FDA Issues a Complete Response Letter for Eflapegrastim for Chemo-Induced Neutropenia

The FDA has issued a complete response letter to Spectrum Pharmaceuticals regarding the biologics license application (BLA) for eflapegrastim (Rolontis) as a potential option for the management of chemotherapy-induced neutropenia.¹

In the letter, the regulatory agency cited deficiencies associated with the manufacturing of the agent and specified that a reinspection will be needed. The biopharmaceutical company shared that they are seeking further clarification from the FDA and shared plans to meet with the agency as soon as possible.

The BLA for the agent was supported by data from 2 similarly-designed phase 3 clinical trials, ADVANCE (NCT02643420) and RECOVER (NCT02953340), which both examined the safety and efficacy of eflapegrastim in a total of 643 patients with early-stage breast cancer who required treatment for myelosuppressive chemotherapy–induced neutropenia.^2,3

Both studies showed noninferiority with eflapegrastim with respect to duration of severe neutropenia (DSN), and a comparable safety profile to pegfilgrastim (Neulasta) when examined in this patient population. Moreover, in both studies, eflapegrastim demonstrated noninferiority to pegfilgrastim in the DSN across all 4 treatment cycles (P < .0001).

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

Previously, in March 2019, Spectrum Pharmaceuticals voluntarily withdrew the application for eflapegrastim because the company needed more time to complete the FDA’s request for additional manufacturing-related data.⁴ Notably, the regulatory agency did not cite concerns associated with preclinical and clinical modules of the BLA and did not request additional clinical trials examining the agent. In October 2019, the company resubmitted an updated application to the FDA requesting the approval of the agent for use in this setting.⁵

The multicenter, active-controlled ADVANCE trial enrolled a total of 406 patients with early-stage breast cancer who received chemotherapy comprised of docetaxel and cyclophosphamide every 3 weeks.

To participate, patients needed to be at least 18 years of age, and have a new diagnosis of histologically confirmed, early-stage breast cancer that was defined to be operable stage I to stage IIIA disease. Moreover, patients needed to be eligible to receive adjuvant or neoadjuvant chemotherapy, have an ECOG performance status of 0 to 2, and acceptable renal, hematologic, and hepatic function.

If patients had an active concurrent malignancy or a life-threatening disease, locally recurrent/metastatic or contralateral breast cancer, previously underwent hematopoietic stem cell transplant or radiation therapy, or prior exposure to filgrastim (Neupogen), pegfilgrastim, or other granulocyte colony-stimulating factor products before eflapegrastim, they were excluded.

Study participants received the agent at a fixed dose of 13.2 mg/0.6 mL via subcutaneous injection on day 2 of each treatment cycle. Pegfilgrastim was also administered via subcutaneous injection at a single dose of 6 mg/0.6 ML on day 2 of each cycle.

The primary end point of the trial was DSN (absolute neutrophil counts [ANC] <0.5 x 109/L) in cycle 1 of chemotherapy, based on central laboratory assessment of ANC over the treatment cycle. The key secondary end points of the research were time to ANC recovery, depth of ANC nadir, and incidence of febrile neutropenia in cycle 1.

Data from the trial demonstrated that the mean DSN with eflapegrastim was 0.19 (0.478) days vs 0.34 (0.668) days with pegfilgrastim, thus showing noninferiority (95% CI of ∆DSN: [-0.260, -0.035; P < .0001). Moreover, noninferiority of eflapegrastim for DSN was maintained across all 4 cycles.

In terms of safety, toxicities were noted in 10% or more of patients were mostly hematologic and included neutropenia, lymphopenia, anemia, and leukopenia. Effects proved to be comparable between the treatment arms.

The international, controlled, RECOVER trial enrolled a total of 237 patients who had stage I to stage IIIA breast cancer and who received myelosuppressive chemotherapy.

Study participants received treatment on day 1 of each 4, every-3-week cycles with either adjuvant or neoadjuvant docetaxel and cyclophosphamide. On day 2 of each treatment cycle, participants were randomized to 1 13.2-mg/0.6 L–dose of subcutaneous eflapegrastim (n = 118) or a 6-mg dose of pegfilgrastim (n = 119).

The primary end point of this trial was noninferiority between the 2 agents, which had been defined by mean DSN in cycle 1 with a noninferiority margin of <0.62 days. Important secondary end points included time to ANC recovery, depth of ANC nadir, and incidence of FN at cycle 1.

Findings from the trial revealed that the mean DNS with eflapegrastim was 0.31 (0.688) days vs 0.39 (0.949) days for those who were given pegfilgrastim; this reached the threshold of noninferiority (95% CI of ∆DSN: [-0.292, 0.129]; P < .0001). Noninferiority for eflapegrastim for DSN was also maintained across the 4 cycles.

The grade 3 or 4 adverse effects that were most frequently observed in 5% or more of patients proved to be comparable between the study arms and again, were mostly hematologic. Patients experienced neutropenia, lymphopenia, anemia, and leukopenia. Grade 3 or 4 bone pain and febrile neutropenia rates were comparable between the investigative and control arms and were less than 5%.

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/3AlxoGT
2. Schwartzberg LS, Yang Z, Peguero JA, et al. Safety and efficacy of eflapegrastim in reducing severe neutropenia in patients treated with myelosuppressive chemotherapy in a phase 3 randomized controlled trial compared to pegfilgrastim (ADVANCE trial). J Clin Oncol. 2018;36(suppl 15):e12513. doi:10.1200/JCO.2018.36.15_suppl.e12513
3. Schwartzberg LS, Bhat G, Mezei K, et al. Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial). Cancer Res. 2019;79(4). doi:10.1158/1538-7445.SABCS18-P1-13-05
4. 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
5. Spectrum Pharmaceuticals announces submission to the U.S. Food and Drug Administration of updated biologics license application for Rolontis. News release. Spectrum Pharmaceuticals. October 24, 2019. Accessed August 6, 2021. https://yhoo.it/2qFX6aE