SABCS 2020: AKT Inhibitors for TNBC


Adam M. Brufsky, MD, PhD: I want to end with another thing that is also going to be a pretty big mystery: AKT inhibition in triple-negative breast cancer. We’re going to see. We already saw the ER-positive part of the IPATunity130 trial. Ipatasertib has been promoted by Genentech/Roche as this AKT inhibitor that, with chemotherapy and hormonal therapy, could supposedly give some benefit. We already know that capivasertib in the FAKTION trial, when given with fulvestrant, does have activity. At ESMO [the European Society for Medical Oncology Virtual Congress], they did 1 section of this IPATunity program where they did the randomized trial with people with ER+ disease who did or did not have an AKT mutation, and then got paclitaxel with or without ipatasertib. That was negative.

They’re now doing it in the triple negative cohort, which they’re going to present. As you know, 10% to 15% of the patients have AKT, PTEN, or, or PI3 kinase mutations. Everybody gets paclitaxel with or without ipatasertib. I’m going to be curious to see. I’m worried that, based on the ER+ idea, they’re not going to see much. I thought this was going to work. They had neat phase 2 stuff that was presented by Peter Schmidt [MD, PhD,] a couple years ago. I saw the randomized phase 2 study, in which the patients who got this mutation seemed to have a survival benefit, and I was excited. I then saw the data from ESMO, and I thought “Uh-oh.” So, I don’t know, what do you think?

Erika P. Hamilton, MD: You mentioned this, but they did the triple negative study with capivasertib too.

Adam M. Brufsky, MD, PhD: Right.

Erika P. Hamilton, MD: These drugs are similar: they’re AKT1, 2, and 3, pan-AKT inhibitors. Although, it’s another trial like you were mentioning where we only saw an improvement of progression-free survival of about a month and a half, but there was a 7-month improvement of overall survival.

To be quite honest, I’m excited about this class of AKT inhibitors. They’re in a variety of phase 3 studies, whether patients are ER+ or triple negative, and a lot of studies are combining them there. We think of first-line triple negative cancers, and we now have immunotherapy. The reality is that, in my experience, I haven’t seen quite a 40% positivity on testing. It’s probably more like 30% to 35% in the real world, so that’s for a minority of patients. I would certainly like to be able to improve upon single-agent taxane for those patients. I like the idea of the AKT inhibitors because you don’t have to have a mutation to benefit like you do with PI3 kinase inhibitors. It’s an attractive class of molecules if we have benefit.

Adam M. Brufsky, MD, PhD: Right. I agree. There’s something there with this. Clearly, the FAKTION trial shows that there is activity, so we know there’s activity: it’s a question of where and how. The adverse effect profile is manageable. To me, it’s similar to the PI3 kinase inhibitors; they’re slightly different. The toxicities are hopefully going to be manageable, and hopefully, they’ll have some place somewhere. There may be differences between capivasertib and ipatasertib just like there are with the CDK4/6 inhibitors. We’re going to have to wait and see because we [at the University of Pittsburg] are participating in the CAPItello trial. I don’t know if you [at the Sarah Cannon Research Institute, Tennessee Oncology] are. We didn’t do the IPATunity; we decided to do the CAPItello trial, which is the AZ [AstraZeneca] with capivasertib. We’ll see what happens. We’ve got to wait and see on these drugs. I’m excited about it.

Transcript edited for clarity.

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