

Background: The aim of this review and meta-analysis was to identify, assess, meta-analyze and summarize the comparative effectiveness and safety of filgrastim in head-to-head trials with placebo/no treatment, pegfilgrastim (and biosimilar filgrastim to update advances in the field. Methods: The preferred reporting items for systematic reviews and meta-analyses PRISMA statement were applied, and a random-effect model was used. Primary endpoints were the rate and duration of grade 3 or 4 neutropenia, and an incidence rate of febrile neutropenia. Secondary endpoints were time to absolute neutrophil count ANC recovery, depth of ANC nadir (lowest ANC), neutropenia-related hospitalization and other neutropenia-related complications. For filgrastim versus biosimilar filgrastim comparison, the primary efficacy endpoint was the mean difference in duration of severe neutropenia DSN. Results: A total of 56 studies were considered that included data from 13,058 cancer patients. The risk of febrile neutropenia in filgrastim versus placebo/no treatment was not statistically different. The risk ratio for febrile neutropenia was 0.58, a 42% reduction in favor of filgrastim. The most reported adverse event with FIL was bone pain. For pegfilgrastim versus filgrastim, no statistically significant difference was noted. The risk ratio was 0.90 (95% CI 0.67 to 1.12). The overall difference in duration of severe neutropenia between filgrastim and biosimilar filgrastim was not statistically significant. The risk ratio was 1.03 (95% CI 0.93 to 1.13). Conclusions: Filgrastim was effective and safe in reducing febrile neutropenia and related complications, compared to placebo/no treatment. No notable differences were found between pegfilgrastim and filgrastim in terms of efficacy and safety. However, a similar efficacy profile was observed with FIL and its biosimilars.

Biosimilar uptake of filgrastim and impact on spending in Medicare Part D from 2015 to 2019.

67 Background: The introduction of a filgrastim biosimilar in 2014 was associated with substantial cost savings in Medicare Part B and Medicaid programs. However, Medicare Part D is unique since it is unable to directly negotiate prices with drug manufacturers. We sought to investigate the uptake of filgrastim biosimilars and impact on spending among Part D beneficiaries. Methods: We evaluated utilization trends for filgrastim (Neupogen), filgrastim-sndz (Zarxio), and tbo-filgrastim (Granix) using the 2015-2019 Medicare Part D Prescription Drug Event data. We conducted a retrospective cross-sectional review of annual spending, number of beneficiaries, number of claims, spending per beneficiary, and spending per dosage unit. We excluded filgrastim-aafi (Nivestym) due to recent approval and adjusted for inflation using 2019 dollars. Results: In 2019, total aggregate Part D spending on filgrastim products was $78 million. From 2015 to 2019, the biosimilar share of total aggregate spending increased from $1.8 million (2%) to $44 million (56%), with combined biosimilar spending (Zarxio and Granix) eclipsing originator Neupogen in 2018 (within 4 years of FDA approval of Zarxio). Total spending on Neupogen reduced 58% from 2015 to 2019. While biosimilar uptake progressively increased every year, total aggregate spending on all filgrastim forms reduced only 7% from 2015 to 2019 ($84 million to $78 million). For all 3 forms, from 2015 to 2019, trends in spending were: average spending per claim ($3193 to $2549, -20%), average spending per beneficiary ($5880 to $6722, +15%), and average spending per dosage unit of filgrastim ($583 vs $571, -2%). Detailed results in Table. Conclusions: We demonstrate that the significant uptake of biosimilar filgrastim products in Medicare Part D from 2015 to 2019 was associated with a small decrease in aggregate spending, essentially unchanged per unit spending, and increased spending per beneficiary on filgrastim products. Our findings contrast with experiences across Medicare Part B and Medicaid, that demonstrated significant cost savings with biosimilar filgrastim uptake. This may be due to inability of Medicare Part D to directly negotiate prices with manufacturers (in contrast to Medicare Part B and Medicaid), supporting ongoing Congressional policy being debated in the United States Senate (H.R. 3).[Table: see text]

Real World Clinical Experience of Biosimilar G-CSF (Grastofil) for Autologous Peripheral Blood Stem Cell Mobilization: Single Center Experience in Canada Following Early Adoption

Introduction: Granulocyte colony-stimulating factor (G-CSF) is the first line treatment for mobilization, most commonly using a regimen of daily filgrastim. The use of biosimilars can provide substantial cost savings to the health care system while delivering comparable efficacy outcomes. In 2016, the Saskatchewan Cancer Agency was a leader in Canada, instituting formulary changed from a G-CSF originator product to a cost savings alternative biosimilar for stem cell mobilization prior to autologous stem cell transplant (ASCT) and for engraftment. The purpose of this study was to investigate the clinical comparability of biosimilar G-CSF to its reference product in a real-world clinical setting and to validate use of the biosimilar in mobilization and engraftment—an indication which had been granted by extrapolation. Methods: A retrospective chart review was completed including all patients diagnosed with a hematological malignancy between 2012 and 2018 who underwent ASCT. To assess real-world outcomes across a diverse population, successful CD34+ stem cell collection was compared between patients mobilized with originator filgrastim, Neupogen, and biosimilar filgrastim, Grastofil. Additional comparisons included the number of apheresis required, time to absolute neutrophil count (ANC) engraftment, platelet engraftment, length of hospital stay, and Plerixafor use. Results: 217 patients were mobilized and transplanted during the study period. There was no statistically significant difference in success rate between patients mobilized with biosimilar filgrastim and those who had received originator G-CSF (100% vs. 92.4%, p = 0.075). Neither disease type, nor concurrent chemomobilization regimen resulted in a detectable difference between the two G-CSF products in successful stem cell harvest. Engraftment was highly similar between groups, as demonstrated by ANC recovery (11.6 days Neupogen vs. 11.6 days Grastofil), platelet recovery (14.0 days Neupogen vs. 14.2 days Grastofil), and total length of hospital stay (22.4 days Neupogen vs. 22.3 days Grastofil). No statistically significant difference in adjunctive use of Plerixafor® was observed between Neupogen and Grastofil patients (25.9% vs. 23.4%, p = 0.72). Conclusion: Extrapolation of indications for biosimilars is justified. This real-world evidence builds upon registrational studies to confirm that no clinically meaningful differences were detected between originator Neupogen and biosimilar Grastofil in the setting of PBSC mobilization and engraftment post ASCT. Biosimilars are as safe and effective as originator products. Implementation across all approved indications without hesitation maximizes cost savings to the provincial system, allowing for more optimal allocation of health care resources.

Effect on Patients’ Outcomes of a Change to Biosimilar Filgrastim Product in Autologous Stem Cell Mobilization

Background: Following addition of a biosimilar filgrastim product to the formulary, sites in the authors’ provincial health authority transitioned from using the originator filgrastim to the biosimilar for autologous stem cell mobilization. Objective: To assess the effect on patient outcomes of a universal change to use of the biosimilar filgrastim in stem cell mobilization. Methods: This retrospective pre–post study included patients undergoing autologous stem cell mobilization at 2 cancer hospitals in Alberta, Canada, between July 1, 2018, and November 30, 2019. Clinical outcomes were investigated for patients treated with a granulocyte colony-stimulating factor (biosimilar or originator product) for mobilization before stem cell transplant, approximately 6 months before and after the defined date of product change. Results: In total, 102 patients were treated with the originator product and 101 patients with the biosimilar. Effectiveness was similar between the originator and biosimilar products, with 98% successful harvest of stem cells in all patients treated. Independent t tests showed no statistically significant differences between patients receiving the originator and those receiving the biosimilar in terms of time from mobilization to collection (difference of means –0.9 days, 95% confidence interval [CI] –2.12 to 0.32), time for neutrophil engraftment (difference of means 0 days, 95% CI –0.36 to 0.36), time for platelet engraftment (difference of means 1 day, 95% CI –0.55 to 2.55), average length of stay (difference of means –0.7 day, 95% CI –2.71 to 1.31), and CD34+ value (difference of means –1 × 106/kg body weight, 95% CI –2.11 to 0.11). A 98% rate of conversion to use of the biosimilar filgrastim was achieved, with an estimated annual drug-cost saving of $67 500. Conclusions: In this pre–post study, changing to the biosimilar product from the originator maintained clinical effectiveness outcomes while decreasing overall drug expenditures. A well-planned change to the biosimilar product, executed in conjunction with clinician consultation and monitoring of effectiveness outcomes, can ensure appropriate patient therapy while significantly improving the uptake of biosimilars and decreasing expenditures for biologic drugs. RÉSUMÉ Contexte : À la suite de l’ajout d’un produit filgrastim biosimilaire à la liste des médicaments, les sites relevant de l’autorité sanitaire provinciale des auteurs sont passés de l’utilisation du filgrastim princeps à la version générique pour la mobilisation des cellules souches autologues. Objectif : Évaluer l’effet sur les résultats des patients d’un changement généralisé visant à utiliser le filgrastim générique pour la mobilisation des cellules souches. Méthodes : Cette étude rétrospective pré-post comprenait des patients soumis à une mobilisation des cellules souches autologues dans deux hôpitaux de cancérologie en Alberta (Canada) entre le 1er juillet 2018 et le 30 novembre 2019. L’examen des résultats cliniques des patients traités à l’aide d’un facteur stimulant les colonies de granulocytes (G-CSF) (générique ou princeps) pour une mobilisation avant la greffe de cellules souches a eu lieu environ six mois avant et après la date du changement de produit. Résultats : Au total, 102 patients ont été traités à l’aide du produit princeps et 101 patients à l’aide du générique. Les deux produits présentaient une efficacité similaire, et 98 % de réussite dans la récolte de cellules souches chez tous les patients traités. Des tests t indépendants n’ont montré aucune différence statistique significative entre les patients recevant le princeps et ceux recevant le biosimilaire en termes de temps allant de la mobilisation à la collecte (différence des moyennes –0,9 jour, intervalle de confiance [IC] 95 % –2,12 à 0,32); temps de la prise de la greffe neutrophile (différence des moyennes 0 jour, IC 95 % –0,36 à 0,36); temps de la prise de la greffe des plaquettes (différence des moyennes 1 jour, IC 95 % –0,55 à 2,55); durée moyenne du séjour (différence des moyennes –0,7 jour, IC 95 % –2,71 à 1,31) et valeur CD34+ (différence des moyennes –1 × 106/kg masse corporelle, IC 95 % –2,11 à 0,11). Un taux de conversion de 98 % visant à utiliser le filgrastim générique a été atteint, avec une estimation des économies annuelles sur le coût des médicaments de 67 500 $. Conclusions : Dans cette étude pré-post, le passage du produit princeps au générique a préservé l’efficacité des résultats cliniques, tout en diminuant les dépenses générales liées au médicament. Un changement bien programmé pour passer au produit générique, mené conjointement avec la consultation d’un clinicien et un contrôle des résultats d’efficacité, peut assurer une thérapie du patient appropriée tout en améliorant grandement la prise de produits génériques et en diminuant les dépenses associées aux médicaments biologiques.

Primary Prophylaxis With Biosimilar Filgrastim for Patients at Intermediate Risk for Febrile Neutropenia: A Cost-Effectiveness Analysis

PURPOSE: Temporary COVID-19 guideline recommendations have recently been issued to expand the use of colony-stimulating factors in patients with cancer with intermediate to high risk for febrile neutropenia (FN). We evaluated the cost-effectiveness of primary prophylaxis (PP) with biosimilar filgrastim-sndz in patients with intermediate risk of FN compared with secondary prophylaxis (SP) over three different cancer types. METHODS: A Markov decision analytic model was constructed from the US payer perspective over a lifetime horizon to evaluate PP versus SP in patients with breast cancer, non–small-cell lung cancer (NSCLC), and non-Hodgkin lymphoma (NHL). Cost-effectiveness was evaluated over a range of willingness-to-pay thresholds for incremental cost per FN avoided, life year gained, and quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty. RESULTS: Compared with SP, PP provided an additional 0.102-0.144 LYs and 0.065-0.130 QALYs. The incremental cost-effectiveness ranged from $5,660 in US dollars (USD) to $20,806 USD per FN event avoided, $5,123 to $31,077 USD per life year gained, and $7,213 to $35,563 USD per QALY gained. Over 1,000 iterations, there were 73.6%, 99.4%, and 91.8% probabilities that PP was cost-effective at a willingness to pay of $50,000 USD per QALY gained for breast cancer, NSCLC, and NHL, respectively. CONCLUSION: PP with a biosimilar filgrastim (specifically filgrastim-sndz) is cost-effective in patients with intermediate risk for FN receiving curative chemotherapy regimens for breast cancer, NSCLC, and NHL. Expanding the use of colony-stimulating factors for patients may be valuable in reducing unnecessary health care visits for patients with cancer at risk of complications because of COVID-19 and should be considered for the indefinite future.