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SABCS 2022 | BYLieve Study Cohort A: alpelisib + ET in PIK3CA-mutant, HR+, HER2-, advanced breast cancer

Hope Rugo, MD, Helen Diller Family Comprehensive Cancer Center, provides an overview of the Phase II BYLieve (NCT03056755) trial investigating the α-selective PI3K inhibitor alpelisib in combination with endocrine therapies in patients who progressed on CDK4/6 inhibitor administered with an endocrine therapy. Previous results from the Phase III SOLAR-1 (NCT02437318) trial demonstrated that progression-free survival (PFS) of more than 18 months is achievable for patients treated with alpelisib after progression with an aromatase inhibitor. The benefit of alpelisib is predominantly observed in patients who have a PIK3CA mutations, a specific subset of patients included in SOLAR-1. Thus, BYLieve also included patients with PIK3CA mutations. In BYLieve Cohort A, patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer treated with alpelisib plus fulvestrant after CDK4/6 inhibitor,25.6% of patients achieved long-term disease control with a median PFS of 24.8 months and 16.5% achieve very long-term disease control. This interview took place at the San Antonio Breast Cancer Symposium (SABCS) 2022 in San Antonio, TX.

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Transcript (edited for clarity)

So one thing we presented at this poster spotlight at San Antonio in 2022 was an analysis of subgroups enrolled in the BYLieve Study. So BYLieve looked at alpelisib in combination with different endocrine partners in patients who had all had disease progression on a prior CDK4/6 inhibitors given with an endocrine therapy. The reason for this was that SOLAR-1, the Phase III registration trial for alpelisib, the alpha-specific PI3-Kinase Inhibitor was done in a time when we didn’t have CDK4/6 inhibitors in most places in the world so just a tiny percentage of patients were exposed to CDK4/6 inhibitors...

So one thing we presented at this poster spotlight at San Antonio in 2022 was an analysis of subgroups enrolled in the BYLieve Study. So BYLieve looked at alpelisib in combination with different endocrine partners in patients who had all had disease progression on a prior CDK4/6 inhibitors given with an endocrine therapy. The reason for this was that SOLAR-1, the Phase III registration trial for alpelisib, the alpha-specific PI3-Kinase Inhibitor was done in a time when we didn’t have CDK4/6 inhibitors in most places in the world so just a tiny percentage of patients were exposed to CDK4/6 inhibitors.

As you know, the benefit from alpelisib is seen in patients who have PIK3CA mutations, a specific set that were used in the trial, and so we used that same criteria for BYLieve. Patients were eligible who had the PIK3CA mutations. We’ve already shown and published that in patients who progressed on an AI plus a CDK4/6 inhibitor that alpelisib added to fulvestrant in this population seemed to still improve progression-free survival compared to a real-world database from the Flatiron database.

Cohort B patients received an aromatase inhibitor with alpelisib because they’d progressed on fulvestrant and a CDK4/ inhibitor and most of them had previous progression on an AI. So this is a group of patients where you would expect to have a relatively shorter PFS but it was quite good in BYLieve, a little shorter than what we saw in SOLAR-1. So then, we wanted to understand what happened in those two cohorts and the patients who… Because we had these really long ranges for progression-free survival so what we wanted to do is understand who’s out on that outer end, who are the patients who have very long or extremely long progression-free survival or time to progression on alpelisib plus an endocrine partner.

So we defined long as greater than 12 months and very long as greater than 18 months and we looked at some of this data in SOLAR-1 as well and it’s actually really interesting. I mean, if you have endocrine-sensitive disease, you can stay on this second or third line endocrine therapy for much longer than 18 months. In these population of patients, we identified a subgroup of patients, almost a quarter, who were on for more than 12 months and then about 16% who are on for more than 18 months and in that group, it was out to 24.8 months, 25 months. Really amazing.

So what were the criteria that seemed to correlate with that long-term response? It was really low disease burden. So bone-only disease, you can’t find the PIK3CA mutation in cell-free DNA, and long-term response to prior endocrine therapy. So really interesting but it gives us a lot of, I think, information about which patients benefit from these combination therapies and we can use these criteria also to understand the benefit of additional targeted agents moving forward.

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