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An updated biologics license application has been submitted to the FDA for eflapegrastim for the management of chemotherapy-induced neutropenia.
An updated biologics license application (BLA) has been submitted to the FDA for eflapegrastim (Rolontis) for the management of chemotherapy-induced neutropenia, according to Spectrum Pharmaceuticals, the developer of the novel long-acting granulocyte-colony stimulating factor (G-CSF).1
The application is based on data from the two similarly designed ADVANCE2 and RECOVER3 trials, both of which demonstrated the prespecified hypothesis of noninferiority in duration of severe neutropenia (DSN) and a similar safety profile to pegfilgrastim (Neulasta) in patients with early-stage breast cancer who are receiving myelosuppressive chemotherapy. Additionally, in each of the two studies, eflapegrastim showed noninferiority to pegfilgrastim in the DSN across all 4 cycles (P <.0001).
“We have submitted a robust package to the FDA that incorporates strong clinical data and addresses previously communicated FDA requests relating to manufacturing processes,” Joe Turgeon, president and CEO of Spectrum, stated in a press release. “Rolontis could be the first novel G-CSF available to healthcare providers in over 15 years and, if approved, we are looking forward to competing in this multibillion-dollar market.”
In March 2019, Spectrum Pharmaceuticals voluntarily withdrew their BLA for eflapegrastim, which was submitted in December 2018, due to the company needing more time to complete the FDA’s request for additional manufacturing-related information.4 The FDA did not note concerns related to preclinical and clinical modules of the BLA, and did not require further clinical trials.
ADVANCE had been launched in accordance with the FDA Special Protocol Assessment after a successful phase II dose-finding study demonstrated acceptable safety and efficacy profile for eflapegrastim.
In the multicenter, active-controlled, randomized ADVANCE study, 406 patients with early-stage breast cancer who received docetaxel and cyclophosphamide chemotherapy every 3 weeks were enrolled. Patients were randomized 1:1 to treatment with either eflapegrastim (n = 196) or pegfilgrastim (n = 210).
Eflapegrastim was administered in prefilled single-use syringes at a fixed dose of 13.2 mg/0.6 mL for subcutaneous injection on day 2 of each cycle. Pegfilgrastim was given as a single-dose, subcutaneous injection of 6 mg/0.6 mL on day 2 of each cycle. The median age was 61 years (range, 24-84 years).
The primary endpoint was the duration of severe neutropenia (absolute neutrophil counts [ANC] <0.5 × 109/L) in cycle 1 of chemotherapy, based on central laboratory assessment of ANC over the cycle. The secondary endpoints were time to ANC recovery, depth of ANC nadir, and incidence of febrile neutropenia in cycle 1.
To be eligible for enrollment, patients had to be ≥18 years of age, have a new diagnosis of histologically confirmed early-stage breast cancer, defined as operable stage I to stage IIIa disease; be a candidate to receive adjuvant or neoadjuvant docetaxel and cyclophosphamide chemotherapy; have adequate hematologic, renal, and hepatic function; and have an ECOG performance status of ≤2.
Those who had an active concurrent malignancy or a life-threatening disease, locally recurrent/metastatic or contralateral breast cancer, prior hematopoietic stem cell transplant or radiation therapy, or previous exposure to filgrastim, pegfilgrastim, or other G-CSF products prior to the administration of eflapegrastim, were excluded from enrolling on the trial.
Results showed that the mean DSN was 0.19 (0.478) days for eflapegrastim and 0.34 (0.668) days for pegfilgrastim, demonstrating noninferiority (95% CI of ∆DSN: [-0.260, -0.035]; P <.0001). Additionally, noninferiority of eflapegrastim for DSN was maintained across all 4 cycles.
There were no statistically significant differences in secondary endpoints of time to ANC recovery, depth of ANC nadir, and incidence of febrile neutropenia at cycle 1.
Regarding safety, adverse events (AEs) observed in ≥10% of patients were similar across both arms and were mainly hematologic, including neutropenia, lymphopenia, anemia and leukopenia.
In the international, controlled, phase III RECOVER trial, 237 patients with stage I to stage IIIA breast cancer who were treated with myelosuppressive chemotherapy were treated on day 1 of each of 4 every-3-week cycles with either adjuvant or neoadjuvant docetaxel and cyclophosphamide. On day 2 of each cycle, patients were randomized to receive 1 dose of eflapegrastim subcutaneously at 13.2 mg/0.6 mL (n = 118) or pegfilgrastim at 6 mg (n = 119). The median age was 59 years (range, 29-88).
The primary endpoint was noninferiority between eflapegrastim and pegfilgrastim, defined by mean DSN in cycle 1 with a noninferiority margin of <0.62 day. Secondary endpoints included time to ANC recovery, depth of ANC nadir, and incidence of FN at cycle 1.
Results showed that the mean DSN was 0.31 (0.688) days for eflapegrastim compared with 0.39 (0.949) days for those who received pegfilgrastim, reaching the threshold for noninferiority (95% CI of ΔDSN: [-0.292, 0.129]; P <.0001). Also, in this study, noninferiority of eflapegrastim for DSN was maintained across all 4 cycles. There were no statistically significant differences across the secondary endpoints.
The common grade 3/4 AEs observed in ≥5% of patients were similar across both arms and were mainly hematologic including neutropenia, lymphopenia, anemia, and leukopenia. Moreover, grade 3/4 bone pain and febrile neutropenia rates were similar across both arms and were <5%.