Eflapegrastim Still Not Approved by FDA After New Complete Response Letter

The FDA has issued a complete response letter to the developer of eflapegrastim (Rolontis), for which a biologics license application was submitted for the treatment of chemotherapy-induced neutropenia. The FDA has cited manufacturing deficiencies and is requiring that the facilities be reinspected, according to a press release from the developer.¹

This CRL follows withdraw of an application for approval in 2019² and a resubmission of the BLA for approval after the FDA first discovered the manufacturing issues in 2019.³ However, the data supporting eflapegrastim for the treatment of chemotherapy-induced neutropenia are promising, according to the randomized, active-controlled, open-label, multicenter phase 3 ADVANCE trial (NCT02643420) and the multicenter, randomized, active-controlled, open-label phase 3 RECOVER trial (NCT02953340).

The ADVANCE study showed that overall eflapegrastim was non-inferior to pegfilgrastim (Neulasta).

A total of 406 patients with stage I to IIIA breast cancer were included in the ADVANCE trial and randomized 1:1 to receive either eflapegrastim or pegfilgrastim. Patients were administered eflapegrastim 13.2 mg/0.6 mL along with adjuvant or neoadjuvant docetaxel and cyclophosphamide chemotherapy for 4 cycles in the experimental arm. Patients in the control arm received the matching chemotherapy with the addition of pegfilgrastim 6 mg on day 2 of each cycle.⁴

The primary end point of the study noninferiority of eflapegrastim to pegfilgrastim, which was determined by the mean duration of severe neutropenia during cycle 1, according to the absolute neutrophil count (ANC) <0.5×109/L. The results showed that there was no difference between the 2 agents in any of the 4 treatment cycles. Further, the were no differences observed with the secondary end points of ANC recovery, depth of ANC nadir, and incidence of febrile neutropenia in cycle 1.

The noninferiority of eflapegrastim compared with pegfilgrastim was further demonstrated in the RECOVER trial. In the study, a lower granulocyte-colony stimulating factor (G-CSF) dose showed noninferior efficacy and comparable safety between eflapegrastim and pegfilgrastim.

The primary end point in RECOVER was the duration of severe neutropenia in cycle 1, which was investigated in 237 patients with stage I to https://digiday.com/media/post-covid-traffic-declines-set-some-sites-back-two-years/IIIA breast cancer. Patients were randomized to receive either adjuvant or neoadjuvant docetaxel and cyclophosphamide with the addition of either eflapegrastim or pegfilgrastim.1,⁵

The mean duration of severe neutropenia was 0.31 days (standard deviation [SD], 0.688) with eflapegrastim treatment and 0.39 days (SD, 0.949) with pegfilgrastim, which was a demonstration of noninferiority (95% CI, -0.292 to 0.129; P < .0001). This noninferiority was maintained across all 4 cycles of treatment. In terms of the secondary end points, there were no significant differences in the eflapegrastim or pegfilgrastim arm in time to ANC recovery, depth of ANC nadir, or incidence of febrile neutropenia in cycle 1.⁵

Both the ADVANCE and RECOVER studies are now completed.^4,5

“We are disappointed with this outcome and look forward to fully understanding the remediation timelines for the program,” said Joe Turgeon, president, and chief executive officer of Spectrum Pharmaceuticals, in a press release.1 “We continue to believe in Rolontis and plan to diligently complete the regulatory process to bring Rolontis to market.”

_References:

_{1. Spectrum Pharmaceuticals Receives Complete Response Letter from FDA for Rolontis® (eflapegrastim). News release. Spectrum Pharmaceuticals. August 6, 2021. Accessed August 6, 2021. https://bit.ly/37vCcNv}

_{2. Spectrum Pharmaceuticals Provides BLA Filing Update for ROLONTIS (eflapegrastim). News release. Spectrum Pharmaceuticals March 15, 2019. Accessed August 6, 2021. https://on.mktw.net/2TDx6dI.}

_{3. Spectrum Pharmaceuticals announces submission to the U.S. Food and Drug Administration of updated biologics license application. News release. Spectrum Pharmaceuticals. October 24, 2019. Accessed August 6, 2021. https://bit.ly/3xuIEz9}

_{4. Schwartzberg LS, Bhat G, Peguero J, et al. Eflapegrastim, a long‐acting granulocyte‐colony stimulating factor for the management of chemotherapy‐induced neutropenia: results of a phase III trial. Oncologist. 2021;25(8): e1233–e1241. doi: 10.1634/theoncologist.2020-0105}

_{5. Cobb PW, Moon YW, Mezei K, et al. 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. Cancer Med. 2020;9(17): 6234– 6243. doi: 10.1002/cam4.3227}