Lasofoxifene Elicits Durable CR in ESR1+, ER+/HER2- Metastatic Breast Cancer

A patient with estrogen receptor positive, HER2-negative metastatic breast cancer enrolled in the phase 2 ELAINE 1 trial demonstrated a durable complete response when treated with lasofoxifene.

Lasofoxifene demonstrates durable complete response (CR) which could be characterized as complete clinical remission in women with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations, according to data from the phase 2 ELAINE 1 trial (NCT03781063).1

The investigational, third-generation, oral selective ER modulator (SERM) lasofoxifene has improved tumor growth inhibition and metastases reduction vs fulvestrant in preclinical models.

Findings from the multicenter, phase 2 ELAINE 1 study showed that at week 16, the patient enrolled had scans showing an improvement up to complete radiological disappearance of all measurable and non-measurable lesions with the radiological CR maintained at 80 weeks.

“Achieving a complete response in metastatic breast cancer with endocrine treatment post CDK4/6 inhibitor is exceedingly uncommon, particularly with single-agent endocrine therapy,” said Einav Nili Gal-Yam, MD, PhD, principal investigator of the ELAINE 1 trial, head of the Breast Oncology Institute at Chaim Sheba Medical Center in Ramat Gan, Israel, in the press release. “This is a very gratifying result, pointing to lasofoxifene’s potentially significant role in addressing the unmet needs of patients with ESR1 mutations. We look forward to the continued clinical development of this drug.”

The multicenter, phase 2 ELAINE 1 study (NCT03781063) examined the efficacy of oral lasofoxifene vs intramuscular fulvestrant in patients with ER-positive, HER2-negative breast cancer harboring ESR1 mutations who progressed on prior aromatase inhibitors (AIs) plus a CDK4/6 inhibitor.2

Those enrolled in the trial were randomly assigned to receive 5 mg of oral lasofoxifene and 500 mg of fulvestrant as an intramuscular injection on days 1, 15, and 29, then every 4 weeks thereafter. Treatment continued until progression, death, unacceptable toxicity, or withdrawal.

The primary end point of the trial was progression-free survival (PFS) with secondary end points including overall response rate (ORR), clinical benefit rate, overall survival, and safety.

The patient evaluated in ELAINE 1 began treatment on December 16, 2020. Eight weeks after lasofoxifene initiation via PET-FDG scan, her first radiological assessment revealed no pathological uptake in her pleural lesions, a sum diameter of 14 mm (55% reduction), and significant reduction of the bony lesion in the ilium with no new pathological findings.

At week 16, scans showed further improvement up to complete radiological disappearance of all measurable and non-measurable lesions with the radiological CR maintained at 80 weeks.

Additionaltop-line data were also presented at the European Society for Medical Oncology Congress 2022, showing that patients treated with lasofoxifene (n = 52) achieved a median PFS of 6.04 months (95% CI, 2.82-8.04) vs 4.04 months (95% CI, 2.93-6.04) for those who received fulvestrant (n = 51; HR, 0.699; 95% CI, 0.445-1.125; P = .138). At 6- and 12-months, PFS rates in the lasofoxifene arm were 53.4% and 30.7%, respectively, vs 37.9% and 14.1%, respectively, in the fulvestrant arm (P = .138).3

Among those enrolled in the lasofoxifene arm and the fulvestrant arm, the median age was 61.6 years (range, 33-84) and 60.1 years (range, 38-82). Most patients had measurable disease (73.1% and 64.7%) and visceral disease (67.3% and 64.7%). In the metastatic setting, rates of prior chemotherapy were 5.8% and 5.9% in the lasofoxifene and fulvestrant groups, respectively.

All patients had received prior treatment with an AI and CDK4/6 inhibitor. The median duration of treatment with an AI and CDK4/6 inhibitor was 2.5 years and 2.2 years in the lasofoxifene and fulvestrant arms. Additionally, all patients had an ESR1 mutation with ESR1 Y537S mutations reported in 40% and 47% of patients in the lasofoxifene and fulvestrant groups, respectively.

Four patients in the lasofoxifene arm were ongoing treatment vs 2 in the fulvestrant arm by the time of the data cut-off, and 43 patients in each arm stopped treatment due to disease progression.

Lasofoxifene demonstrated an ORR of 13.2% compared with 2.9% for fulvestrant (P = .12). Among patients in the lasofoxifene arm, 1 achieved a CR with a duration of 18 month, and 4 patients had partial responses (PRs) with a median duration of 13.75 months. In the fulvestrant arm, 1 patient achieved a PR with a duration of 16 months. After 24 weeks, the clinical benefit rate in the lasofoxifene arm was 36.5% vs 21.6% in the fulvestrant arm (P = .12).

An exploratory circulating tumor DNA (ctDNA) analysis assessed the baseline and 8-week ctDNA samples of 61 patients for ESR1-mutant allele fraction. The median relative change for all variants in the lasofoxifene arm was –87.1% compared with –14.7% in the fulvestrant arm. In patients with ESR1 Y537S mutations, the median mutant allele fraction change was –89% in the lasofoxifene arm and –82% in the fulvestrant arm.

Most adverse events (AEs) were grade 1/2. The most common treatment-emergent AEs of any grade included nausea (27.5% and 18.8% in the lasofoxifene and fulvestrant arms, respectively), fatigue (23.5% and 37.5%), arthralgia (21.6% and 22.9%), hot flush (21.6% and 10.4%), constipation (15.7% and 12.5%), dizziness (15.7% and 4.2%), hypertension (15.7% and 14.6%), and cough (15.7% and 10.4%). Additionally, no thrombotic AEs were observed.

While lasofoxifene elicited a benefit in ORR and clinical benefit rate, lasofoxifene alone did not produce a statistically significant improvement in progression-free survival. Although these data were not statistically significant, the results of the study numerically favored lasofoxifene.

1. Sermonix pharmaceuticals shares details of first-ever known durable complete clinical response in a metastatic ER+/HER2- breast cancer patient with an ESR1 mutation after prior CDK4/6 inhibitor treatment via single-agent hormonally based regimen. News release. Sermonix Pharmaceuticals. September 14, 2022. Accessed September 16, 2022.
2. Evaluation of lasofoxifene versus fulvestrant in advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation. Updated August 26, 2021. Accessed September 16, 2022.
3. Goetz MP, Plourde P, Stover DG, et al. Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089
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