Confirmed biosimilarity of ZARXIO to NEUPOGEN® (filgrastim)1,2
Biosimilarity was confirmed by the PIONEER study and a PK/PD study that demonstrated equivalence with regard to ANC* and CD34+ cell counts1,2
PIONEER was a randomized, double-blind, comparative study of efficacy and safety between ZARXIO and NEUPOGEN® in 218 breast cancer patients treated with myelosuppressive chemotherapy.2†
- Study duration: 24 weeks1
- All patients received 6 cycles (3 weeks per cycle) of TAC‡ combination chemotherapy administered on Day 1 of each cycle2
- Starting on Day 2 of each chemotherapy cycle, ZARXIO or NEUPOGEN® was administered daily and continued until the ANC recovered to 10 x 109/L after the nadir or up to a maximum of 14 days (whichever occurred first)
- The study included 4 arms in total2
- 2 arms received treatment with either ZARXIO or NEUPOGEN® across all cycles
- 2 arms started with either ZARXIO or NEUPOGEN® in Cycle 1, then alternated treatment in each subsequent cycle
Study Design
*ANC is absolute neutrophil count.2
†A total of 218 patients were randomized in the study of which 204 were included in the primary prophylaxis (PP) population for the primary analysis. A total of 34 patients did not complete the study as planned or discontinued study treatment prematurely. The PP patients were on average 49.0 years old with an overall range between 23 and 76 years. The median duration since breast cancer diagnosis was 2.0 months (range from 0 to 171 months) and the majority of patients had stage II cancer (51.4%) or stage III cancer (41.6%). A total of 163 patients (76.2%) had an ECOG status of 0 and 51 patients (23.8%) had an ECOG status of 1.1
‡TAC combination chemotherapy includes docetaxel, doxorubicin, and cyclophosphamide.2
Efficacy
Primary endpoint for equivalence (in Cycle 1): mean duration of severe neutropenia (DSN)1,4§
§Defined as the number of consecutive days with severe neutropenia (ANC less than 0.5 x 109/L) in Cycle 1.1
IIANCOVA with treatment, disease status, and baseline ANC level.4
Biosimilarity demonstrated through the totality of evidence5
Secondary endpoints (in Cycle 1)1,2¶
#Defined as oral temperature ≥38.3°C while having an ANC <0.5 x 109/L (both measured on the same day).1,2
**ANC recovery was defined as the time in days from ANC nadir until the patient's ANC increases to ≥2 x 109/L after the nadir in Cycle 1.1,2
††Defined as the patient's lowest ANC in Cycle 1.1,2
‡‡Defined as oral temperature ≥38.3°C.1,2
ANC profiles of ZARXIO and NEUPOGEN®2
Secondary endpoint: depth of ANC nadir in Cycle 12§§
§§The nadir occurred around Days 7 and 8. There were no marked differences in the mean ANC between ZARXIO and NEUPOGEN® up to Day 10. Following Day 10, when in most patients the ANC had recovered by reaching at least 10 x 109/L, the number of patients with measurements decreased markedly as the ANC recovered in more and more patients.2
No antibodies against rhG-CSF were detected throughout the PIONEER study for either ZARXIO or NEUPOGEN®.2
Safety
Cardinal adverse events (between-group comparison)4
||||Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, pain, pain in extremity, or spinal pain.
¶¶Includes injection site erythema, extravasation, hematoma, pain, or pruritus.
Treatment-emergent adverse events (TEAEs) >5% in Cycle 11
The overall safety profile of ZARXIO was similar across all 6 cycles with continuous treatment.4
Prescribing Information adverse reactions6
The following most common adverse reactions listed in the ZARXIO Prescribing Information are based on the reference biologic.
ADVERSE REACTIONS
Most common adverse reactions in patients:
- With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased
- With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
- With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity
- Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache
- With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia
CONTRAINDICATIONS6
- Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products
WARNINGS AND PRECAUTIONS6
- Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture
- Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS
- Serious allergic reactions, including anaphylaxis: Permanently discontinue ZARXIO in patients with serious allergic reactions
- Fatal sickle cell crises: Have occurred
- Glomerulonephritis: Evaluate and consider dose-reduction or interruption of ZARXIO if causality is likely
USE IN SPECIFIC POPULATIONS6
- ZARXIO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
- It is not known whether filgrastim products are excreted in human milk
Learn about the PIONEER study from Ronald M Bukowski, MD, Medical Oncologist of the Cleveland Clinic Foundation and Ali McBride, PharmD, MS, BCPS, with the University of Arizona Cancer Center. Hosted by Jayson Dupre, DO.
References: 1. Data on file. Sandoz Inc. Princeton, NJ. 2. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26:1948-1953. http://annonc.oxfordjournals.org/content/26/9/1948.full.pdf. Accessed May 3, 2017. 3. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy [supplementary data]. Ann Oncol. 2015;26(9):1948-1953. http://annonc.oxfordjournals.org/content/early/2015/06/28/annonc.mdv281/suppl/DC1. Accessed May 3, 2017. 4. US Food and Drug Administration. Presentations for the January 7, 2015 Meeting of the Oncologic Drugs Advisory Committee. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf. Published January 7, 2015. Accessed May 3, 2017. 5. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Washington, DC: US Dept of Health and Human Services; April 2015. 6. ZARXIO Prescribing Information. Sandoz Inc. December 2017.
ZARXIO is a registered trademark of Novartis AG.
NEUPOGEN is a registered trademark of Amgen Inc.
