Lasofoxifene Shows Clinical Significance in ESR1+, ER+/HER2- Metastatic Breast Cancer

Matthew P. Goetz

Findings from the ELAINE-1 trial (NCT03781063)of lasofoxifene vs fulvestrant (Faslodex) in patients with locally advanced/metastatic breast cancer and an estrogen receptor 1 (ESR1) mutation who progressed on aromatase and CDK 4/6 inhibitors, revealed there to be a durable complete response (CR) which could be characterized as complete clinical remission.

Lasofoxifene is an investigational, third-generation, oral selective ER modulator (SERM). In preclincal models, lasofoxifene has improved tumor growth inhibition and metastases reduction when compared with fulvestrant.

During the 2022 European Society for Medical Oncology (ESMO) Congress, Matthew P. Goetz, MD, highlighted research on estrogen receptor (ER) mutations with an evaluation of results from the ELAINE-1 trial.

In the ELAINE 1 trial, the safety and efficacy of lasofoxifene vs fulvestrant was evaluated. Patients enrolled were randomized 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 study was progression-free survival. Secondary end points consisted of overall response rate, clinical benefit rate, overall survival, and safety.

When evaluating a patient who began treatment on December 16, 2020, investigators found that her first radiological assessment, which took place 8 weeks after lasofoxifene initiation via PET-FDG scan, 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.

Results revealed that 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 an interview with Targeted Oncology^TM, Goetz, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discussed these recent data on ER mutations in patients with breast cancer. He also provided expert insight on the results of ELAINE-1.

Targeted Oncology: Can you discuss what ESR1 mutations look like in the breast cancer space?

Goetz: Estrogen receptor mutations are something that's relatively new in terms of the study of hormonal therapy. It's been thought for some time that these mutations might be present and indeed, the work done 20-30 years ago, when people looked at this, found that these mutations are very rare in the primary tumor, but they do occur and are selected, if you will, in the setting of ongoing hormonal therapy, in particular, aromatase inhibitors.

These mutations confer ligand-independence. That means that the receptors constituently active, it signals and can induce the effects of what otherwise would occur in the presence of the ligand, and that is the estrogen. One of the things that we know is that these mutations are a major driver of resistance to aromatase inhibitors. They occur fairly frequently, up to 30%-40% of the time in the metastatic setting.

We also have emerging data that these mutations tend to confer a worse prognosis, especially those that have multiple mutations. This worse prognosis is clinically associated with higher rates of metastases. Certainly, therapeutic resistance, presents of visceral disease, and again, worse overall survival.

Can you explain the background of the ELAINE-1 study of lasofoxifene in ER–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations?

A major question for the field and for these ESR1 mutations is how best to target them. In the setting of PALOMA-3 [NCT01942135], the addition of a CDK4/6 inhibitor to fulvestrant improved outcome in patients that had these ESR1 mutations. CDK4/6 inhibitors are clearly an advance. The remaining question that comes up is, what's the best endocrine therapy that should be used to target these ESR1 mutations? We've thought for quite some time that fulvestrant would be the best drug based on both preclinical and early clinical data. We have data with the oral selective estrogen receptor down regulators [SERDS] and these have clearly demonstrated a signal of benefit preclinically as well as clinically.

That leads us to a new drug called lasofoxifene in a new class, meaning being tested in 2022, but not a new class overall as the SERMs that have been around quite some time. Lasofoxifene is an older drug that was tested years ago and has shown to be an effective drug for the prevention of breast cancer. In the last 5 years, it's been tested in preclinical models and demonstrated that this drug effectively targets and inhibits the growth and metastases of ER-positive or HER2-negative breast cancer models that are the contain ESR1 mutations. With that in mind, the ELAINE-1 trial is testing whether lasofoxifene would be superior to fulvestrant for the treatment of ESR1-mutated metastatic breast cancer.

What did the design of the study entail?

The ELAINE-1 clinical trial enrolled women who had a diagnosis of estrogen receptor-positive, HER2-negative metastatic breast cancer and evidence for an ESR1 mutation as detected by a circulating tumor DNA assay. These patients had prior progression on an aromatase inhibitor and CDK4/6 inhibitor, and they were randomized in a 1:1 fashion to receive either fulvestrant or lasofoxifene.

What were the findings of the study?

The results of the trial demonstrated that lasofoxifene led to a median progression-free survival of a little over 6 months compared with fulvestrant, which had a median progression-free survival of 4 months. This corresponded to a hazard ratio of 0.699 and this result was not statistically significant but a clear signal that lasofoxifene may have some benefit.

Some of the secondary end points that were looked at also provided evidence for that signal, including overall response rates where lasofoxifene led to a response rate of greater than 13% vs fulvestrant at a little less than 3%. Similarly, clinical benefit rate was also prolonged. Again, both the response rate and clinical benefit rate did not meet statistical significance, but these are favorable signals are something that should be evaluated in larger studies.

The most interesting finding from the ELAINE-1 clinical trial was the fact that when we looked at a pharmacodynamic signal in these ESR1 mutations in the mutant allele fraction, what we found was that lasofoxifene was effectively targeting these mutant allele fractions with a dramatic decrease of all the variants with a greater decrease with lasofoxifene than with fulvestrant.

We were most interested in the Y537S alteration, which we know is a very difficult alteration to treat. Clinically, this mutant in was a stratification factor in ELAINE-1. What we found was that in patients treated with lasofoxifene, there was a dramatic decrease in the Y537S alteration at the 8-week mark. In contrast with fulvestrant, there was an increase which give us good evidence of what I would say is an on-target effect of lasofoxifene. It provides further evidence that this drug should be studied further in combination with other targeted therapies.

What are the next steps when looking at lasofoxifene?

A very important next step is to look at the efficacy of lasofoxifene in combination with CDK4/6 inhibitors. In fact, we already have those data that was the ELAINE-2 trial [NCT04432454] that was presented at the American Society of Clinical Oncology meeting in 2022. The ELAINE-2 trial is a single arm study evaluating the combination of abemaciclib plus lasofoxifene in women who had progressed on a CDK4/6 inhibitor. Many of them had progressed on chemotherapy and again, had evidence of an ESR1 mutation. In that trial, the overall response rate was 50% with a median progression-free survival that approached 14 months.

What we believe is that effective targeting of patients who have these ESR1 mutations will include both a drug that effectively targets ESR1 as well as a drug, such as the CDK4/6 inhibitor, targeting these alternative pathways. I think that's where we're going to see the further development of lasofoxifene in combination with other targeted therapies.