Stephen K.L. Chia, MD, FRCPC, on Advanced HER2-Negative and ER-Positive Breast Cancer: SERD and AKT Inhibitor

This is a randomized phase three placebo-controlled trial looking specifically in the second-line setting in a population of patients following first-line CDK4/6 inhibitors and aromatase inhibitors. The rationale really is that mechanisms of resistance develop to either the endocrine backbone, here being aromatase inhibitor, and/or the CDK4/6 inhibitor first-line. So we need better and perhaps more precise mechanisms selecting what is the optimal second-line therapy. We randomized 250 patients across multiple sites in Canada, Australia, and New Zealand with our goal of statistically improving the progression-free survival with a planned hazard ratio 0.6 mentioned. All patients came from first-line CDK4/6 aromatase inhibitors and either had to have measurable or evaluable disease, performance status 0 to 1. One particular aspect of the study is to select 1/4 of patients that might drive greater benefit as one of the stratification factors was alterations in the pathway, which is either PI3 kinase, AKT, or PTEN. In this trial, we used ctDNA methodology with the FoundationOne assay to detect whether there's an alteration in the pathway or not. In total, over a little over three years of enrollment, we enrolled 250 patients, majority were postmenopausal. We did include three men in the trial. About 40% had de novo metastatic disease at presentation and about 17% had bony metastases. By ctDNA methodology, we could identify alterations in about 44% of the population in this AKT pathway. Importantly, only in two out of 250 was there insufficient tumor content on the ctDNA to genomically type them, so they were classified as unknown, which is actually a very low rate. Our primary endpoint was investigator-initiated progression-free survival in the intent-to-treat population. This study demonstrated a statistical improvement in progression-free survival in the primary endpoint with a hazard ratio of approximately 0.61. The median progression-free survival in the control arm, which is placebo and fulvestrant, was a little under two months and improved by a little over three months to about 5.3 months in the ipatasertib arm and fulvestrant. And this was statistically significant and in our conclusions was clinically meaningful. Our statistical plan was then to look at a hierarchical statistical manner. If we met our primary endpoint, to then look at the altered cohort and this would be again the AKT-altered cohort, which is 44% of the population. Here we also had a statistical improvement in progression-free survival in the AKT-altered cohort, hazard ratio of 0.47, and the median PFS has improved from a little under two months to about 5.5 months overall. There were other secondary endpoints including blinded independent central review which basically confirmed as a very similar hazard ratio. Toxicity profile of greater than or 10% or greater or associated with ipatasertib was mainly GI. The majority of the patients on ipatasertib, about 80%, did experience grade 1 to 3 diarrhea. Fortunately, only 15% were grade 3, the majority were grade 1 to 2. High rates of nausea, vomiting, stomatitis, fatigue. In terms of hyperglycemia, we saw a 10% absolute increase in grade 1 hyperglycemia, no increase in grade 2 or grade 3. Overall, the study met its primary endpoint in improving progression-free survival in a homogeneous population of patients whose disease progressed on first-line standard therapy, CDK4/6 and aromatase inhibitor. It pretty well confirmed what we saw in a prior study called CAPItello-291. I think confirms that this is a pathway to consider as a treatment option and there is already available treatment option with another AKT inhibitor, but this opens up for other opportunities of other further studies of combination therapy or again additional access to another AKT inhibitor.