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

Abstract

Eflapegrastim (Rolontis®) is a novel, long‐acting hematopoietic growth factor consisting of a recombinant human granulocyte‐colony stimulating factor (rhG‐CSF) analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. We report results from a second pivotal, randomized, open‐label, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim for reducing the risk of chemotherapy‐induced neutropenia. Patients with Stage I to IIIA early‐stage breast cancer (ESBC) were randomized 1:1 to fixed‐dose eflapegrastim 13.2 mg (3.6 mg G‐CSF) or pegfilgrastim (6 mg G‐CSF) administered one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary objective was to demonstrate noninferiority (NI) of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN; Grade 4) in Cycle 1. A total of 237 eligible patients were randomized 1:1 to receive either eflapegrastim (n = 118) or pegfilgrastim (n = 119). Cycle 1 severe neutropenia was observed in 20.3% (n = 24) of patients receiving eflapegrastim and 23.5% (n = 28) receiving pegfilgrastim. The DSN of eflapegrastim in Cycle 1 was noninferior to pegfilgrastim with a mean difference of −0.074 days (NI P‐value < .0001). Noninferiority was maintained throughout the four treatment cycles (P < .0001 in all cycles). Other efficacy endpoints results were comparable between treatment arms, and adverse events, irrespective of causality and grade, were comparable between treatment arms. The results demonstrate noninferior efficacy and comparable safety for eflapegrastim, at a lower G‐CSF dose, vs pegfilgrastim. The potential for the increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study.

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

“…In the phase 3 ADVANCE and RECOVER studies, the response to therapy, that is, mean duration of severe neutropenia, did not vary as a function of body weight for eflapegrastim and pegfilgrastim, ranging over the observed weights from 0.16 to 0.38 days and from 0.15 to 0.55 days, respectively. 13,14…”

“…Results from 2 phase 3 studies clearly showed that patient weight did not affect efficacy. 13,14 The wide range of weights (ie, 40-170 kg) provides a rich database to confirm that patients will be appropriately dosed by a fixed eflapegrastim dose of 13.2 mg (3.6 mg G-CSF), independent of body weight.…”

“…The 2 phase 3 studies (ADVANCE and RECOVER) were randomized, comparative multinational studies conducted at 82 active sites (United States, Canada, South Korea) and 74 active sites (United States, Canada, Hungary, Poland, India, South Korea), respectively, and are described in detail elsewhere 13,14 . All patients or their legally authorized representatives gave written informed consent.…”

“…The 2 phase 3 studies (ADVANCE and RECOVER) were randomized, comparative multinational studies conducted at 82 active sites (United States, Canada, South Korea) and 74 active sites (United States, Canada, Hungary, Poland, India, South Korea), respectively, and are described in detail elsewhere. 13,14 All patients or their legally authorized representatives gave written informed consent. These studies evaluated eflapegrastim versus pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early stage breast cancer who were receiving docetaxel and cyclophosphamide chemotherapy.…”

“…The fixed dose of 13.2 mg eflapegrastim (equivalent to 3.6 mg G‐CSF), given once per chemotherapy cycle, was evaluated in an intensive PK study (ClinicalTrials.gov identifier: NCT03135951) and pegfilgrastim (6 mg G‐CSF) as a comparator in 2 phase 3 clinical studies (ClinicalTrials.gov identifiers: NCT02643420 [ADVANCE] and NCT02953340 [RECOVER]). The phase 3 studies are described in detail elsewhere 13,14 …”