We know that ESR1 mutations are seen in around 50% of patients after first-line AI therapy. Crosstalk between ER and PIK3-MTOR-AKT pathway is an additional mechanism of endocrine resistance we can see. So therefore, there is rationale for targeting both the ESR1 and PAM pathway concurrently.

With the EMERALD trial, we saw improvement in PFS in patients with ESR1 mutations after progression on one to two prior lines of endocrine therapy, including a CDK4/6 inhibitor. And now we have this single agent, elacestrant, approved in this setting. This was actually the first oral SERD approved for metastatic breast cancer. Then in CAPItello-291, capivasertib and fulvestrant were combined, and we saw superior PFS over single-agent fulvestrant in AKT pathway-altered patients in the second-line setting.

So we don't currently have an approval for an oral SERD and AKT pathway drug combination. Currently, these mutations are addressed with sequential regimens that address these targets individually.

ELEVATE is seeking to assess safety and efficacy of combining elacestrant with capivasertib, but also with elacestrant with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. This trial allows patients that have metastatic advanced breast cancer and one to two prior lines of endocrine therapy plus or minus a CDK4/6 inhibitor, and patients are eligible regardless of their ESR1 mutation status.

So this abstract specifically is looking at the combination of elacestrant and capivasertib on the ELEVATE trial. So far, we're seeing manageable safety with elacestrant and capivasertib, consistent with the AEs that we see in CAPItello-291, which of note was a capivasertib dose of 400 mg. In ELEVATE, the recommended phase II dose was determined to be 320 mg for capivasertib, determined based on safety profile and pharmacokinetic analysis. Thirty-one patients were enrolled in the phase Ib cohort; enrollment for phase II for this combination with 64 patients is complete, and we are awaiting results.

There's no new safety signals and key adverse event considerations are not surprising, include diarrhea, fatigue, nausea, rash, and hyperglycemia. Treatment-related adverse events at the recommended phase II dose that led to dose reductions or discontinuations were low, and there was no drug-drug interaction seen between these two agents. Also, we're seeing good efficacy with this combination, with a 24-week clinical benefit rate of 67%, and an overall response rate of 33%, and a median PFS of 11.3 months. So enrollment for phase II is complete.

This combination may provide an oral treatment option targeting both PAM and ESR1 mutation pathways in the near future for our metastatic ER-positive breast cancer patients.