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Distinguishing Among the Available CDK4/6 Inhibitors


Joyce A. O’Shaughnessy, MD provides insight into the differences among the available CDK4/6 inhibitors including their dosing schedules.


Joyce A. O’Shaughnessy, MD: I have been impressed with abemaciclib in the most virulent breast cancers. I think those metastatic breast cancers are least likely to be sensitive to endocrine therapy. For patients who recurred on adjuvant AI [aromatase inhibitors] and perhaps weren't on the adjuvant AI very long, I'm going to choose fulvestrant and abemaciclib. The subset analyses showed that patients with a treatment-free interval less than 3 years had a very strong favorable impact from abemaciclib and those with a longer treatment-free interval did not benefit as greatly.

The differential was toward the more virulent disease. Likewise, grade 3 disease, PR [progesterone receptor]-negative disease, liver metastases, and all the poor prognosis subsets really benefitted in both MONARCH-2 and MONARCH-3 from abemaciclib. That's also been my personal experience. I've been using abemaciclib now for years since it was first introduced. I’ve had patients who hadn't had a CDK4/6 inhibitor ever, and they were very heavily pretreated and seeing major responses very late in line with abemaciclib.

It was just remarkable, and in my experience as well, I've had the best outcomes for first-line metastatic patients and those with substantial liver disease, or more virulent disease. I've had the best success with abemaciclib, so the subset analysis data do jive with my personal experience. One thing about abemaciclib is that it inhibits more than CDK4 and CDK6. It has some ability to inhibit CDK1/2 and some of the other CDKs [cyclin-dependent kinases].

Whether or not all patients have enough of a plasma level of abemaciclib to inhibit CDK 1/2 is debated. The point is that it’s a broader mechanism of action agent which I think likely helps explain its benefit, plus the fact that for very fast-growing cancers you don’t have to take a week off. You're getting it twice a day continuously without a break. I think all of those features go into making it my choice for the most virulent of disease.

I’ll put the palbociclib and ribociclib together in my thinking. I have utilized them interchangeably for patients with more indolent disease, or disease that I think is going to be more sensitive to endocrine therapy. This is not the most virulent of disease, but more like the ESMO [European Society for Medical Oncology] definition of endocrine therapy-sensitive disease. That’s clearly where I would use the palbociclib. Ribociclib is my choice in the premenopausal population, based on the survival data in MONALEESA-7.

I'm going to use fulvestrant first line, let's say if, for example, a woman was totally unable to tolerate adjuvant aromatase inhibitors. She had terrible adverse effects, so she didn't take it. Now, she's developed metastatic disease. I'm going to use fulvestrant. I'm going to choose ribociclib with fulvestrant based on the MONALEESA-3 data. Interestingly, in MONALEESA-3, as I mentioned, even in the primary endocrine therapy-refractory population, the ribociclib provided benefit.

At ASCO [American Society of Clinical Oncology Annual Meeting] this year, there were data looking at MONALEESA-3 and MONALEESA-7 with regard to survival in patients with liver metastases, and it looked very good. I think ribociclib is clearly an option, even in patients who I think will be refractory to endocrine therapy. It's an agent that I certainly would be interested in using across all the various subsets of breast cancer.

It's very well tolerated. For my most virulent, symptomatic, heavily tumor burdened, luminal B, genomically unstable, heterogeneous disease, I still am going to use abemaciclib for those patients. But if someone had substantial liver metastases but it wasn't the most virulent, and had more of a history of endocrine therapy sensitivity, I think ribociclib would be a very good choice for those patients, as would palbociclib.

Palbociclib and ribociclib have myelosuppression, particularly neutropenia, as their main adverse effect, so you can dose them accordingly. It’s once daily dosing for 21 days, and then you have to take 7 days off for recovery of the bone marrow. In virulent disease, it’s possible that taking the week off may allow escape of some subclones to come back.

We know in the preoperative setting, for example, when breast cancers are suppressed, their proliferative rate is suppressed with preoperative CDK4/6 inhibitors, and then you stop them to allow the patient to have marrow recovery before going to surgery so that there can be recovery, or partial recovery, of proliferation off of the CDK4/6 inhibitors. We don't know to what extent that's clinically relevant, and many people don't think it is.

Many people say “Look, the first-line metastatic PFS [progression-free survival] data all look exactly the same. The hazard ratios are exactly the same.” That’s true, but the first-line metastatic is not going to be looking at your most virulent, fastest growing population. Those are going to be a small percentage of the population buried among patients where it doesn't matter if they get 3 weeks on, 1 week off versus the abemaciclib, which is twice a day continuously without a break because it doesn't have myelosuppression as a major feature of its toxicity.

With regard to adherence to the CDK4/6 inhibitors, 1 thing I would say is that in general, metastatic breast cancer patients are highly motivated to take their oral medications, and they're willing to tolerate adverse effects more than they would in the curative setting. I think women are motivated to take their CDK4/6 inhibitors, but sometimes there is confusion about when it's time to stop the CDK4/6 inhibitor where you need to take your week off.

I've certainly had patients have confusion about that and continue their CDK4/6 inhibitor. Sometimes the blister packs that just have 21 days in them are helpful, and then you have 7 days off. Those can be helpful. If people just get a bottle of pills, I think that can be confusing initially to some patients, but with more education and such, patients do get the hang of it.

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