Sermonix Pharmaceuticals and Quantum Leap Healthcare Collaborative™, a 501c(3) charitable organization established in 2005 as a collaboration between medical researchers at University of California, San Francisco and Silicon Valley entrepreneurs, have agreed to evaluate lasofoxifene, an investigational next-generation targeted endocrine therapy, in a new study arm of the ongoing I-SPY endocrine program sponsored by Quantum Leap. This portion of the study targets patients with newly diagnosed estrogen receptor-positive (ER+) invasive cancer.
The arm is part of the I-SPY 2 Endocrine Optimization Platform (EOP), which is focused on patients with clinically high risk (stage 2/3) estrogen receptor positive (ER+)/HER2- breast cancer, but molecularly low risk (MammaPrint low risk signature). These patients often have substantial risk for recurrence that occurs later (after five years), and thus are in great need of novel agents that are more tolerable and more effective treatments than the current standard of care.
Novel endocrine therapy
Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals, is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast particularly in the presence of ESR1 mutations. 
“Lasofoxifene is a novel endocrine treatment that has demonstrated activity in patients with heavily pre-treated ER+/HER2- metastatic breast cancer, including patients harboring tumors with ESR1 mutations,” said Laura Esserman MD, MBA. of the University of California San Francisco, founder and leader of the I-SPY Program.
“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 five years of aromatase inhibitor (AI) therapy.”
A. Jo Chien, MD, Associate Clinical Professor, Department of Medicine, University of California in San Francisco (UCSF Helen Diller Family Comprehensive Cancer Center). who is also the principal investigator of the EOP study, added: “Lasofoxifene is reported to promote vaginal and sexual health benefits, which are known and challenging side effects of AIs. 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.”
The investigational drug has demonstrated anti-tumor activity as monotherapy and in combination with abemaciclib (Verzenio®; Eli Lilly & Co) in phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies with beneficial effects seen on vagina and bone in previous clinical studies.
I-SPY 2 Endocrine Optimization Platform
Quantum Leap opened the EOP program in 2021 to specifically address the need for better options for this subset of patients, and to find an early endpoint to measure success of therapy. I-SPY 2 had previously only focused on women with high clinical and molecular risk where complete pathologic response is highly predictive of treatment efficacy.
“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,” noted David Portman, MD, founder and chief executive officer of Sermonix Pharmaceuticals.
“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,” Portman added.
The I-SPY 2 Endocrine Optimization Platform is a sub-study within the main I-SPY-2 clinical trial utilizing neoadjuvant endocrine therapy in patients whose tumors are predicted to be sensitive to endocrine therapy but for whom chemotherapy is expected to provide little or no benefit. Lasofoxifene will be evaluated along with other investigational agents in separate study arms as part of the platform trial.
In two successfully completed Phase 2 studies (ELAINE-1 and ELAINE-2), lasofoxifene was found to be safe and well tolerated and demonstrated compelling anti-tumor activity, both as monotherapy (ELAINE-1) and in combination with abemaciclib (ELAINE-2). Of particular note, Sermonix shared a case study from ELAINE-1 detailing the first ever known finding of a durable complete response that could be characterized as complete clinical remission in a metastatic estrogen receptor-positive (ER+)/HER2- breast cancer patient with an ESR1 mutation after prior CDK4/6 inhibitor treatment upon participation in any single-agent hormonally based therapy. Additionally, lasofoxifene-treated patients in ELAINE-2 demonstrated mean progression-free survival over 13 months. Full results from the ELAINE-1 and ELAINE-2, which provide strong support for a Phase 3 combination study in 2023, were presented at the European Society for Medical Oncology (ESMO) Congress 2022 in Paris and 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, held at McCormick Place in Chicago, respectively.
As part of the agreement, Sermonix will supply lasofoxifene and provide financial support to Quantum Leap for this study. Quantum Leap is sponsor of the I SPY program, which includes 30 open sites and at least 10 more expected to be added in the first quarter of 2023. All I SPY sites have the EOP program open.
The I-SPY 2 trial of neoadjuvant treatment for locally advanced breast cancer established a new benchmark for efficiency of phase II clinical trials. The approach is widely regarded as a groundbreaking pioneer of the ‘platform’ trial. The success of the I-SPY 2 studies continues to be a major influence on the development of next-generation trial designs in oncology and beyond.
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation – NCT03781063
Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (ELAINEII) – NCT04432454
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) – NCT05696626
 Lainé M, Fanning SW, Chang YF, Green B, Greene ME, Komm B, Kurleto JD, Phung L, Greene GL. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Breast Cancer Res. 2021 May 12;23(1):54. doi: 10.1186/s13058-021-01431-w. PMID: 33980285; PMCID: PMC8117302.
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