Promising findings from the phase 2 ELAINE-1 and ELAINE-2 trials have led to the start of a phase 3 study where investigators will evaluate lasofoxifene and abemaciclib as a treatment for patients with ER-positive/HER2-negative breast cancer and an ESR1 mutation.
A phase 3 study has commenced which will compare targeted lasofoxifene in combination with the CDK 4/6 inhibitor abemaciclib vs fulvestrant (Faslodex) plus abemaciclib (Verzenio) in pre- and post-menopausal patients with locally advanced or metastatic estrogen receptor (ER)-positive/HER2-negative breast cancer with an ESR1 mutation, according to Sermonix Pharmaceuticals Inc.
"The ELAINE 3 clinical trial is evaluating a new strategy for the treatment of ESR1-mutated breast cancer. While fulvestrant as well as the novel oral SERDs have been studied for the treatment of ESR1-mutated breast cancer, the antitumor activity with these molecules is limited. Furthermore, data from the ELAINE-1 study suggest fulvestrant exhibited limited efficacy for the difficult to treat Y537S mutation," Matthew Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, told Targeted OncologyTM.
Lasofoxifene, an investigational novel endocrine therapy, is currently in clinical development and has demonstrated robust target engagement as an ESR1 antagonist in patients with breast cancer harboring ESR1 mutations.
Previously, lasofoxifene led to anti-tumor activity when used as a monotherapy and in combination with abemaciclib in phase 2 studies. Now, this phase 3 study is supported by previously presented findings from the ELAINE-1 (NCT03781063) and ELAINE-2 (NCT04432454) trials.
"Lasofoxifene demonstrated antitumor activity in ELAINE-1, compared with fulvestrant, and in ELAINE-2 in combination with abemaciclib. The data in ELAINE-2 were compelling, where lasofoxifene in combination with abemaciclib was studied in patients that had progressed on a CDK 4/6 inhibitor and had an activating ESR1 mutation. In this pilot study, the response rates were >50% with median PFS of > 12 months. Based on these compelling data, patients with hormone receptor positive breast cancer who progress on first line CDK 4/6 inhibitor and who have an ESR1 mutation will be eligible for ELAINE-3. In this trial, patients will be randomized to abemaciclib plus fulvestrant compared with abemaciclib plus lasofoxifene," added Goetz.
“The totality of data we have compiled on lasofoxifene to date, including from our completed ELAINE-1 and ELAINE-2 phase 2 studies, show compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations,” said Paul Plourde, MD, vice president for clinical oncology development at Sermonix, in the press release. “We look forward to further studying lasofoxifene in a large, rigorously designed phase 3 study, which will include the use of the Guardant360 CDx test to identify patients who have an ESR1 mutation upon progression after first line therapy.”
ELAINE-3 will be a global randomized study which plans to enroll 400 pre- and post-menopausal women or men with locally advanced or metastatic ER-positive/HER2-negative breast cancer harboring an ESR1 mutation. To be included in the study, patients must have progressed on palbociclib or ribociclib plus an aromatase inhibitor (AI) and had up to 1 line of chemotherapy.
The study will randomize patients in a 1:1 fashion to receive either lasofoxifene or fulvestrant. Both groups will also be given abemaciclib 150 mg twice daily.
Study subjects will be prospectively screened for an ESR1 mutation using the Guardant360® CDx liquid biopsy, a next generation sequencing (NGS)-based test that detects genomic alterations using circulating tumor DNA from blood.
Investigators are evaluating the primary end point of progression-free survival along with the key secondary end points of overall response rate and overall survival. Other end points included in the study are clinical benefit rate, duration of response, time to disease recurrence, time to chemotherapy, quality of life, patient reported outcomes on vaginal and sexual health, and safety.
"If positive, this approach could lead to lasofoxifene in combination with abemaciclib being approved for the treatment of ESR1-mutated breast cancer. This would be a major advance and provide a needed treatment option for patients with ESR1-mutated breast cancer," stated Goetz.
Sermonix expects the first patient to be dosed in the first half of 2023.
“The initiation of this phase 3 combination study is a significant step forward for Sermonix, as we work to develop a novel targeted endocrine treatment option for metastatic breast cancer patients who are post-CDK4/6i with an ESR1 mutation and have limited treatment options that can provide meaningful clinical response,” said David Portman, MD, Sermonix founder and chief executive officer, in the press release. “We believe the inclusion of the Guardant360 CDx liquid biopsy to accurately identify eligible trial participants will enable us to execute this important study as efficiently as possible. We look forward to dosing the first patients very soon in this area of great unmet medical need.”