Sermonix Pharmaceuticals and Quantum Leap Healthcare Collaborative announced positive results from a Phase 2 clinical trial evaluating lasofoxifene as a neoadjuvant endocrine therapy for HR+/HER2- locally advanced breast cancer. The I-SPY 2 TRIAL arm showed that lasofoxifene was well-tolerated and demonstrated promising early activity in suppressing the Ki67 protein, a marker of cancer cell division, in both premenopausal and postmenopausal patients.
The study, part of the Endocrine Optimization Pilot Protocol (EOP) within the I-SPY 2 TRIAL, enrolled 20 patients (10 pre- and 9 postmenopausal women, and 1 male). The results, presented at RISE UP for Breast Cancer, indicated that early Ki67 suppression in premenopausal patients was observed even without ovarian function suppression (OFS).
Ki67 Suppression and Tolerability
Median Ki67 expression decreased from 10% at baseline (range 1.0-40%) to 4% (1.0-18.0%) at Week 3. At three weeks, Ki67 expression was suppressed to <10% in 14 out of 16 (88%) patients, and to <2.7% in 6 out of 16 (38%) patients. Adverse events (AEs) were primarily grade 1-2, with the most common being hot flushes (65%), constipation (40%), fatigue (40%), and nausea (25%).
Expert Commentary
"Lasofoxifene continued to demonstrate a strong tolerability profile while showing promising Ki67 suppression in this Phase 2 study, supporting our plans to further explore its potential in the neoadjuvant setting," said Dr. David Portman, Sermonix founder and chief executive officer. He added, "We are currently studying lasofoxifene in the ELAINE-3 Phase 3 combination study with abemaciclib in the ESR1-mutated metastatic breast cancer setting. We are excited to see it continue to demonstrate broad potential while offering unique quality of life benefits for people confronted with breast cancer."
Dr. Jo Chien, principal investigator of the sub-study, noted, "Lasofoxifene has demonstrated significant activity based on early Ki67 suppression, not only in postmenopausal women, but also in 10 premenopausal women without concomitant ovarian function suppression, with baseline Ki67 of 12.5% (1.0-40.0%) going to 3.0% (1.0-15%) at Week 3. It is exciting to see that lasofoxifene is well-tolerated even in our youngest patients who are often most impacted by the debilitating side effects of current standard endocrine therapy options."
Lasofoxifene's Potential
Lasofoxifene is an investigational novel endocrine therapy that has shown robust target engagement as an ESR1 antagonist, particularly in the presence of ESR1 mutations. It has demonstrated anti-tumor activity as a monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies. Its unique tissue selectivity, with beneficial effects on the vagina and bone, distinguishes it from other endocrine therapies. Sermonix licensed lasofoxifene globally from Ligand Pharmaceuticals Inc. The drug's bioavailability and activity in mutations of the estrogen receptor could potentially benefit patients who have acquired endocrine resistance due to ESR1 mutations, an area of high unmet medical need.
