At the 2022 San Antonio Breast Cancer Symposium, Matthew Goetz, MD, Mayo Clinic, Rochester, Minnesota, presented on a translational end point from the ELAINE-1 trial, which examined patient outcomes with lasofoxifene compared to fulvestrant for HR-positive, HER2-negative ESR1-mutant breast cancer that had progressed on CDK4/6 inhibitors.

Dr Goetz stated these results confirm there is an on-target effect with lasofoxifene as well as a correlation between the clinical benefit of lasofoxifene and progression-free survival. He also stressed the importance of clinicians recognizing 2 classes of drugs—selective estrogen receptor degraders (SERDs) and selective estrogen receptor modulators (SERMs)—that can be used to target ESR1-mutant cancers.

Transcript:

Hi, my name is Dr. Matthew Goetz. I'm a professor of oncology and pharmacology at the Mayo Clinic in Rochester, Minnesota. I'm here at the 2022 San Antonio Breast Cancer Symposium presenting a translational end point for the ELAINE-1 clinical trial. The ELAINE-1 clinical trial was a randomized, phase 2 trial that took patients who had a history of hormone receptor-positive breast cancer. They had progressed on a CDK4/6 inhibitor and the eligibility for this study required patients to have an ESR1 mutation that was detected by circulating tumor DNA.

In the trial, patients were randomized to either fulvestrant or to lasofoxifene. We reported at the European Society for Medical Oncology [ESMO] Congress earlier this year in September that lasofoxifene led to an improvement in progression-free survival [PFS] that was a numerically higher than fulvestrant alone from about 4 to 6 months, with higher clinical benefit rates and higher response rates from about 13% versus 2%.

At this meeting, we are presenting a translational end point looking at the clonal dynamics with regard to the ESR1 mutations, which is the target for lasofoxifene. What we found and what we're presenting here today in San Antonio is that for patients who were treated with lasofoxifene versus fulvestrant, we see a much greater degree of reduction in these ESR1 mutants. Overall, we see a nearly 90% reduction in patients who have detectable – that is at baseline and at 8 weeks – ESR1 mutants with lasofoxifene. For the fulvestrant arm, to a much less degree, in that 20 to 30% range.

Probably one of the most interesting findings is related to the Y537S alteration. This alteration is a mutant-ESR1 that is associated with a poor prognosis and tends to be quite resistant. What we found was that patients who were treated with lasofoxifene, in nearly 90% of patients there was a reduction with this mutant, whereas we saw an increase with fulvestrant.

One of the things that we did in this trial and for this presentation was look at the outcomes for patients who were treated with lasofoxifene versus fulvestrant based on whether we saw an increase or a decrease in these ESR1 mutants. What we found was in the lasofoxifene arm, if we saw evidence for an on-target effect that as these ESR1 mutants were decreasing, the clinical benefit and PFS was substantially longer. In fact, for those patients who had a decrease in their ESR1 mutant alleles, we saw a median PFS more than 8 months versus those patients that did not have that change, we saw much less benefit of lasofoxifene.

Interestingly, for fulvestrant, we didn't see this as much. Fulvestrant had variant reductions or increases in these ESR1 mutant. We didn't see this change in clinical outcome based on reductions or increases in the ESR1 mutant alleles fraction.

In summary, we can say, number one, we're seeing an on-target effect with lasofoxifene. If we see evidence that these ESR1 mutants are decreasing, we see longer clinical benefit. That is quite reassuring because we have a target. We want to make sure that we're hitting the target, and we're seeing that that target is being eliminated. Then, importantly, we see a correlation with clinical benefit and PFS.

I think the other thing that has been lost on a lot of investigators and individuals here at San Antonio and otherwise, is that we have now several ways to target these ESR1 mutants. We have the oral selective estrogen receptor degraders [SERDs]. We hear a lot about the oral SERDs, but we now have a selective estrogen receptor modulator [SERM] that can effectively target these ESR1 mutants. In my mind, this is going to be critically important that we have 2 different classes of drugs, SERDs and SERMs, that can be used to target these ESR1 mutants. This is going to be critically important as we move into combination therapies.

We are really excited about the fact that an FDA registration trial will be pursued and will open in 2023, which will be taking patients who have progressed on a CDK46 inhibitor and who have an ESR1 mutation. The patients will be randomized to receive the combination of lasofoxifene and abemaciclib versus fulvestrant and abemaciclib, again, for patients who progressed on first-line CDK4/6 inhibitor, either palbociclib or ribociclib. This will be a very important trial. We're excited about it based on some of the data that's been seen with ELAINE-2, where we see that the combination of abemaciclib along with lasofoxifene leads to very high response rates, clinical benefit, and prolonged PFS in patients with these ESR1 mutants.

Source:

Goetz MP, Gal-Yam E, Stover DG, et al. “Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2− metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study.” Presented at San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Poster P5-05-04