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Role of CDK4/6 Inhibitors and Patient Selection


Experts in the field of breast cancer management discuss the role of CDK4/6 inhibitors and patient selection for treatment.


Bruce Feinberg, DO: Bill, it seems to me that the initial adoption rate after the Ibrance [palbociclib] approval was low. There are 2 things I think that may have affected. One is the everolimus story proceeding it. I think the question is, are these just drugs that overcome hormone resistance and therefore don’t have innate activity? The second is that I think there is a general perception that hormone receptor-positive patients do better than they actually do. In the original Ibrance trial that led to approval, the PFS [progression-free survival] was only 10 months in the nonexperimental arm. When I was often doing more general market research among oncologists, they saw the hormone receptor-positive population as the good patients, or those who were going to get a prolonged response. I often did polling to look at things like what that means. They would often get responses like “2 years of control with initial first-line intervention.” I’m curious about the slow uptake. Now, it seems that the adoption rate is very high. Could you comment on that?

William J. Gradishar, MD: Yes, I think it’s probably multifactorial. I think that when the CDK4/6 inhibitors were first introduced, the everolimus experience probably colored things a bit because you had this perception that endocrine therapy is largely well tolerated. Patients go about their life, nothing bothers them, and everything is good. Then, you add another agent, and in the case of everolimus, maybe some patients had stomatitis and other adverse effects. Suddenly, endocrine therapy wasn’t so friendly.

Then, with the CDK4/6 inhibitors, there was this concern, perhaps shared by some, that if you added a CDK4/6 inhibitor, you’re adding a chemotherapy-lite agent to endocrine therapy. Now you’re dealing with low blood counts, and you’re basically just adding chemotherapy to endocrine therapy. I think there was a false impression that you were changing the way that patients were experiencing their therapy, that they couldn’t be compliant, or some other variety of issues. But I think what happened over time is that there was a realization that the CD4/6 inhibitor adverse-effect profile well tolerated by patients, for the most part. I think once there was a broader appreciation of the uptick in PFS, which was a dramatic improvement, the uptake of the drug class was expanded. Most people now, regardless of which CDK4/6 inhibitor you use, find that the adverse effects are pretty manageable, and for the most part, patients do well. You can’t dismiss the marked improvement in PFS that patients are experiencing.

Bruce Feinberg, DO: Thanks. Joyce, in selecting patients who are appropriate, we’ve already addressed that issue of visceral crisis, but we have other factors. One of those factors is the extent to which they had prior adjuvant therapy—prior adjuvant therapy with chemotherapy, the extent of their primary neutropenia, primary adjuvant therapy with hormonal agents. What do you then do? There is also a consideration of duration—either time off therapy or duration of benefit from the prior adjuvant. Could you build out that branching tree of how you approach those patients for CDK4/6 therapy and who’s eligible? Then, which of the partner endocrine agents are you using based on that history? It would be helpful to get a sense of how an expert approaches this.

Joyce A. O’Shaughnessy, MD: I and nearly everyone else go by the actual eligibility criteria for the pivotal trials that led to FDA approval. With regard to pairing 1 of the CDK4/6 inhibitors with an aromatase inhibitor [AI], patients had to either be de novo metastatic—they had not had any therapy at all for prior breast cancer—or, if they had prior adjuvant endocrine therapy, they had to have completed it and been off of it at least a year. Then, they were eligible for frontline AI plus/minus a CDK4/6 inhibitor. If they recurred on adjuvant aromatase inhibitor therapy, whether they were on it for 5 years or 8 years, then the AI didn’t make a great deal of sense for them as a therapy. Those patients were eligible for the fulvestrant plus/minus CDK4/6 inhibitor in the so-called second-line trials, although for some it was their first line if they recurred on an adjuvant AI.

Patients could also have progressed on an AI in the metastatic setting and then be eligible for the fulvestrant plus/minus CDK4/6 inhibitor trial. That’s how I and many others will approach it. If you want to get the benefit that you see in these trials on PFS, you really do want to adhere as closely as you can to the eligibility criteria that were in the protocol.

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