FDA Grants Fast Track Designation to Lasofoxifene for ER+, ESR1-Mutant Metastatic Breast Cancer

The FDA has granted a fast track designation to the investigational agent lasofoxifene for the treatment of women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who have an ESR1 mutation.¹ The agent is currently being investigated in a phase II trial in this setting.

"Lasofoxifene's fast track designation highlights the significant unmet medical needs of patients who have ER-positive/HER2-negative breast cancer with an ESR1 mutation," said David Portman, MD, the CEO of Sermonix, in a statement. "Fast track will allow us to more quickly complete our development program and, if successful, make lasofoxifene available to patients sooner."

Lasofoxifene is a nonsteroidal selective estrogen receptor modulator that is being considered a potential precision medicine treatment for women with breast cancer who have ESR1 mutations as the agent has demonstrated activity against mutations of the estrogen receptor. ESR1 mutations are commonly found in the metastatic setting in breast cancers, especially among women who have progressed on prior endocrine therapies, which is why this is considered an area of high unmet need in oncology.

"We are very encouraged to receive fast track designation, a recognition of lasofoxifene's potential promise as a precision medicine for [patients] with ER+ metastatic breast cancer," Anthony H. Wild, PhD, chairman of Sermonix, said in a statement.

The open-label, randomized, multicenter phase II ELAINE trial is exploring the use of lasofoxifene in comparison with fulvestrant (NCT03781063). The trial is enrolling up to 100 postmenopausal women with locally advanced or metastatic ER-positive, HER2-negative breast cancer with an acquired ESR1 mutation, as detected by a cell-free circulating-tumor DNA liquid biopsy test, who have progressed on an aromatase inhibitor in combination with a CDK4/6 inhibitor. Eligible patients must have received 1 prior chemotherapy regimen in the neoadjuvant or adjuvant setting and have an ECOG score of 0 or 1.

The primary endpoint of the study is progression-free survival and secondary endpoints include clinical benefit rate, objective response rate, duration of response, time to response, overall survival, and safety. An exploratory analysis will also explore the presence of select mutations, including NF1 and KRAS, from tumor-free DNA.

Preclinical findings for lasofoxifene will be presented at the 2019 ASCO Annual Meeting.² According to the abstract, lasofoxifene demonstrated greater efficacy than fulvestrant at inhibiting metastasis in xenograph models. In addition, in a study of lasofoxifene or fulvestrant in combination with palbociclib (Ibrance) in mice, the combination of lasofoxifene and palbociclib demonstrated greater reduction of primary tumor growth. The study showed that lasofoxifene can disrupt the active conformation of the ER-alpha Y537S ligand-binding domain.

As a result of the fast track designation, Sermonix is looking to potential breakthrough and priority review designations for a future new drug application for the agent.

REFERENCES:

1. Sermonix Receives FDA Fast Track Designation for Investigational Drug Lasofoxifene [news release]. Columbus, OH: Sermonix Pharmaceuticals LLC; May 28, 2019. Accessed May 28, 2019. https://bit.ly/2HH9Ofm?rel=0

2. Laine M, Fanning SW, Greene M, et al. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer.J Clin Oncol.2019;37(suppl; abstr 1056).