Mean Duration Of Severe Neutropenia Research Articles

Safety, tolerability, and quality of life (QoL) of single-agent plinabulin (Plin) for the prevention of docetaxel (Doc) chemotherapy (chemo)-induced neutropenia (CIN) in non-small cell lung cancer (NSCLC) patients (pts) from two randomized trials.

e21168 Background: Plin, is a novel, non-G-CSF, small molecule agent with comparable CIN-preventive effects vs pegfilgrastim. In contrast to pegfilgrastim, Plin is given on the same day of chemo (30 mins after chemo), and does not cause bone pain, nor thrombopenia. In the two randomized controlled (placebo (Plac)/no treatment) cancer trials, Phase (Ph) 2 Study 101 and Ph3 Study 103, single-agent (SA) Plin reduced estimated Doc-induced mean duration of severe neutropenia by > 1 Day vs Plac. We conducted a post hoc analysis of safety, tolerability, and QoL in NSCLC pts from these trials. Methods: NSCLC pts in 2nd/3rd line, with at least 1 NCCN FN risk factor, were randomized to Doc (75 mg/m2) + Plin (n = 116; at the CIN dose of 20 mg/m2 or its pharmacokinetic equivalent), or Doc + Plac (n = 296) in trials 101 (NCT00630110) and 103 (NCT02504489). Doc was given on day (D) 1, and Plin was given twice per cycle, on D1 and D8 (Plin D1 and D8 dosing is supratherapeutic for CIN but facilitated a more robust safety/tolerability evaluation [the CIN Plin dose is D1 only]). Safety blood draws and AE collection on D1 and D8; tolerability; and QoL (pre-dose and D8) were evaluated over 4 cycles. All pts received dexamethasone premedication. QoL scores were obtained in study 103 only, with Plin (n = 80) and Plac (n = 234), by validated questionnaires (EORTC QLQ C30, to evaluate global health status/QoL; the combined symptom scales/items, and the lung cancer-specific QoL questionnaire QLQ-LC13). Results: QoL scores over 4 cycles between Plin and Plac were similar, indicating Plin was well-tolerated. Grade (Gr) 3/4 AEs of interest for Plin (+Doc) and Plac (+Doc) are summarized in the table. With Plin, AE frequency of diarrhea was slightly higher (5.2% vs 1%; 1 Gr4 case with Plin), but was manageable, and so was hypertension (11.2% vs 1.7%; all Gr3 cases) vs Plac. Hypertension occurred around the time of infusion and was short-lasting (~2-4 hours) and typically self-limiting. Plin had less AEs of neutropenia (16.4% vs 50.3%) and leukopenia (15.5% vs 38.5%) vs Plac. Conclusions: Plin is an effective agent for CIN, has a favorable safety, tolerability, and QoL profile, and has the advantage of dosing on the same day of chemo. Clinical trial information: NCT02504489 . [Table: see text]

Comparison of Efficacy and Safety of Lupin’s Pegfilgrastim with Neulastim® as an Adjunct to Chemotherapy in Patients with Non Myeloid Malignancies: A Randomised Phase III Clinical Study

Introduction: Pegfilgrastim is indicated in patients receiving myelosuppressive anticancer drugs to reduce the Duration of Severe Neutropenia (DSN) and incidence of Febrile Neutropenia (FN). The efficacy and safety of a proposed pegfilgrastim biosimilar should be compared with an approved biologic drug to establish therapeutic equivalence. Aim: To compare the efficacy of Lupin’s biosimilar Pegfilgrastim versus Neulastim® (Amgen Inc.) as an adjunct to chemotherapy in patients with non-myeloid malignancies. Materials and Methods: The present prospective, open-label, randomised phase lll clinical study was conducted on a total of 170 patients with histologically or cytologically confirmed non-myeloid malignancies eligible to receive a myelosuppressive chemotherapy regimen. The participants were administered Lupin’s Pegfilgrastim (n=86) or Neulastim® (n=84) 6 mg by subcutaneous injection, once in each chemotherapy cycle for a maximum of three cycles. Patients were chemotherapy naive or had not received myelosuppressive chemotherapy within last 12 months of screening. The primary efficacy endpoint was DSN (number of days on which absolute neutrophil count <0.5×109 /L) in cycle 1 of chemotherapy. Equivalence was confirmed if 95% Confidence Intervals (CI) were within the equivalence margin of ±1 day. Safety evaluation included assessment of Adverse Events (AEs), rate of discontinuation due to AEs, vital signs, and laboratory parameters. Statistical analysis were done using SAS Enterprise guide 9.4 (SAS Institute Inc., Cary, 2000). Results: Of the 170 patients balanced for demographic characteristics, 161 patients completed cycle 1, 151 patients completed cycle 2, and 142 patients completed cycle 3. The mean±Standard Deviation (SD) DSN in cycle 1 was 0.127±0.5533 days with Pegfilgrastim (n=63) and 0.197±0.6615 days with Neulastim® (n=66) in the Per Protocol (PP) assessment; and 0.174±0.636 days with Pegfilgrastim and 0.193±0.671 days with Neulastim® in the modified Intent-to-Treat (mITT) assessment. The mean DSN between the groups did not differ significantly (PP: p=0.5167, mITT: p=0.8554). The 95% CI of difference in mean DSN in PP (-0.2796 to 0.1481) and mITT (-0.2103 to 0.1889) assessments was contained within the predefined equivalence margin of ±1 day. Secondary outcomes and safety profiles were also comparable between the two groups. Conclusion: The present study establishes Lupin’s Pegfilgrastim as a therapeutically equivalent biosimilar alternative to Neulastim® in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy

Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.

547 Background: Peg is the current standard of care (SoC) for the prevention of CIN, with a low absolute neutrophil (N) count (ANC) week 1 after chemotherapy (chemo) with normalization in week 2. Breakthrough designation agent from FDA, Plin, a novel, non-G-CSF agent for the prevention of CIN, produces a normal ANC in week 1 of cycle (C) 1 by potentially protecting progenitor cells in bone marrow from chemo assault, and also has anticancer activity (Blayney, St Gallen 2019; ASCO 2019). Here we report data from a pre-specified interim analysis from PROTECTIVE-1 (Study 105; NCT03102606). Methods: Breast cancer (BC), lung (NSCLC) and prostate cancer (HRPC) pts with at least 1 risk factor as per NCCN, received docetaxel (Doc) 75 mg/m2 with either Peg 6mg (n=53) or Plin 40 mg (n=52) over 4 cycles, and had ANC blood draws on Day (D) 1, 2,6,7,8,9,10,15 in C1 (Covance Central Laboratory). Plin was given on D1, as a 30 min IV infusion, 30 min after Doc, and Peg, 24 hrs after Doc. Primary objective was to demonstrate non-inferiority (NI) of SA Plin vs SA Peg for duration of severe neutropenia (DSN) in C1. NI of Plin vs Peg would be declared if the upper limit of 95% confidence interval for the mean DSN difference between Plin and Peg would be <0.65 day. Other endpoints included C1 platelet count, C1 bone pain scores (validated questionnaire), C1-4 clinical sequelae of CIN through [febrile neutropenia (FN), infection, antibiotic and hospitalization rate, and Doc discontinuation (Discont) and delays], and safety (AEs, hematology and chemistry, vital signs) Results: Predefined DSN NI criterion between SA Plin and SA Peg was met. C1 Grade 4 toxicity was not different between Plin and Peg (p=NS). Clinical sequelae of CIN were comparable or slightly better for Plin vs Peg (see Table). Plin caused less bone pain (p=0.01) and less thrombocytopenia (p<0.0001 on D15) vs Peg. AE frequency and overall safety was comparable for SA Plin and SA Peg. Conclusions: SA Plin has efficacy for Doc CIN prevention non-inferior compared to SoC Peg, and accordingly has comparable (or numerically better) profile for clinical sequelae of CIN. Plin has an advantage for bone pain, platelet counts, convenience of use (same day vs next day dosing) over SoC Peg and has anticancer activity. Clinical trial information: NCT03102606. [Table: see text]

Abstract OT-06-02: Protective-2 (bpi-2358-106): A confirmatory trial to demonstrate superiority of the plinabulin+pegfilgrastim (plin/peg) combination versus standard of care pegfilgrastim for the prevention of chemotherapy-induced neutropenia (cin) in breast cancer (bc) patients (pts)

Abstract Introduction. BC is a potentially curable cancer condition, with more favorable outcomes with avoidance of CIN. Peg is the standard of care for the prevention of CIN, but does not fully prevent CIN (Masuda 2015). Plin is a novel, small molecule, non-G-CSF agent, given as a single dose per cycle, by 30 min IV infusion, 30 min after Chemotherapy (Chemo), on the same day of Chemo. In contrast to Peg, Plin does not cause bone pain or thrombocytopenia. The mechanism of action (MoA) of Plin exerts its CIN preventive effects predominantly in week 1 of the cycle, whereas Peg primarily in week 2. This was the rationale to combine these two agents, to obtain superior CIN protection throughout the entire cycle (Blayney ASCO 2019). Data from Phase (Ph) 2 portion of PROTECTIVE-2 (NCT0329457) with the Plin/Peg combination demonstrated superiority in CIN protection vs Peg alone, with a favorable safety/tolerability profile (Blayney, St Gallen 2019). Additionally, the addition of Plin to Peg almost eradicated the Peg-induced bone pain. The Ph 3 portion of PROTECTIVE-2 aims to confirm superiority of the Plin/Peg combination vs Peg standard of care for avoidance of CIN and Bone Pain-prevention. Trial Design PROTECTIVE-2 is a global, multicenter, randomized, double-blind Study to Evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Arm 2) in preventing Severe Neutropenia ( defined as Absolute Neutrophil Count (ANC) of <0.5×10E9/L) in early stage (Stage I and II) and Stage III BC (node positive or node negative with a high risk of recurrence) pts with ECOG status 0 or 1 (target of approximately n=222 pts) receiving myelosuppressive Chemo with Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC). A non-binding Interim Analysis was a planned at approximately n=100 pts completing Cycle 1. TAC and Plin were given on Day (D) 1 and Peg on D2.ANC (Covance Central Laboratory) was assessed before and after during Cycle 1 on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Bone Pain was assessed by a validated at regular timepoints in Cycle 1 with a validated PRO questionnaire. The Primary objective was to compare the percentage of pts with a Duration of Severe Neutropenia (DSN) of 0 days in treatment Cycle 1 between the Plin/Peg vs Peg alone. Secondary objectives in Cycle 1 included mean DSN, mean ANC NADIR, average change in Bone Pain from baseline, the rate of composite risk (infection, FN, hospitalization, significant disability, life threatening and death), and over 4 Cycles, the percentage of patients with Relative Dose Intensity (RDI) < 85%. Following the pre-planned Interim Analysis, the DSMB recommended the trial to continue without modifications. Current Status: Patient accrual has been completed. Citation Format: Douglas W. Blayney, Lan Huang, Ramon W. Mohanlal. Protective-2 (bpi-2358-106): A confirmatory trial to demonstrate superiority of the plinabulin+pegfilgrastim (plin/peg) combination versus standard of care pegfilgrastim for the prevention of chemotherapy-induced neutropenia (cin) in breast cancer (bc) patients (pts) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-06-02.

Abstract OT-06-01: Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898)

Abstract Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day and 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC) administration, the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of Efla same-day (3 different dosing timepoints) in patients receiving TC for treatment of ESBC. Trial Design: This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla (3.6 mg G-CSF) following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Patients will be randomized 1:1:1 to Efla dose schedules of 0.5, 3, and 5 hours after TC. The primary endpoint is DSN (ANC <0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Eligibility Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are >18 years of age, are candidates for neoadjuvant or adjuvant TC chemotherapy, have an ECOG of <2, with adequate hematological, renal, and hepatic function. Patients will be excluded if they have a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant, or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters. The sample size produces a 2-sided 95% CI with a distance from the mean DSN to the limits that is equal to 0.554 using t-distribution when the estimated standard deviation is 1.0 days. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Citation Format: Lee S. Schwartzberg, Jawad Francis, Hlalah Osama, Manuel Modiano, Jayaram Bharadwaj, Shanta Chawla, Gajanan Bhat, Francois Lebel, Nishan Tchekmedyian. Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-06-01.

Protective-2 (BPI-2358-106): A Confirmatory Trial to Demonstrate Superiority of the Plinabulin+Pegfilgrastim (Plin/Peg) Combination Versus Standard of Care Pegfilgrastim for the Prevention of Chemotherapy-Induced Neutropenia (CIN) in Breast Cancer (BC) Patients (pts)

Introduction. BC is a potentially curable cancer condition, with more favorable outcomes with avoidance of CIN. Peg is the standard of care for the prevention of CIN, but does not fully prevent CIN (Masuda 2015). Plin is a novel, small molecule, non-G-CSF agent, given as a single dose per cycle, by 30 min IV infusion, 30 min after Chemotherapy (Chemo), on the same day of Chemo. In contrast to Peg, Plin does not cause bone pain or thrombocytopenia (Blayney JAMA Onc in press). The mechanism of action (MoA) of Plin exerts its CIN preventive effects predominantly in week 1 of the cycle, whereas Peg primarily in week 2. This was the rationale to combine these two agents, to obtain superior CIN protection throughout the entire cycle (Blayney ASCO 2019). Data from Phase (Ph) 2 portion of PROTECTIVE-2 (NCT0329457) with the Plin/Peg combination demonstrated superiority in CIN protection vs Peg alone, with a favorable safety/tolerability profile (Blayney, St Gallen 2019). Additionally, the addition of Plin to Peg almost eradicated the Peg-induced bone pain. The Ph 3 portion of PROTECTIVE-2 aims to confirm superiority of the Plin/Peg combination vs Peg standard of care for avoidance of CIN and Bone Pain-prevention. Trial Design PROTECTIVE-2 is a global, multicenter, randomized, double-blind Study to Evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Arm 2) in preventing Severe Neutropenia (defined as Absolute Neutrophil Count (ANC) of <0.5×10E9/L) in early stage (Stage I and II) and Stage III BC (node positive or node negative with a high risk of recurrence) pts with ECOG status 0 or 1 (target of approximately n=222 pts) receiving myelosuppressive Chemo with Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC). A non-binding Interim Analysis was a planned at approximately n=100 pts completing Cycle 1. TAC and Plin were given on Day (D) 1 and Peg on D2. ANC (Covance Central Laboratory) was assessed before and after during Cycle 1 on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Bone Pain was assessed by a validated at regular timepoints in Cycle 1 with a validated PRO questionnaire. The Primary objective was to compare the percentage of pts with a Duration of Severe Neutropenia (DSN) of 0 days in treatment Cycle 1 between the Plin/Peg vs Peg alone. Secondary objectives in Cycle 1 included mean DSN, mean ANC NADIR, average change in Bone Pain from baseline, the rate of composite risk (infection, FN, hospitalization, significant disability, life threatening and death), and over 4 Cycles, the percentage of patients with Relative Dose Intensity (RDI) < 85%. Following the pre-planned Interim Analysis, the DSMB recommended the trial to continue without modifications. Current Status: Patient accrual has been completed. Disclosures Blayney: BeyondSpring Pharma: Other: Research Funding to Institution. Mohanlal:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company. Huang:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company.

Eflapegrastim, a novel, long-acting GCSF for reducing chemotherapy-induced neutropenia: Integrated results from two phase III trials in breast cancer patients.

61 Background: Eflapegrastim (E) is a novel, long-acting GCSF comprised of recombinant human GCSF covalently linked to human IgG4 Fc fragment via a PEG linker (MW, 72 kDa). E showed increased potency vs pegfilgrastim (P) in preclinical and Phase I and II trials. Two identically designed Phase III pivotal trials (NCT02643420, NCT02953340) were conducted globally with a fixed dose of 13.2 mg E containing 3.6 mg GCSF to evaluate E vs P (6 mg) in pts receiving chemotherapy for early-stage breast cancer. Methods: Each open-label trial randomized pts 1:1 to a single subcutaneous dose of E 13.2 mg/0.6 mL or P 6 mg/0.6 mL on Day 2 of each of four 21-day cycles following Day 1 adj/neoadj docetaxel 75 mg/m2 + cyclophosphamide 600mg/m2 (TC) . The primary endpoint was to demonstrate E non-inferiority (NI) to P as measured by mean duration of severe neutropenia (DSN) in Cycle 1. Results: A total 643 intent-to-treat pts (314 E/329 P) with median age 60 yrs (24–88) were enrolled. Cycle 1 mean (SD) DSN was 0.24 (0.581) vs 0.36 (0.789) days for E and P, confirming NI (p<.0001) and suggesting statistical superiority (p<.029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight (>75kg) pts, DSN was reduced for E vs P. In Cycle 1, E showed an absolute risk reduction for severe neutropenia of 6.5% vs P (27.1% relative risk reduction, p<.043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p=ns) in Cycle 1. Incidence of FN was low for both E and P, 1.6% vs 1.8% in Cycle 1 and 3.2% vs 3.0% overall. ANC profiles showed sustained increased levels for E vs P in the recovery phase across all cycles. Safety profiles including events of special interest, irrespective of grade, were mostly similar for E and P. The most common ≥ Grade 3 adverse events were hematologic due to chemotherapy. Conclusions: These integrated pivotal trial results confirm a similar safety profile and non-inferiority in reducing neutropenic risk for E at a lower GCSF dose vs P. The data also suggests the potential for increased potency of E to deliver improved clinical benefit, a possibility that warrants further clinical trials. Clinical trial information: NCT02643420 and NCT02953340.

Eflapegrastim, a novel and potent long-acting GCSF for reducing chemotherapy-induced neutropenia: Integrated results from two phase III trials in breast cancer patients.

539 Background: Eflapegrastim (E) is a novel long-acting GCSF comprised of recombinant human GCSF covalently linked to human IgG4 Fc fragment via a PEG linker (MW, 72 kDa). E showed increased potency vs pegfilgrastim (P) in preclinical and Phase I and II trials. Two identically designed Phase III pivotal trials (NCT02643420, NCT02953340) were conducted globally with a fixed dose of 13.2 mg E containing 3.6 mg GCSF to evaluate E vs P (6 mg) in pts receiving chemotherapy for early-stage breast cancer. Methods: Each open-label trial randomized pts 1:1 to a single subcutaneous dose of E 13.2 mg/0.6 mL or P 6 mg/0.6 mL on Day 2 of each of four 21-day cycles following Day 1 adj/neoadj docetaxel 75 mg/m2 + cyclophosphamide 600mg/m2 (TC). The primary endpoint was to demonstrate E non-inferiority (NI) to P as measured by mean duration of severe neutropenia (DSN) in Cycle 1. Results: A total 643 intent-to-treat pts (314 E/329 P) with median age 60 yrs (24–88) were enrolled. Cycle 1 mean (SD) DSN was 0.24 (0.581) vs 0.36 (0.789) days for E and P, confirming NI (p < .0001) and suggesting statistical superiority (p < .029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight ( > 75kg) pts, DSN was reduced for E vs P. In Cycle 1, E showed an absolute risk reduction for severe neutropenia of 6.5% vs P (27.1% relative risk reduction, p < .043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p = ns). Incidence of FN was low for both E and P, 1.6% vs 1.8% in Cycle 1 and 3.2% vs 3.0% overall. ANC profiles showed sustained increased levels for E vs P in the recovery phase across all cycles. Safety profiles were similar for E and P, including primarily for expected hematologic AEs and for bone pain and other musculoskeletal pain. Conclusions: These integrated pivotal trial results confirm a similar safety profile and non-inferiority in reducing neutropenic risk for E at a lower GCSF dose vs P. The data also suggests the potential for increased potency of E to deliver improved clinical benefit, a possibility that warrants further clinical trials. Clinical trial information: NCT02643420, NCT02953340.

GX-G3, a long-acting G-CSF, compared with pegfilgrastim in reducing duration of severe neutropenia after chemotherapy for non-Hodgkin’s lymphoma.

e19065 Background: G-CSF is used in patients at significant risk for developing severe neutropenia (neutrophil count < 0.5 × 109/L or grade 4 neutropenia) following myelosuppresive chemotherapy. GX-G3, human G-CSF fused to hyFc is a proposed alternative to Neulasta. Methods: An open-label, randomized, phase II study was designed to compare the effects of subcutaneous (SC) injection of GX-G3 (a long-acting G-CSF) at doses of 150, 250 and 350 μg/kg with Neulasta 6 mg administered SC in patients receiving R-CHOP for advanced NHL (n = 65). The primary objective was to assess the duration of severe neutropenia after 1st cycle of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). The following parameters were also assessed: duration of severe neutropenia after 2nd cycle of chemotherapy, optimal time for GX-G3 intervention (two GX-G3 250 μg/kg cohorts; administered 24 and 72 hours after R-CHOP), incidence of severe neutropenia and febrile neutropenia post R-CHOP, pharmacokinetics, and safety. Patients were randomly assigned to receive GX-G3 or reference drug, Neulasta, one dose after 1st and 2nd cycle of R-CHOP for a total of 2 doses. Results: The mean duration of severe neutropenia after 1st cycle was shortest in GX-G3 350 μg/kg group [GX-G3 150, 250 (24h, 72h), 350 μg/kg and Neulasta®; 3.2, 2.3, 2.0, 1.3 and 2.4 days, respectively]. The results of all GX-G3 groups and Neulasta were not significantly different for duration of severe neutropenia after 2nd cycle of R-CHOP, incidence of severe neutropenia and febrile neutropenia, or toxicity profile. The elimination half-life of GX-G3 and Neulasta ranged from 29.8 to 66 hours and 19.2 to 76.8 hours, respectively. Conclusions: GX-G3, in all tested dosage regimen, was safe and well tolerated in this patient population. A single injection of GX-G3 per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by Neulasta. GX-G3 administration after 24 hours, compared to 72 hours post R-CHOP treatment resulted in relatively shorter duration of severe neutropenia. Clinical trial information: 2015-002693-20.

Abstract P1-13-05: Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second Phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial)

Abstract Background: Eflapegrastim is a novel investigational biologic comprised of recombinant human G-CSF covalently linked to the human immunoglobulin G4FC fragment using proprietary LAPSCOVERY™ technology with potentially unique distribution to areas rich in FcRn receptors. RECOVER is the second Phase 3 study to investigate the non-inferiority (NI) of eflapegrastim to pegfilgrastim in patients receiving chemotherapy for breast cancer. The first Phase 3 study, ADVANCE, has demonstrated the non-inferiority of eflapegrastim comparing to pegfilgrastim in the duration of severe neutropenia (DSN) in breast cancer patients receiving docetaxel and cyclophosphamide (TC) and was previously published at ASCO 2018 meeting. TrialDesign: Patients with Stage I to Stage IIIA breast cancer from centers in the USA, Canada, Poland, Hungary, South Korea and India were treated on Day 1 of each of four 21-day cycles with adjuvant or neo-adjuvant TC. On Day 2 of each cycle, patients received a single subcutaneous dose of either eflapegrastim 13.2 mg/0.6 mL (equivalent to 3.6 mg G-CSF) or pegfilgrastim (6 mg) in a 1:1 ratio. Patients had CBCs drawn on Day 1 prior to chemotherapy and Days 4-15 daily or until recovery of neutropenia in Cycle 1. CBC was also collected on Days 1, 4, 7, 10 and 15 in Cycles 2-4. The primary endpoint was to demonstrate the non-inferiority of eflapegrastim comparing to pegfilgrastim as measured by the mean DSN in Cycle 1 with NI margin of <0.62 day. Results: In a total of 237 intent-to-treat patients (randomized to 118 eflapegrastim; 119 pegfilgrastim), median age was 59 years (range 29 to 88 years); mean (SD) DSN was 0.31 (0.688) days for eflapegrastim and 0.39 (0.949) days for pegfilgrastim, demonstrating the non-inferiority (95% CI of ΔDSN: [-0.292, 0.129]; p<0.0001). Non-inferiority of eflapegrastim for DSN was maintained across all 4 cycles. There were no statistically significant differences in secondary endpoints: time to ANC recovery, depth of ANC nadir and incidence of FN at Cycle 1. The common Grade 3/4 adverse events observed in≥5%of patients were similar across both arms and were mainly hematologic including neutropenia, lymphopenia, anemia and leukopenia. Grade 3/4 bone pain and febrile neutropenia rates were similar across both arms and were less than 5%. Conclusions: Eflapegrastim, a novel long acting G-CSF demonstrated non-inferiority to pegfilgrastim in the reduction of DSN in breast cancer patients treated with TC and has validated the results from the first Phase 3 ADVANCE study. Eflapegrastim was safe and well-tolerated with a similar safety profile to pegfilgrastim. Citation Format: Schwartzberg L, Bhat G, Mezei K, Lang I, Moon YW, Senviratne L, Chawla S, Cobb P, Yang Z. Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second Phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-05.

Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving chemotherapy

BackgroundTreatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen.MethodsTwo hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 109/L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2–4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes.ResultsThe mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI -0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified.ConclusionsTreatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated.Trial registrationThe trial was registered prospectively, prior to study initiation. EudraCT number (2013–003166-14). The date of registration was 12 July, 2013.

1696P - A randomized, open-label, non-inferiority study comparing the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B-cell non-Hodgkin lymphomas (B-NHL): AVOID neutropenia

Background: Lipegfilgrastim (LONQUEX®) has proven to be non-inferior to pegfilgrastim (NEULASTA®) in the reduction of the duration of severe neutropenia (DSN) in breast cancer patients. The efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with B-NHL at high risk for R-CHOP-21-induced neutropenia was investigated. The primary efficacy endpoint was the DSN in cycle 1. Methods: One hundred and one patients with NHL, median age of 74 years, were randomized to receive either 6 mg of lipegfilgrastim or pegfilgrastim per cycle during 6 cycles of R-CHOP-21. Results: Lipegfilgrastim was non-inferior to pegfilgrastim in the DSN in cycle 1: the mean DSN (days) in cycle 1 was 0.8±.96 and 0.9±1.08 in the per-protocol population, respectively with an adjusted mean difference (95% confidence interval) between groups of -0.3 (-0.70, 0.19). The upper boundary was below the predefined non-inferiority margin of 1. Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of febrile neutropenia (FN) in cycle 1 was 2% (1/41) in the lipegfilgrastim and 0% (0/44) in the pegfilgrastim group. The incidence of severe neutropenia in cycle 1 was similar in the lipegfilgrastim (21/41; 51%) and pegfilgrastim (23/44; 52%) groups. The mean time to absolute neutrophil count recovery to a threshold of ≥ 2.0 × 109/L was similar in lipegfilgrastim (8.3 days) and pegfilgrastim (8.7 days) groups. Adverse events (AEs) occurred in 98% of patients; in 45/46 of lipegfilgrastim and 49/50 of the pegfilgrastim group. Serious AEs occurred in 46% of patients; 21/46 in the lipegfilgrastim and 23/50 in pegfilgrastim group; none were assessed as treatment-related by the investigator. Fatal AEs occurred in 4% (2/46) of lipegfilgrastim and 10% (5/50) of the pegfilgrastim group. Study withdrawal due to AEs occurred in 2% (1/46) of the lipegfilgrastim and 18% (9/50) of the pegfilgrastim group. Conclusions: Lipegfilgrastim was non-inferior to pegfilgrastim in the reduction of the DSN in elderly patients with B-NHL. The safety of lipegfilgrastim was comparable to pegfilgrastim. Clinical trial identification: EudraCT: 2013-001284-23. Legal entity responsible for the study: Merckle GmbH (part of Teva Pharmaceuticals group). Funding: Merckle GmbH (part of Teva Pharmaceuticals group). Disclosure: H. Link: Advisory boards, investigator in sponsored trial: Teva. G. Illerhaus, U.M. Martens, A. Salar, R. Depenbusch, A. Kohler, M.M. Engelhardt, S. Mahlmann, M. Zaiss: Investigator in Teva sponsored trial. A. Lammerich, P. Bias, A. Buchner: Employee and stock options: Teva.

Clinical confirmation to demonstrate similarity for a biosimilar pegfilgrastim: a 3-way randomized equivalence study for a proposed biosimilar pegfilgrastim versus US-licensed and EU-approved reference products in breast cancer patients receiving myelosuppressive chemotherapy

BackgroundChemotherapy-induced neutropenia is a common result of myelosuppressive chemotherapy treatment. Infections such as febrile neutropenia (FN) are sensitive to the duration of neutropenia as well as the depth of absolute neutrophil count (ANC) at nadir. Filgrastim, a granulocyte colony stimulating factor (G-CSF), can stimulate the function of mature neutrophils. Pegfilgrastim, a long-acting form of filgrastim, has been shown to reduce FN to a greater extent compared to filgrastim. G-CSF agents have been recommended for prophylactic administration with chemotherapy. Apotex developed a proposed pegfilgrastim biosimilar. This study was conducted to confirm that no clinically meaningful efficacy or safety differences exist between Apotex’s proposed biosimilar and its reference product.Methods589 breast cancer patients were randomized and dosed with the proposed pegfilgrastim biosimilar, US-licensed pegfilgrastim reference product, or EU-approved pegfilgrastim reference product. The primary endpoint assessed was the duration of severe neutropenia (DSN) and secondary endpoints included rate of FN and ANC nadir.ResultsData showed that the mean DSN, the primary endpoint measured, was comparable across all three treatments. The As Treated arm had a 95% confidence interval within the equivalence range for the proposed pegfilgrastim biosimilar with the US-licensed and EU-approved pegfilgrastim reference products. Secondary endpoints, which included depth and peak of ANC nadir, time to ANC recovery post-nadir and rates of FN, also showed similarity between the three different treatment groups. The adverse event incidence was similar across treatment arms and there were no unexpected safety events.ConclusionsOverall, these results show that the proposed pegfilgrastim biosimilar is similar to Amgen’s US-licensed and EU-approved pegfilgrastim reference products with regard to the clinical efficacy and safety endpoints assessed.Trial registration EMA: European Union Clinical Trials Register: (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-002678-21) Eudract # 2011-002678-21 Registered: 01/10/2012

1574P - Efficacy and safety of RGB-02, a proposed biosimilar pegfilgrastim to prevent chemotherapy-induced neutropenia: Results of a randomized, double-blind, phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving docetaxel/doxorubicin

Background: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02, a pegylated G-CSF (pegfilgrastim) developed by Gedeon Richter is a proposed biosimilar to the reference pegfilgrastim product Neulasta®. Here we are presenting the results of a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen (EudraCT nr: 2013-003166-14). Methods: 239 women presenting with breast cancer were randomized to RGB-02 (n = 121) and to the reference pegfilgrastim, Neulasta® (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 x109/L) in Cycle 1 (2-sided CI interval 95%). Secondary endpoints included incidence and duration of severe neutropenia, incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. Results: The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI -0.2, 0.4). Therapeutic equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ± 1 day. The incidence of severe neutropenia decreased from cycle 1 to 2 in both groups with no statistical significant differences, for RGB-02 from 84.6% (99 patients) to 54.1% (60 patients) and from 77.0% (87 patients) to 43.7% (45 patients) in the comparator group. Both groups were similar regarding mean time to ANC recovery with 3.4 ± 1.84 days (RGB-02) and 3.7 ± 1.88 days (reference) during Cycle 1. Safety profiles were comparable between groups. Conclusions: Therapeutic equivalence and similar safety profiles between RGB-02 and Neulasta® as once-per-cycle administration could be demonstrated. RGB-02 can provide a biosimilar alternative for the prevention of neutropenia. Clinical trial identification: EudraCT nr: 2013-003166-14 Legal entity responsible for the study: Gedeon Richter Plc. Funding: Gedeon Richter Plc. Disclosure: K. Horvat-Karajz, A. Illes: Employee of Gedeon Richter Plc. All other authors have declared no conflicts of interest.

Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer

BackgroundFollowing 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 methodsLA-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.ResultsA 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.ConclusionsThis 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 numbersNCT01735175 and NCT01516736.

Abstract P2-11-05: Safety, immunogenicity and efficacy of proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in breast cancer: Pooled analysis of two randomized, double-blind, phase III trials

Abstract Background: Biosimilars are highly similar to a biological reference product with no clinically meaningful differences in terms of efficacy and safety. Here we present the pooled analysis of two randomized trials (PROTECT1 and 2) comparing the efficacy, safety and immunogenicity of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim (Neulasta®*). Methods: Two multinational, independent, prospective, double-blind, phase III studies (EudraCT: 2011-004532-58; 2012-002039-28) enrolled adult chemotherapy-naïve women with breast cancer scheduled to receive ≤6 cycles of (neo)-adjuvant chemotherapy with docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC). Patients were randomized to receive a single 6 mg injection of LA-EP2006 or reference on Day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) (number of consecutive days with ANC &amp;lt;0.5x109/L) in Cycle 1. Equivalence was confirmed if the 95% confidence intervals (CI) for the difference in mean DSN between groups were within a pre-defined margin of ±1 day. Secondary efficacy endpoints included incidences of febrile neutropenia (FN), fever and infections, and depth of ANC nadir and time to ANC recovery (≥2×109/L after the nadir) in Cycle 1. Safety was assessed at each visit with follow-up visits at 4 weeks and 6 months (PROTECT1 only) after last administration of pegfilgrastim. Immunogenicity was assessed before the first pegfilgrastim injection, on Day 15 of cycle 6, and 4 weeks and 6 months (PROTECT1 only). Results: A total of 624 patients were randomized (LA-EP2006: n=314; reference: n=310). Baseline demographics were well balanced (mean age: LA-EP2006: 49.3 years, reference: 49.8; median duration (months) since initial diagnosis: LA-EP2006: 1.33 [0.1−76.0], reference: 1.35 [0.2−11.2]; ECOG status 0: LA-EP2006: 78%, reference: 75%). Mean DSN difference in Cycle 1 was -0.04 days (95% CI: -0.19, 0.11), showing statistical equivalence. FN was reported in 5.7% of patients with LA-EP2006 vs. 8.4% with reference in Cycle 1 (all cycles: 8.0% vs. 10.3%). Across all cycles, frequency of fever (LA-EP2006: 18.5%; reference: 19.7%) and infections (LA-EP2006: 15.6%; reference: 18.1%) were similar in both groups. Mean ANC time courses were almost superimposable in the two groups, with similar time and depth of ANC nadir and median time to ANC recovery was 2 days in both groups in Cycle 1. Treatment-emergent adverse events (TEAEs) were similar across groups (LA-EP2006: 92%; reference: 89%), and TEAEs with a suspected relationship to pegfilgrastim were reported in 22.6% of patients with LA-EP2006 and 21.3% with reference across all cycles, with the most frequent being musculoskeletal and connective tissue disorders (LA-EP2006: 10.2%; reference: 9.7%). Serious TEAEs were reported in 14.3% (LA-EP2006) vs. 17.1% (reference) across all cycles. No neutralizing or clinically relevant anti-pegfilgrastim antibodies were identified. Conclusions: LA-EP2006 demonstrated similar clinical efficacy and safety to reference pegfilgrastim in patients with breast cancer receiving myelotoxic chemotherapy. *Neulasta® is a registered trademark of Amgen Inc. Citation Format: Blackwell K, Gascon P, Jones CM, Nixon A, Nakov R, Mo M, Krendyukov A, Nadia H. Safety, immunogenicity and efficacy of proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in breast cancer: Pooled analysis of two randomized, double-blind, phase III trials [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-05.

Abstract OT1-01-11: Randomized phase 3 study of a novel, long-acting G-CSF (eflapegrastim) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study)

Abstract Background: Eflapegrastim is a distinct biologic that uses an innovative, proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™). Eflapegrastim consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors including its site of action in the bone marrow. A successful dose-finding Phase 2 trial including a pegfilgrastim control arm established the dose for a Phase 3 non-inferiority trial. Trial Design: This is a randomized, open-label, active-controlled, multinational, multicenter, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim. Patients (n=580) will be randomized in a 1:1 ratio to receive either eflapegrastim (equivalent to 3.6 mg G-CSF) or pegfilgrastim (equivalent to 6.0 mg G-CSF) once per chemotherapy cycle (up to 4 cycles), approximately 24 hours after chemotherapy. The primary endpoint is to compare the efficacy of a single dose of eflapegrastim with pegfilgrastim in patients with ESBC receiving TC, as measured by the Duration of Severe Neutropenia (DSN) in Cycle 1. Key secondary objectives include Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1; Depth of ANC Nadir in Cycle 1; incidence of Febrile Neutropenia. Safety and pharmacokinetics will also be assessed. Eligibility Criteria: This study is enrolling histologically confirmed ESBC patients who are: eligible to receive adjuvant or neoadjuvant TC chemotherapy; at least 18 years of age, with adequate hematologic, renal and hepatic function. Patients will be excluded if they have: active concurrent malignancy or life-threatening disease; a known sensitivity or previous reaction to E. coli derived products or any of the products to be administered during study participation; concurrent adjuvant cancer therapy; locally recurrent/metastatic or contralateral breast cancer; previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development prior to the administration of study drug; bone marrow or hematopoietic stem cell transplant or radiation therapy prior to enrollment, or are pregnant or breast-feeding. Statistical Methods: The goal of this study is to demonstrate non-inferiority. For the Primary Efficacy Analysis, the mean DSN in Cycle 1 will be compared between the eflapegrastim and pegfilgrastim treatment arms. A 2-sided 95% confidence interval (CI) of the difference between the mean DSN of the eflapegrastim arm and the mean DSN of the pegfilgrastim arm will be calculated using bootstrap resampling with treatment as the only stratification factor. For the Secondary Efficacy Analyses, the results will each be summarized by treatment arm and cycle. The two-sided 95% CI for the difference between the treatment arms will be calculated. Target Accrual: Approximately 580 patients. Enrollment began January 2016. Contact Information: Spectrum Pharmaceuticals. advance@sppirx.com. Citation Format: Schwartzberg LS, Bharadwaj J, Peguero JA, Vacirca JL, Ibrahim EN, Bhat G, Choi MR, McGregor K, Agajanian R. Randomized phase 3 study of a novel, long-acting G-CSF (eflapegrastim) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-11.

LBA2 Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer receiving myelotoxic chemotherapy: Pooled subgroup analysis of two randomized trials

Background Two prospective, double-blind, randomized, phase III trials (PROTECT1 and 2) showed similar efficacy and safety with proposed biosimilar pegfilgrastim (LA- EP2006) and reference pegfilgrastim (NeulastaVR , Amgen Inc.) in patients with breast cancer receiving myelotoxic chemotherapy. Here we present a pooled subgroup analysis of patients of Asian ethnicity enrolled in these trials. Methods Adult chemotherapy-na¨ıve women with breast cancer scheduled to receive (neo)-adjuvant chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2, ::;6 cycles) were enrolled in two trials of similar design. Patients were randomized to 6 mg of LA-EP2006 or reference pegfilgrastim on Day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) (number of consecutive days with absolute neutrophil count [ANC] <0.5x109/L) during Cycle 1, analyzed using analysis of covariance with corresponding 95% confidence intervals (CI). Equivalence was shown if 95% CIs for the difference in mean DSN between groups were within a pre-defined margin of 6 1 day. Safety and immunogenicity were assessed during treatment with follow-up visits at 4 weeks and 6 months (PROTECT1 only) after last dose. Results A total of 174 Asian patients were randomized (LA-EP2006: n = 90; reference: n = 84). Baseline characteristics were similar in both groups. Mean DSN in Cycle 1 was 1.36 ± 0.98 days (LA-EP2006) vs. 1.35 ± 1.06 days (reference) (difference 0.01 days; 95% CI: -0.30, 0.32, indicating equivalence). There were no clinically meaningful differences between groups in secondary endpoints. Treatment-emergent adverse events (TEAEs) were similar across groups (LA-EP2006: 96.7%; reference: 97.6%) (all cycles). Serious TEAEs were reported in: LA-EP2006: 31.1%; reference: 32.1% (all cycles). No neutralizing anti-pegfilgrastim antibodies were detected. Conclusions In Asian patients with breast cancer receiving cytotoxic chemotherapy, LA-EP2006 showed similar clinical efficacy and safety compared with reference pegfilgrastim. These data were similar to the overall study population. Clinical trial identification: NCT01735175, NCT01516736 Legal entity responsible for the study Sandoz GmbH, Kundl, Austria Funding Sandoz GmbH, Kundl, Austria Disclosure N. Harbeck: Honoraria for lectures (Amgen). Honoraria for lectures/ consulting (Sandoz/Hexal). Chair of Data safety Monitoring Board. A. Krendyukov, R. Nakov: Employee of Hexal AG. M. Mo: Employee of Sandoz Inc. K.L. Blackwell: Honoraria for consulting (Sandoz, Novartis). All other authors have declared no conflicts of interest.

New developments in the treatment of chemotherapy-induced neutropenia: focus on balugrastim

Neutropenia and febrile neutropenia are two major complications of chemotherapy. Dose reductions, delays in treatment administration, and the use of granulocyte colony-stimulating factors are equally recommended options to preserve absolute neutrophil count in case of chemotherapy regimens bringing a risk of febrile neutropenia of 20% or higher. Recombinant granulocyte colony-stimulating factors, such as filgrastim and lenograstim, have a short elimination half-life (t1/2) and need to be used daily, while others, like pegfilgrastim and lipegfilgrastim, are characterized by a long t1/2 requiring only a single administration per cycle. Balugrastim is a novel long-acting recombinant granulocyte colony-stimulating factor obtained by means of a genetic fusion between recombinant human serum albumin and granulocyte colony-stimulating factor. Albumin binding increases the molecular weight and determines a high plasmatic stability leading to a t1/2 of ~19 days. Balugrastim’s efficacy, safety, and tolerability have been assessed in four different clinical trials involving breast cancer patients treated with doxorubicin and docetaxel. Pegfilgrastim was chosen as a comparator. Balugrastim was noninferior to pegfilgrastim with regard to the reduction of mean duration of severe neutropenia during cycle 1. Moreover, both treatments were comparable in terms of efficacy and safety profile. Balugrastim was well tolerated, with the only related adverse event being mild to moderate bone pain. The aim of this review is to summarize the currently available literature data on balugrastim.

Abstract OT3-02-13: Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study)

Abstract Background: SPI-2012 is a distinct biologic that uses the innovative, proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™) to enhance the activity of G-CSF. SPI-2012 consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, more potent, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors. The primary endpoint of this Phase 3 study is to compare the efficacy of a single dose of SPI-2012 with pegfilgrastim in patients with early-stage breast cancer (ESBC) receiving TC chemotherapy, as measured by the Duration of Severe Neutropenia (DSN) in Cycle 1. Key secondary objectives include the comparison of SPI-2012 with pegfilgrastim during Cycle 1 in: Time to Absolute Neutrophil Count (ANC) Recovery; Depth of ANC Nadir and Incidence of Febrile Neutropenia. Safety and pharmacokinetics will also be assessed. Trial Design: This is a randomized, open-label, active-controlled, multicenter study comparing the efficacy and safety of SPI-2012 to pegfilgrastim. Patients (n=506) will be randomized in a 1:1 ratio to receive either SPI-2012 (equivalent to 3.6 mg G-CSF) or pegfilgrastim (equivalent to 6.0 mg G-CSF) once per chemotherapy cycle (up to 4 cycles), approximately 24 hrs after chemotherapy. Eligibility Criteria: This study will enroll histologically confirmed ESBC patients who are eligible to receive adjuvant or neoadjuvant TC chemotherapy and at least 18 years of age, with adequate hematologic, renal and hepatic function. Patients will be excluded if they have active concurrent malignancy or life-threatening disease; a known sensitivity or previous reaction to E. coli derived products or any of the products to be administered during study participation; concurrent adjuvant cancer therapy; locally recurrent/metastatic or contralateral breast cancer; previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development prior to the administration of study drug; bone marrow or hematopoietic stem cell transplant or radiation therapy prior to enrollment or are pregnant or breast-feeding. Statistical Methods: The goal of the study is to demonstrate non-inferiority of SPI-2012 to pegfilgrastim. For the Primary Efficacy Analysis, the mean DSN in Cycle 1 will be compared between the SPI-2012 and pegfilgrastim treatment arms. A 2-sided 95% confidence interval (CI) of the difference between the mean DSN of the SPI-2012 arm and the mean DSN of the pegfilgrastim arm will be calculated using bootstrap resampling with treatment as the only stratification factor. For the Secondary Efficacy Analyses, the results will each be summarized by treatment arm and Cycle. The two-sided 95% CI for the difference between the treatment arms will be calculated. Target Accrual: Approximately 506 pts. Citation Format: Schwartzberg L, Vacirca JL, Hager SJ, Adoo CS, Ibrahim EN, Bhat G, Choi MR, Allen LF, Tedesco KL, Agajanian R. Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-13.