Lasofoxifene Aims to Amplify Efficacy of Abemaciclib in ESR1-Mutated ER+/HER2– Metastatic Breast Cancer

With the development of the third-generation selective estrogen receptor (ER) modulator lasofoxifene, investigators are hoping to add an effective combination component to the treatment paradigm of estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer and have initiated the phase 3 ELAINEIII trial (NCT05696626), which is examining the agent in combination with abemaciclib (Verzenio) in this patient population whose disease harbors ERS1 mutations.1

“Elacestrant [Orserdu] is the only commercial selective ER modulator available for patients with metastatic breast cancer that’s ER-positive, HER2-negative [with] an activating ESR1 mutation and, for some patients, it does work really well in terms of survival and clinical response rates,” Sagar D. Sardesai, MBBS, said in an interview with OncLive®. “However, there are currently no approved combinations with a selective ER modulator that are commercially available. This clinical trial offers an opportunity for patients to receive a targeted therapy [such as] lasofoxifene, along with abemaciclib, which is a unique CDK4/6 inhibitor that has shown a clinical response beyond progression on frontline CDK4/6 therapy.”

Sardesai is a breast medical oncologist in the Division of Medical Oncology and a member of the Cancer Control Program at the Ohio State University Comprehensive Cancer Center—James in Columbus.

In May 2019 the FDA granted fast track designation to lasofoxifene for the treatment of patients with ER-positive, HER2-negative metastatic breast cancer with an ESR1 mutation.2 The agent was previously evaluated in the phase 2 ELAINEI (NCT03781063) and ELAINEII (NCT04432454) studies.3,4

Lasofoxifene Shows Value as Monotherapy and Combination Component

Lasofoxifene monotherapy was evaluated in adult pre- or postmenopausal female patients with ERS1-mutated ER-positive, HER2-negative metastatic breast cancer in ELAINEI.3 In order to be eligible for the study, patients needed to have experienced disease progression on an aromatase inhibitor (AI) in combination with a CDK4/6 inhibitor as their most recent line of endocrine therapy, an ECOG performance status of 1 or less, adequate organ function, and have received a maximum of 1 prior line of cytotoxic chemotherapy for metastatic breast cancer.

Patients were randomly assigned 1:1 to receive oral lasofoxifene at a dose of 5 mg daily (n = 52) or fulvestrant (Faslodex; n = 51) at a dose of 500 mg on days 1, 15, and 29, then monthly, until disease progression, intolerable toxicity, or patient withdrawal. The primary end point was progression-free survival (PFS); key secondary end points included clinical benefit rate (CBR), objective response rate (ORR), overall survival (OS), and safety.

Data from ELAINEI showed that patients treated with lasofoxifene experienced a median PFS of 24.2 weeks (95% CI, 11.3-32.1) compared with 16.2 weeks (95% CI, 11.7-24.1) in the fulvestrant arm (HR, 0.699; 95% CI, 0.434-1.125; log-rank P = .138). The CBR was 36.5% vs 21.6%, respectively (P = .117), and the confirmed ORR was 13.2% vs 2.9%, respectively (P = .124). One patient in the lasofoxifene arm achieved a complete response; the median time to response in the lasofoxifene arm was 15.8 weeks and the median duration of response (DOR) was 52.4 weeks.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 94.1% and 95.8% of patients in the lasofoxifene (n = 51) and fulvestrant (n = 48) arms, respectively. Grade 3 or 4 TEAEs occurred at respective rates of 19.6% vs 20.8%, and there were no grade 5 TEAEs in either arm. Common any-grade TEAEs occurring in at least 10% of patients included nausea (27.5% vs 18.8%), fatigue (23.5% vs 37.5%), arthralgia (21.6% vs 22.9%), and hot flush (21.6% vs 10.4%).

The single-arm ELAINE 2 study enrolled pre- and postmenopausal adult female patients with ESR1-mutated ER-positive, HER2-negative metastatic breast cancer who experienced disease progression on prior therapies, which could have included a CDK4/6 inhibitor.4 Eligible patients must have received 1 or 2 prior lines of endocrine therapy, an ECOG performance status of 1 or less, and adequate organ function.

All patients received daily oral lasofoxifene at a dose of 5 mg daily in combination with abemaciclib at a dose of 150 mg twice daily until disease progression, death, unacceptable toxicity, or patient withdrawal. The primary end point was safety and tolerability; secondary end points included PFS, CBR, ORR, DOR, and time to response (TTR).

The ORR among patients with measurable lesions (n = 18) was 55.6% (95% CI, 33.7%-75.4%) with a median TTR of 5.7 months. The median DOR was 6.4 months and 7 patients who experienced a partial response remained on treatment for over 1 year. The censored median PFS was 56.0 weeks (95% CI, 31.9-not estimable); the 6-, 12-, and 18-month PFS rates were 76.1% (95% CI, 54.4%-88.5%), 56.1% (95% CI, 34.9%-72.8%), and 38.8% (95% CI, 20.0%-57.3%), respectively.

Regarding safety, TEAEs led to dose interruption of abemaciclib or lasofoxifene at respective rates of 51.7% and 41.4%. Common any-grade TEAEs included diarrhea (82.8%), nausea (51.7%), and fatigue (37.9%). Any-grade adverse effects of special interest reported in at least 10% of patients included anemia (27.6%), decreased white blood cell count (27.6%), and neutropenia/decreased neutrophil count (20.7%).

ELAINEIII Set to Examine Lasofoxifene-Based Combination in ER+/HER2– Metastatic Breast Cancer

ELAINEIII is an open-label, multicenter study comparing lasofoxifene plus abemaciclib with fulvestrant plus abemaciclib in adult patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer harboring an ESR1 mutation.1,5 Eligible patients need to have received prior ribociclib (Kisqali) or palbociclib (Ibrance)-based treatment, no evidence of disease progression for at least 6 months following treatment with an AI- or CDK-inhibitor based combination for advanced disease, an ECOG performance status of 1 or less, and adequate organ function. One prior line of cytotoxic chemotherapy regimen in the metastatic setting is allowed.

“There are no major barriers to enrollment for the ELAINEIII trial, but one [factor] I’ve come across in speaking with or screening patients is that patients with prior fulvestrant [exposure] are excluded, and oftentimes when patients are on an adjuvant AI [therapy] and experience disease progression, they will often receive fulvestrant as frontline therapy,” Sardesai noted.

Eligible patients will be randomly assigned 1:1 to receive oral daily lasofoxifene at a dose of 5 mg or intramuscular fulvestrant at a dose of 500 mg on days 1, 15, and 29, then monthly, both in combination with oral abemaciclib at a dose of 150 mg twice daily. Treatment in both arms will continue until disease progression, death, unacceptable toxicity, or patient withdrawal.

PFS will serve as the primary end point of the trial. Secondary end points include ORR, OS, CBR, and safety. The study is aiming to enroll approximately 200 patients to each arm. The estimated primary completion of ELAINEIII is April 2027.

“The landscape of ER-positive, HER2-negative metastatic breast cancer is changing very quickly; it’s a good problem to have where we now have several options that help our patients, both in terms of quality of life and prolonging survival,” Sardesai said. “The right choice of therapy will be based on shared decision-making between you and your patient.”

References

1. Evaluation of lasofoxifene combined with abemaciclib compared with fulvestrant combined with abemaciclib in locally advanced or metastatic ER+/​HER2- breast cancer with an ESR1 mutation (ELAINEIII). ClinicalTrials.gov. Updated December 16, 2024. Accessed December 17, 2024. https://clinicaltrials.gov/study/NCT05696626
2. Sermonix receives FDA fast track designation for investigational drug lasofoxifene. News release. Sermonix Pharmaceuticals LLC. May 28, 2019. Accessed December 17, 2024. https://sermonixpharma.com/sermonix-receives-fda-fast-track-designation-for-investigational-drug-lasofoxifene/
3. Goetz MP, Bagegni NA, Batist G, et al. Lasofoxifene versus fulvestrant for ER+/HER2– metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial. Ann Oncol. 2023;34(12):1141-1151. doi:10.1016/j.annonc.2023.09.3104
4. Damodaran S, O’Sullivan CC, Elkhanany A, et al. Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2– breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2. Ann Oncol. 2023;34(12):1131-1140. doi:10.1016/j.annonc.2023.09.3103
5. Goetz MP, Wander SA, Bachelot T, et al. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation. J Clin Oncol. 2024;42(suppl 16):TPS1127. doi:10.1200/JCO.2024.42.16_suppl.TPS1127