Lasofoxifene Suppresses Ki-67 Expression in HR+/HER2– Early-Stage Breast Cancer

Lasofoxifene (Fablyn) was deemed well tolerated and generated early activity signals in both premenopausal and postmenopausal patients with hormone receptor (HR)–positive, HER2-negative, locally advanced breast cancer, according to findings from an arm of the Endocrine Optimization Pilot (EOP) Protocol, which is a substudy of the ongoing phase 2 I-SPY 2 trial (NCT01042379). Data were presented in a poster at RISE UP for Breast Cancer.¹

Among 20 patients enrolled to the lasofoxifene arm of the trial, including 10 premenopausal women, 9 postmenopausal women, and 1 man, investigators observed early Ki-67 suppression, even in the absence of ovarian function suppression (OFS). 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. At week 3, among 16 evaluable patients, Ki-67 expression was suppressed to lower than 10% in 14 patients and to less than 2.7% in 6 patients.^1,2

Among 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 3.2 At week 3, among 10 evaluable patients, Ki-67 expression was suppressed to lower than 10% in 7 patients and to less than 2.7% in 4 patients.

Among postmenopausal patients, the median Ki-67 expression decreased from 10.0% (range, 3.0%-33.0%) at baseline to 6.0% (range, 1.0%-18.0%) at week 3. At week 3, among 9 evaluable patients, Ki-67 expression was suppressed to lower than 10% in 6 patients and to less than 2.7% in 2 patients.

The male patient had a Ki-67 expression of lower than 10% at 3 weeks.

“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,” Jo Chien, MD, principal investigator of the sub-study and medical director of Breast Medical Oncology at the University of California San Francisco, stated in a news release.¹ “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 [AEs] of current standard endocrine therapy options.”

Patients with HR-positive, HER2-negative, MammaPrint low-risk, stage II or III breast cancer, as well as those with MammaPrint-High1 or clinically node-negative tumors, were enrolled in the lasofoxifene arm of the trial between March 2023 and May 2024, where they received treatment for a median of 154 days.^1,2

Lasofoxifene was administered at 5 mg daily for 6 28-day cycles until the day before surgery. Premenopausal patients received OFS starting in cycle 2. The trial’s primary end point was feasibility, defined as at least 75% of patients completing at least 75% of the study therapy.

Patients had a median age of 50.5 years. Seventy-five percent of patients had cT2 tumors; the median estrogen receptor expression level was higher than 95%; 60% of patients had cN-negative tumors; 80% of patients had MammaPrint low-risk tumors; and 85% of patients had tumors that were Sensitivity to Endocrine Therapy–high.

At the time of data analysis, 16 patients (80%) had completed at least 75% of the study therapy. Three patients were still receiving treatment, and 2 patients had discontinued treatment because of physician or patient preference.

The median baseline MRI functional tumor volume (FTV) was 8.4 ccs compared with a median 3-week MRI FTV of 6.2 ccs, representing a median change of 13.3%.

Observed AEs were all grade 1 or 2. The most common AEs included hot flushes (65%), fatigue (40%), constipation (40%), and nausea (25%).

Full results of this study, including pre-operative MRI results and surgical pathology results, will be presented at an upcoming meeting.

“Lasofoxifene continued to demonstrate a strong tolerability profile [and showed] promising Ki-67 suppression in this phase 2 study, supporting our plans to further explore its potential in the neoadjuvant setting,” David Portman, founder and chief executive officer of Sermonix Pharmaceuticals, added in the news release.¹ “We are currently studying lasofoxifene in the [phase 3] ELAINE-3 combination study [NCT05696626] with abemaciclib [Verzenio] in the ESR1-mutated metastatic breast cancer setting. We are excited to see it continue to demonstrate broad potential [and offer] unique quality of life benefits for [patients] confronted with breast cancer.”

References

1. Sermonix Pharmaceuticals’ lasofoxifene is well tolerated, demonstrates promising Ki67 suppression in phase 2 I-SPY 2 arm evaluating therapy in neoadjuvant breast cancer setting. News release. Sermonix Pharmaceuticals Inc. November 2, 2024. Accessed November 4, 2024. https://www.globenewswire.com/news-release/2024/11/02/2973635/0/en/Sermonix-Pharmaceuticals-Lasofoxifene-Is-Well-Tolerated-Demonstrates-Promising-Ki67-Suppression-in-Phase-2-I-SPY-2-Arm-Evaluating-Therapy-in-Neoadjuvant-Breast-Cancer-Setting.html
2. Wei M, Elias AD, Giridhar K, et al. I-SPY2 Endocrine Optimization Pilot (EOP): neoadjuvant lasofoxifene in molecularly selected patients with hormone receptor-positive (HR+)/HER2 negative (HER2-) stage 2/3 breast cancer. Presented at: RISE UP for Breast Cancer. November 1-3, 2024; San Francisco, California.