An open‐label, dose‐ranging study of Rolontis, a novel long‐acting myeloid growth factor, in breast cancer

Abstract

This randomized, open‐label, active‐controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long‐acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 μg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to <1.5 × 109/L. Up to four cycles of TC were investigated. The difference in DSN (time from ANC <0.5 × 109/L to ANC recovery ≥2.0 × 109/L) between the Rolontis and pegfilgrastim groups was −0.28 days (confidence interval [CI]: −0.56, −0.06) at 270 μg/kg, 0.14 days (CI: −0.28, 0.64) at 135 μg/kg, and 0.72 days (CI: 0.19, 1.27) at 45 μg/kg. Noninferiority to pegfilgrastim was demonstrated at 135 μg/kg (P = 0.002) and 270 μg/kg (P < .001), with superiority demonstrated at 270 μg/kg (0.03 days; P = 0.023). The most common treatment‐related adverse events (AEs) were bone pain, myalgia, arthralgia, back pain, and elevated white blood cell counts, with similar incidences across groups. All doses of Rolontis were well tolerated, and no new or significant treatment‐related toxicities were observed. In Cycle 1, Rolontis demonstrated noninferiority at the 135 μg/kg dose and statistical superiority in DSN at the 270 μg/kg dose when compared to pegfilgrastim.

Justification for a Fixed Dose of Eflapegrastim, a Long‐Acting G‐CSF, in Patients Receiving Docetaxel‐Cyclophosphamide Chemotherapy

“…Demographics of the 643 patients enrolled in the 2 phase 3 studies are summarized in Table 1. Similar demographics were observed in the phase 2 dose‐ranging study 11 …”

“…A phase 2 study, wherein eflapegrastim doses of 45, 135, or 270 μg/kg were compared with pegfilgrastim (6 mg), was performed to determine the optimal dose of eflapegrastim for evaluation in phase 3 clinical studies 11 . In this dose‐finding study, eflapegrastim produced a dose‐dependent increase in neutrophil counts after subcutaneous administration.…”

A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy‐induced neutropenia in patients with early‐stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study

“…4 Eflapegrastim shows increased uptake to the bone marrow, presumably due to the interaction of its Fc fragment with Fc receptors (FcRn) on the vascular endothelial surface. 5 The resulting increased potency, as demonstrated by pharmacokinetic and pharmacodynamic data from preclinical and Phase 1 and 2 studies, [5][6][7] gives eflapegrastim the potential to have an improved therapeutic index compared to pegfilgrastim. In nonclinical primate and rat studies, eflapegrastim demonstrated greater biologic activity than pegfilgrastim at reducing neutropenia, at one-third the G-CSF dose of pegfilgrastim.…”

“…8,9 Here we report the results of a second pivotal Phase 3 randomized study comparing eflapegrastim to pegfilgrastim (RECOVER, NCT02953340) in patients with Stage I to IIIA early-stage breast cancer (ESBC) undergoing standard docetaxel/cyclophosphamide (TC) therapy, which demonstrates confirmatory, reproducible evidence from another nearly identically designed, independent study (ADVANCE, NCT02643420) conducted in the same patient population. In contrast to Phase 1 and 2 eflapegrastim studies using weightbased dosing, 6,7 this Phase 3 study tested a fixed dose of 13.2 mg eflapegrastim (3.6 mg G-CSF) that is equivalent to 60% of the 6 mg G-CSF in pegfilgrastim. The 13.2 mg dose is equivalent to 188 µg/kg eflapegrastim (51 µg/kg G-CSF) for a 70 kg person and was chosen based on the results of a Phase 2 dose-ranging study, which showed noninferiority of eflapegrastim vs pegfilgrastim in the primary endpoint, mean Cycle 1 duration of severe neutropenia (DSN), for eflapegrastim 135 µg/kg (37 µg/kg G-CSF) (0.44 vs. 0.31 days, P = .002), and statistical superiority at 270 µg/kg (74 µg/kg G-CSF) (0.03 vs. 0.31 days, P = .023).…”

“…The 13.2 mg dose is equivalent to 188 µg/kg eflapegrastim (51 µg/kg G-CSF) for a 70 kg person and was chosen based on the results of a Phase 2 dose-ranging study, which showed noninferiority of eflapegrastim vs pegfilgrastim in the primary endpoint, mean Cycle 1 duration of severe neutropenia (DSN), for eflapegrastim 135 µg/kg (37 µg/kg G-CSF) (0.44 vs. 0.31 days, P = .002), and statistical superiority at 270 µg/kg (74 µg/kg G-CSF) (0.03 vs. 0.31 days, P = .023). 7 2 | MATERIALS AND METHODS…”