Lasofoxifene (Fablyn) has shown promising early activity in patients with hormone receptor-positive (HR+), HER2-negative, locally advanced breast cancer, according to data from a substudy of the phase 2 I-SPY 2 trial. The results, presented at RISE UP for Breast Cancer, indicated that lasofoxifene was well-tolerated and led to significant suppression of Ki-67 expression, a marker of cell proliferation, in both premenopausal and postmenopausal women.
The study enrolled 20 patients, including 10 premenopausal women, 9 postmenopausal women, and 1 man, between March 2023 and May 2024. Patients received lasofoxifene at 5 mg daily for six 28-day cycles. Premenopausal patients also received ovarian function suppression (OFS) starting in cycle 2. The primary endpoint of the trial was feasibility, defined as at least 75% of patients completing at least 75% of the study therapy.
Ki-67 Suppression
Researchers observed a notable decrease in Ki-67 expression across the study population. The median Ki-67 expression decreased from 10.0% (range, 1.0%-40.0%) at baseline to 4.0% (range, 1.0%-18.0%) at week 3. Among 16 evaluable patients at week 3, Ki-67 expression was suppressed to below 10% in 14 patients and to less than 2.7% in 6 patients.
In premenopausal patients, the median Ki-67 expression decreased from 12.5% (range, 1.0%-40.0%) at baseline to 3.0% (range, 1.0%-15.0%) at week 3. Seven out of 10 evaluable premenopausal patients experienced Ki-67 suppression to below 10%, and 4 patients had levels less than 2.7%.
Postmenopausal patients also showed a reduction in Ki-67 expression, with the median decreasing from 10.0% (range, 3.0%-33.0%) at baseline to 6.0% (range, 1.0%-18.0%) at week 3. In this group, 6 out of 9 evaluable patients achieved Ki-67 suppression to below 10%, and 2 patients had levels less than 2.7%.
Tolerability and Safety
Lasofoxifene demonstrated a favorable safety profile in the trial. Observed adverse events (AEs) were primarily grade 1 or 2, with the most common being hot flushes (65%), fatigue (40%), constipation (40%), and nausea (25%).
Additional Findings
The median baseline MRI functional tumor volume (FTV) was 8.4 ccs, which decreased to a median 3-week MRI FTV of 6.2 ccs, representing a median change of 13.3%.
Expert Commentary
"The I-SPY 2 EOP provides a biomarker-rich platform to test novel endocrine agents in the neoadjuvant setting in a molecularly selected group of patients with tumors that are predicted to have little to no benefit from chemotherapy," said Jo Chien, MD, principal investigator of the substudy and medical director of Breast Medical Oncology at the University of California San Francisco. "Lasofoxifene has demonstrated significant activity based on early Ki-67 suppression, not only in postmenopausal women, but also in 10 premenopausal women without concomitant OFS. It is exciting to see that lasofoxifene is well tolerated even in our youngest patients who are often most impacted by the debilitating adverse effects of current standard endocrine therapy options."
Future Directions
Sermonix Pharmaceuticals is currently investigating lasofoxifene in the phase 3 ELAINE-3 trial in combination with abemaciclib (Verzenio) for patients with ESR1-mutated metastatic breast cancer. "Lasofoxifene continued to demonstrate a strong tolerability profile and promising Ki-67 suppression in this phase 2 study, supporting our plans to further explore its potential in the neoadjuvant setting," said David Portman, founder and chief executive officer of Sermonix Pharmaceuticals.
