Lisa A. Carey, MD, and Kevin Kalinsky, MD, on Advanced Breast Cancer: New Data on Abemaciclib and Fulvestrant From the postMONARCH Trial

Lisa: Kevin, it is such a pleasure to see you. Wonderful work that you've presented at ASCO 2024 from postMONARCH, a very hotly anticipated trial. Can you describe the trial a little bit and kind of the basics of what you found? Kevin: For sure. Thank you, Lisa. There's been this question from a number of randomized phase II trials about the role of sequencing a CDK4/6 inhibitor and switching the endocrine therapy after progression on a CDK4/6 inhibitor. And this is a class of drugs that has really become a gold standard for our patients, and we wanted to know whether we should be continuing or not. And so postMONARCH is a randomized phase III trial, the first phase III trial, the others that we've seen so far were smaller phase II, and it enrolled patients who had a tumor that had progressed on endocrine therapy and CDK4/6 inhibitor, and directly randomized them to fulvestrant with or without abemaciclib. It was placebo-controlled. It was 368 patients. And what we saw, our assumption was that we would see a difference in progression-free survival of about 0.7, and that's what we saw. And there was a statistically significant study demonstrating that there is benefit for some patients for continuing their CDK4/6 inhibitor at the time of progression. Lisa: Well, and I think it was a beautiful study. You guys also looked at some of the other places that we intervene when you get to the second-line, pre-treated settings, specifically patients with PI-3 kinase aberrations, and found the same benefit essentially in them. Kevin: Right. Most of the new targeted therapies that we've had in breast cancer in the advanced setting has been in biomarker-positive patients. Those that have PI3K pathway alterations, so those with ESO-1 mutations. And so in this study, about 85% of patients, we had their baseline ctDNA, their circulating tumor DNA, available and valuable for the Guardant Infinity assay, and we saw regardless of whether a patient had a PI3K alteration, or an ESO-1 mutation, they benefited from the combination. Lisa: Yeah. And it starts to get into the question of what are we going to do with our patients? We have the INAVO120 trial that was also updated, which takes CDK4/6 inhibitors. It adds PI-3 kinase inhibitors. Now with fulvestrant, this suggests that if patients who has had a CDK4/6 inhibitor could reasonably continue on it with a change in the endocrine therapy, or particularly those who have a PI-3 kinase pathway aberration could go on to a drug targeting those. How do your findings inform that decision? Kevin: Right. We have two drugs that we can give to patients who have PI3K mutations, and with capivacertib, it's more broad than that if you have PTEN or AKT alterations as well. And we see a benefit in this study regardless of whether you have a PI3K mutation, and so this offers another potential strategy for our patients. I would keep in mind that there are some toxicities that we can see with some patients with PI3K targeted agents right now, including hyperglycemia, also some diarrhea. And so in the real world, when we have patients that may have uncontrolled diabetes or may have a high hemoglobin A1C, this offers another potential option for them post-CDK4/6 inhibition. The other thing that I will say is this is the world that we are living in at ASCO 2024. There were a number of new endocrine therapies that are coming down the pike, specific CDK inhibitors, specific PI3K inhibitors, and this is a rapidly evolving field. I think just with this study, we proved the strategy. Lisa: Yeah, that's an incredibly important point because the truth is that this is an adjunctive drug. You're adding it to endocrine therapy. The PI-3 kinase, AKT targeted are also adjunctive added to endocrine therapy. As we have more endocrine therapy backbones, the ability to use these is going to be super important in subsequent lines in patients who have persistently endocrine-sensitive disease. Kevin: For sure. I mean, I think for our patients who have hormone receptor positive HER2-negative advanced disease, I describe to patients this is a marathon. We want patients to remain on well-targeted therapies for as long as we can before they need infusions, before they need to spend more time with us getting intravenous treatments. And so- Lisa: Chemo. Kevin: Chemo. Chemo. Exactly. Lisa: That's terrific. Well, congratulations on a wonderful trial and really thought-provoking results. You've been great. Thanks, Kevin. Kevin: Thanks, Lisa.