Benefits and Challenges of CDK4/6 Inhibitors

Kate Jeffers, PharmD: The CDK4/6 class works at a very particular place in the cell cycle, really adding additional benefit to your aromatase inhibitor therapy. You do definitely see increases in progression-free survival. Some of the overall survival is still kind of cooking because the trials are relatively new. Most of these drugs were approved in the last kind of 1 to 3 years. And so, we are still waiting on some of that overall survival benefit data.

In terms of where the CDK4/6 works in the cell cycle, they do work within the DNA replication pathway, basically inhibiting cell replication, arresting the cell in the G1 phase, leading to an inability for the cell to keep replicating. And so that does lead to cell death and apoptosis. It works in conjunction with your AIs [aromatase inhibitors]. Also there is some evidence looking at it with tamoxifen. So when given together, you’re able to overcome some of the resistance patterns that we see with an aromatase inhibitor or your estrogen receptor inhibitors on a monotherapy. These agents are also thought to able to be used in a monotherapy, and so they really are a little bit more dynamic in how they’re able to be used in the medications we’re able to pair them with. And so you see higher progression-free survivals with the combination of an aromatase inhibitor or fulvestrant with the CDK4/6s, whereas with monotherapy, less progression-free survival but higher progression-free survival than AI alone or the placebo.

With the CDK4/6 class, it does add an oral option to our metastatic breast cancer patients, which I think is huge for these patients. If a patient is newly diagnosed in the metastatic setting, they may not have seen prior lines of therapy. But especially for a patient who is more relapsed or recurrent, being able to provide them an oral option that they can take at home really allows these patients to stay with their normal activities and with their normal lifestyles. And I think that can improve quality of life. With that, there are unique benefits of an oral agent, of course. When you have an IV [intravenous] agent, you know the patient is getting the drug. They’re sitting in front of you. You’re putting an IV in. You know they’re getting the dose. With an oral agent, you think they’re getting the dose or they tell you they’re getting the dose, but they may not always be getting the dose. And so I think the adherence part definitely adds a whole other level of complication, and we’re seeing that in oncology in general with our oral agents, and are really focusing on adherence. It’s something that our practice has worked a lot on. But I think that’s a very unique opportunity for patients.

Prior to these agents, we had mostly IV therapies and some of them were fairly toxic. For patients, the more lines of therapy you’ve had, it’s harder to tolerate those agents. Whereas, these are relatively well tolerated. They do have some adverse effects that we’re aware of and we can manage, but you have to focus on them and manage them, and then you’re really able to keep patients on therapy and are able to keep them at home and out of the hospital.