FDA Grants Fast Track Designation to Zotatifin Plus Fulvestrant/Abemaciclib in ER+/HER2– Breast Cancer

The FDA has granted fast track designation to zotatifin (eFT226) for use in combination with fulvestrant (Faslodex) and abemaciclib (Verzenio) as second- or third-line therapy for the treatment of patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer with disease progression following treatment with endocrine therapy and a CDK4/6 inhibitor.1

The designation is based on FDA review of preclinical and clinical data for zotatifin, including safety and efficacy data with the triplet regimen.

"We’re grateful to receive this fast track designation from [the] FDA, which is a meaningful milestone for the development of zotatifin and reflects the demonstrated potential for zotatifin in combination with fulvestrant and abemaciclib to address unmet needs in ER-positive/HER2-negative breast cancer,” Steve Worland, PhD, chief executive officer of eFFECTOR, stated in a news release. “We value the opportunities provided by fast track designation for frequent interactions with the FDA review team as we advance this development program for zotatifin and look forward to providing further data updates and development plans at the 2023 San Antonio Breast Cancer Symposium.”

Zotatifin is a potent and sequence-selective small molecule inhibitor of the RNA helicase eIF4A that is designed to inhibit expression of oncogenic proteins, including cyclins D and E, CDKs 2, 4 and 6 and select RTKs as well as KRAS.

The agent is currently under study in an ongoing phase 1/2 dose-escalation and dose-expansion study (NCT04092673) in patients with ER-positive, HER2-negative metastatic breast cancer. Data presented at the 2023 ASCO Annual Meeting² showed that the triplet led to a 26% (n = 5/19) partial response (PR) rate in RECIST-evaluable patients who had received a median of 4 prior lines of therapy for metastatic disease.1

All five patients who achieved a PR had experienced disease progression on a prior CDK4/6 inhibitor and fulvestrant. Additionally, all 5 patients had previous exposure to at least 1 prior line of chemotherapy in the metastatic setting. Based on the safety and tolerability of the agent, dose escalation with zotatifin and fulvestrant was resumed.

Updated interim analyses with the triplet regimen and dose-escalated cohorts will be presented at the 2023 SABCS meeting in December.

References

1. eFFECTOR receives U.S. FDA fast track designation for zotatifin in combination with fulvestrant and abemaciclib for treatment of ER+/HER2- advanced metastatic breast cancer. News release. eFFECTOR Therapeutics. November 28, 2023. Accessed November 30, 2023. https://www.globenewswire.com/news-release/2023/11/28/2786889/0/en/eFFECTOR-Receives-U-S-FDA-Fast-Track-Designation-for-Zotatifin-in-Combination-with-Fulvestrant-and-Abemaciclib-for-Treatment-of-ER-HER2-Advanced-Metastatic-Breast-Cancer.html
2. Rosen E, Sharma M, Berz D, et al. Phase 1/2 dose expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with ER+ metastatic breast cancer. J Clin Oncol. 2023;41(suppl 16):1080. doi:10.1200/JCO.2023.41.16_suppl.1080