Metastatic Breast Cancer: CDK4/6 Inhibitors

Kate Jeffers, PharmD: Currently on the market there are 3 CDK4/6 inhibitors: so palbociclib, ribociclib, and abemaciclib. All 3 of them are indicated in metastatic breast cancer with slight differences. They are indicated in first-line therapy as well as second-line therapy, and abemaciclib also has a monotherapy indication which I think of more as kind of a third-line type of therapy when patients have progressed through prior therapies. They’re all oral agents, but their dosing is slightly different, with ribociclib and palbociclib being a 3-weeks on and 1-week off regimen, and abemaciclib being just a continuous dosing. And those are due to differences within the way they work on that CDK4/6 pathway. Abemaciclib is a twice-a-day medication, whereas the other 2 are once-a-day medications. And so I think that also comes into play when you’re thinking about educating patients and what’s the easiest for patients to take.

In terms of patients that would be appropriate for the agents, these would be patients who are metastatic breast cancer patients, either pre-, postmenopausal if you’re going to give them with ovarian suppression because they are given with an aromatase inhibitor as well. They are also indicated with fulvestrant, which is more of that kind of second-line setting, which is typically where I think of it as, and then as a monotherapy the abemaciclib, typically patients who progressed through an AI, tamoxifen, and fulvestrant. I’m really giving them that kind of third-line option for that therapy.

In terms of safety profiles, they’re similar with some differences, and it’s related to how they work in the pathways. So, for palbociclib and ribociclib, they are less specific than abemaciclib, which leads them to have more myelosuppression effects. So more neutropenia is seen with those agents. Abemaciclib also targets CDK9 as well as 4 and 6 and that has a higher affinity, so you see less neutropenia with that agent but more GI [gastrointestinal] toxicities. Specifically, diarrhea is the one that we usually focus on with patients, really making sure that they’re educated to have supportive care medications available at all times while starting that medication, particularly for the first 1 to 2 months.

Another adverse effect to think about with these agents is with ribociclib. There is an incidence of QTc prolongation seen in about 3% of patients. It’s definitely something that we do consider when selecting patients for therapy, however. We do include, in our order sets, a baseline EKG [electrocardiogram] for these patients, as well as 1 to 2 weeks after starting and then as clinically indicated. So it’s not an adverse effect we have to think about with the other 2 agents.

In terms of drug interactions, also something to consider, although they’re all relatively equal and that they all have CYP3A4 interactions. And so no kind of benefits with avoiding drug interactions with one agent over the other, but definitely something when starting patients on therapy, you need to look at their medication profiles, other medications that they’re on that may or may not interact and think about other agents that you may have to change. So not just treating their breast cancer, but how do we manage the rest of their therapies as well?