New Study Arm of I-SPY 2 Evaluates Lasofoxifene in ER+/HER2- Breast Cancer


A new arm of the I-SPY 2 Endocrine Optimization Platform will investigate lasofoxifene in patients with clinically high-risk ER-positive/HER2-negative breast cancer who are molecularly low-risk.

Treatment with lasofoxifene will be examined in a new study arm of the ongoing I-SPY 2 endocrine program, which is assessing patients with newly diagnosed estrogen receptor (ER)-positive invasive cancer.1

The I-SPY 2 Endocrine Optimization Platform (EOP) previously focused on women with high clinical and molecular risk where complete pathologic response is highly predictive of treatment efficacy.

In this new arm, treatment with lasofoxifene will be evaluated in patients with clinically high-risk ER-positive/HER2-negative breast cancer who are molecularly low-risk.

“We are looking to evaluate new, and repurposed, endocrine agents to look at both improved efficacy in reducing tumor volume, background enhancement, residual disease, circulating tumor DNA/RNA, and/or improved tolerability. The I-SPY Endocrine Optimization Pilot gives us the opportunity to bring better treatments to women with clinical high risk but molecularly low risk tumors,” Laura J. Esserman MD, MBA, Alfred A. de Lorimier Endowed Chair in General Surgery, director of the UCSF Breast Care Center, told Targeted OncologyTM. “This is a critically important group that needs better treatments. We need to find agents that are more tolerable so we can improve the quality of women’s lives. It would be great to find an agent that is equally or more effective and one that treats vaginal dryness rather than causes it. In our estimation, better tolerability makes a drug superior.”

Currently, there is an unmet need for novel agents that are tolerable and more effective than the standard of care for this patient population as they often have substantial risk for recurrence that occurs after 5 years. The EOP program was initiated in 2021 to specifically address this need.

“Sermonix is delighted to be a part of the truly groundbreaking I-SPY 2 clinical trial, working alongside such esteemed researchers to investigate an area of unmet medical need,” added David Portman, MD, founder and chief executive officer of Sermonix, in a press release on the program. “To date, we have successfully identified activity from lasofoxifene, and will soon be initiating a phase 3 registrational trial. It is exciting to be included in I-SPY and potentially generate additional data that could confirm activity of lasofoxifene in early-stage adjuvant settings as well as support differentiated quality-of-life outcomes.”

EOP is a sub-study within the main I-SPY-2 trial which is using neoadjuvant endocrine therapy in patients whose tumors may be sensitive to this type of therapy and in patients where chemotherapy is expected to provide little to no benefit.

Within separate study arms as a part of the platform trial, lasofoxifene and other investigational agents will be evaluated. The I-SPY program includes 30 open sites and at least 10 more are expected to be added in the first quarter of 2023. Each of the I-SPY sites have the EOP program open.

“Lasofoxifene is a novel endocrine treatment that has demonstrated activity in patients with heavily pre-treated ER-positive/HER2-negative metastatic breast cancer, including patients harboring tumors with ESR1 mutations,” explained Laura Esserman, MD, of the University of California San Francisco, founder and leader of the I-SPY Program, in the press release. “This agent is very well tolerated and thus would be a true advancement for the significant percentage of breast cancer patients who struggle or fail to complete the recommended 5 years of aromatase inhibitor therapy.”

Previously, there have been 2 successful and completed phase 2 trials that have evaluated treatment with lasofoxifene, including ELAINE-1 (NCT03781063) and ELAINE-2 (NCT04432454). In each study, lasofoxifene was safe and well-tolerated. In ELAINE-1, lasofoxifene led to compelling anti-tumor activity as a monotherapy while it was also noted to be safe in combination with abemaciclib (Verzenio) in ELAINE-2.

In ELAINE 1 trial, investigators evaluated the safety and efficacy of lasofoxifene compared with fulvestrant (Faslodex) in patients with locally advanced/metastatic breast cancer (mBC)and an ESR1 mutation who progressed on aromatase and CDK 4/6 inhibitors.2

Those enrolled were randomized to receive oral 5 mg of lasofoxifene and 500 mg of fulvestrant as an intramuscular injection on days 1, 15, and 29, then every 4 weeks thereafter.Progression-free survival (PFS) served as the primary end point of the study along with key secondary end points of overall response rate (ORR), clinical benefit rate (CBR), overall survival, and safety.

According to Sermonix, a case study from the ELAINE-1 trial has detailed the first ever known finding of a durable complete response (CR) in a patient with metastatic ER-positive/HER2-negative breast cancer harboring an ESR1 mutation after receiving prior therapy with a CDK4/6 inhibitor. This response could be characterized as complete clinical remission.1,2

In evaluating this patient who started treatment on December 16, 2020, investigators found that her first radiological assessment showed 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. Then at week 16 of the trial, this patient had scans which showed an improvement up to complete radiological disappearance of all measurable and non-measurable lesions with the radiological CR maintained at 80 weeks.

In addition, patients in ELAINE-2 who were treated with lasofoxifene had a mean PFS greater than 13 months. The ORR observed in the study was 33.3% (95% CI, 16.3-56.3) with 6 confirmed partial responses, and the CBR was 62.1% (95% CI, 44.0-77.3).3

There were no deaths during the course of the study and there were only a few grade 3/4 AEs observed with the most common being diarrhea, nausea, and leukopenia.

Overall, this study showed that lasofoxifene combined with abemaciclib led to meaningful efficacy in women with ER-positive/HER2-negative mBC who had an ESR1 mutation who had progressed on previous CDK4/6 inhibitor therapies, and the treatment was well-tolerated. Each of these trials provide strong support for a phase 3 combination study of the agent.

“Lasofoxifene is reported to promote vaginal and sexual health benefits, which are known and challenging side effects of [aromatase inhibitors]. Should lasofoxifene prove more efficacious and better tolerated than AIs in the neoadjuvant setting, this could have broad implications for both the survival and quality of life for women in the metastatic and early-stage adjuvant settings. Using the I-SPY model, we can accelerate the development of new cancer treatments and target new and innovative treatments to the patients who will benefit most, and we are eager to see data from lasofoxifene-treated subjects in this trial,” concluded Jo Chien, MD, the EOP study’s principal investigator, in the press release.

Sermonix pharmaceuticals and quantum leap healthcare announce new study arm to evaluate lasofoxifene in ongoing I-SPY 2 clinical trial. News release. Sermonix Pharmaceuticals LLC. February 13, 2023. Accessed February 14, 2023.
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
Damodaran S, Plourde PV, Moore HCF, et al. Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022
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