Spectrum Pharmaceuticals has voluntarily withdrawn their biologics license application (BLA) for eflapegrastim (Rolontis), due to the company needing more time to complete the FDA’s request for additional manufacturing-related information.1
The company stated in a press release that it plans to resubmit a BLA as soon as possible. In its request, the FDA did not note concerns related to preclinical and clinical modules of the BLA, or the requirement for further clinical trials. The application was submitted to the FDA in December 2018.
Eflapegrastim, which is a novel long-acting granulocyte-colony stimulating factor (G-CSF), is being evaluated as a novel agent for the management of chemotherapy-induced neutropenia in patients undergoing myelosuppressive chemotherapy. The BLA is based on findings from the phase III ADVANCE2
trials, which showed that eflapegrastim was noninferior to pegfilgrastim (Neulasta), in terms of absolute risk reduction of severe neutropenia, in patients with early-stage breast cancer who experienced neutropenia due to myelosuppressive cytotoxic chemotherapy.
“We are continuing to have productive discussions with the FDA and will deliver the additional information needed to support the application,” said Joe Turgeon, president and CEO of Spectrum Pharmaceuticals, in a press release. “We remain confident in the Rolontis program and look forward to a successful resubmission and its ultimate approval.”
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 trial, 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 duration of severe neutropenia (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.