Prof. Matthew Goetz: ELAINE 1 Study - Treatment Options for Patients with ESR1 Mutated Breast Cancer after CDK4/6i Progression

Editor's note: The 47th Annual Meeting of the European Society of Medical Oncology (ESMO) was held earlier in Paris, France, where the results of the ELAINE 1 study were unveiled. Oncology Frontier invited the study's principal investigator, Prof. Matthew Goetz of Mayo Medical Center, USA, to share the study design and results of ELAINE1.

 

Oncology Frontier：First, please give us a brief introduction to the ELAINE 1 study.

 

Prof. Matthew Goetz：The ELAINE 1 clinical trial was testing whether lasofoxifene, which is a selective estrogen receptor modulator, provided better anti-tumor activity than the drug fulvestrant in patients with ESR1 mutated breast cancer. Stepping back, we know that the estrogen receptor is mutated in approximately 30 to 40% of patients who are treated with an aromatase inhibitors.

 

These ESR1 mutations have been shown to be a major problem that they lead to not only endocrine resistance, but they are associated with a worse prognosis. Patients tend to have higher rates of metastasis, especially to visceral disease sites.

 

So, there has been great interest in developing new drugs that would target these ESR1 mutations. Of course, we are familiar with fulvestrant. Both pre-clinical and clinical studies have demonstrated that fulvestrant appears to be a superior drug to aromatase inhibitors for targeting these ESR1 mutations.

 

In the last few years, we have seen a lot of data with regard to the oral SERDs (selective estrogen receptor downregulators). At this meeting, we also heard some data with regard to the oral SERDs. Lasofoxifene is a SERM, a selective estrogen receptor modulator, and it is an older drug. It was tested back in the 1990s as a drug for the prevention of breast cancer, and was shown in the PEARL trial to reduce the incidence of breast cancer, as well as being an effective drug in treating osteoporosis.

 

There was substantial pre-clinical data demonstrating that lasofoxifene tightly bound the mutated estrogen receptor, and specifically had effects to inhibit estrogen receptor (ER) transcriptional activity, as well as to inhibit tumor growth and metastases. These studies were done both as a single agent and in combination with a CDK4/6 inhibitor.

 

The ELAINE 1 trial was a very simple design taking women who had a diagnosis of ER-positive, HER2-negative metastatic breast cancer, who had progressed on an aromatase and a CDK4/6 inhibitor, and they had circulating tumor DNA evidence for ESR1 mutation. Patients (approximately 200) were screened for these ESR1 mutations, and approximately 100 were randomized to either fulvestrant or lasofoxifene. The results of the trial demonstrated that lasofoxifene improved progression-free survival from 4 months with fulvestrant, up to 6 months with lasofoxifene.

 

However, these results were not statistically significant. Similarly, when we look at other markers of efficacy, such as response rates and clinical benefit rate, again, both of these were improved with lasofoxifene. For example, the response rate with lasofoxifene was 13% versus <3% with fulvestrant. Again, a trend towards statistical significance, but it didn’t meet the criteria.

 

One of the most intriguing aspects of this study was evaluating the mutant allele fraction for the ESR1 variants. When looking at the baseline in week 8 results, we found that lasofoxifene did a much better job of decreasing ESR1 variants in the blood stream compared with fulvestrant. More specifically, focusing on the Y537S alteration (which is a fairly nasty/difficult mutation and one that we stratified patients on), lasofoxifene decreased this alteration in nearly all patients by a significant amount, where by in the fulvestrant arm, we saw an increase in the mutant allele fraction for the Y537S alteration.

 

This tells us that lasofoxifene is having an on-target effect, and really a proof-of-principle. So where do we go from here? Where we go from here is quite clear because based on the ELAINE 2 trial (a trial presented at the American Society of Clinical Oncology Meeting back in June), that trial tested lasofoxifene plus abemaciclib in patients with ESR1-mutated breast cancer, and again, in highly refractory disease (these patients had progressed on CDK4/6 inhibitors, and most of them, chemotherapy). In that trial, a very impressive 50% response rate, and a clinical benefit rate of nearly 14 months was seen. Going forward, the plan is to test lasofoxifene in combination with other targeted therapies, such as abemaciclib or other targeted therapies. for example, mTOR inhibitors.

 

Oncology Frontier：What are the implications of the disclosure of this study for the treatment of patients with HR+/ HER2-advanced breast cancer?

 

Prof. Matthew Goetz：I think the implications for patients based on the ELAINE 1 trial are that there will be more options down the road for treating patients with ESR1 mutations. Now, ELAINE 1 was not sufficient obviously for regulatory approval. That would require a much larger study. However, the implications are that lasofoxifene appears to be an effective drug in terms of its ability to target the ESR1 mutation. I say effective in terms of its pharmacodynamic effect and the positive efficacy signals we are seeing. I think the major take-home for patients is that, going forward, these drugs, whether a SERD or SERM, will need to be tested and studied in combination with other targeted therapies, such as the CDK4/6 inhibitors.

 

Oncology Frontier：In terms of population characteristics, the breast cancer patients enrolled in the study were older and staged later. How safe is Lasofoxifene treatment for patients?

 

Prof. Matthew Goetz：With regard to the safety lasofoxifene was really, extre