ELAINE 1 was a clinical trial testing the SERM, selective estrogen receptor modulator, lasofoxifene versus fulvestrant in women with ESR1 mutated metastatic breast cancer who had progressed on an aromatase inhibitor and a CDK4/6 inhibitor. The background here is that these ESR1 mutations are common, they’re one of the most common mechanisms of resistance in the metastatic setting for ER positive/HER2 negative breast cancer and they typically arise in the setting of aromatase inhibitors. They’ve also been seen to arise in the setting of aromatase inhibitors plus palbociclib and other CDK4/6 inhibitors. So they certainly are a viable target, they’re associated with a worse prognosis, that is metastases and worse overall survival.
A very important study to look at whether, in this case, a novel endocrine agent, in this case a SERM, lasofoxifene, could effectively target these ESR1 mutations and also whether that might lead to some clinical improvement. This trial tested lasofoxifene and compared it to fulvestrant. In the overall trial there were over 200 patients screened, 100 patients randomised and the results demonstrated that the median progression free survival of lasofoxifene was a bit over 6 months whereas for fulvestrant it was 4 months. This was not statistically significant but certainly there was a suggestion here that the drug may have a benefit.
If we also look at response rates, again we saw higher response rates with lasofoxifene, over 13%, versus not quite 3% with fulvestrant. Again, not meeting statistical significance but really again suggesting that there is clearly a signal that this drug has activity.
So probably one of the most provocative findings, from my standpoint, was the finding as it relates to the ESR1 mutants that we were actually following in the bloodstream. Again, patients in order to be eligible for the trial had a ctDNA blood test that allowed us to detect these ESR1 mutants. Then we simply asked did these mutants decrease or go away in the bloodstream with the addition of lasofoxifene. When we compared lasofoxifene and fulvestrant as it relates to these mutants, what we saw is that there was a greater decrease with lasofoxifene compared to fulvestrant. Probably one of the most interesting findings to me was the Y537S alteration, which was a stratification factor in this trial. This is a difficult to treat ESR1 mutation, probably one of the more difficult ones to treat. What we saw was that lasofoxifene had clearly an on-target effect; it decreased the mutant allele fraction substantially for the Y537S. Interesting, with fulvestrant it actually increased with the Y537S. So that tells us that the drug is clearly having a pharmacodynamics on-target effect.
Where we go from here now is certainly this trial was not powered satisfactorily to be able to see a 2-3 month difference so a larger trial would be needed. But where we’re really going with this drug is in combination therapy. There was another trial presented at the American Society of Clinical Oncology meeting earlier this year and that was the ELAINE 2 trial. In the ELAINE 2 trial these were women with ESR1 mutated metastatic breast cancer, progressed on CDK4/6 inhibitor, many of them progressed on chemotherapy. They received the combination in a single arm of abemaciclib along with lasofoxifene. What was seen in that trial was, again a relatively small population, an impressive 50% response rate and a median progression free survival of almost 14 months.
So it looks to us that it’s clearly important to target these ESR1 mutants but it may not be enough – we’re going to need to use a combination therapy along with the endocrine therapy.