Case 2: CDK4/6 Inhibitors in ER+ Breast Cancer

Adam Brufsky, MD, PhD: Interestingly enough, I think a lot of the behaviors of the approved CDK4/6 inhibitors can probably be predicted by their IC50 [half-maximal inhibitory concentration].I think that palbociclib and ribociclib are equipotent, and it’s really the potency as opposed to their ratio to the CDK6 that is responsible for the neutropenia. It’s interesting, though, because palbociclib is about the same—11 nM versus 15 nM. Whereas ribociclib is 10 nM versus about 40 nM. Although interestingly enough, the amount of neutropenia is nearly the same with both of them.

Abemaciclib has a lower IC50, so it’s more potent. And it’s a 5:1 ratio between CDK4/6, so there’s less neutropenia with this drug. Palbociclib and ribociclib are given 3 weeks on, 1 week off to prevent neutropenia. Because there’s a 5:1 CDK4/6 ratio with abemaciclib, you can give it continuously, which is what we do with abemaciclib. There are very large clinical trials for all these drugs.

Palbociclib was approved more than 5 years ago. Abemaciclib was the last one approved, actually in 2017. Here’s the data from the first-line metastatic trials. Overall, it appears there is a bit more response rate with palbociclib than with ribociclib, but I wouldn’t put too much stock in that. I think they’re all generally better than the control arm. That’s the most important thing. The clinical benefit is better than the control arm, and there is a near doubling of progression-free survival, regardless of which agent you use.

I think that’s a really important point because we all get a lot of information from the various pharmaceutical companies pointing to this one and that one. There may be some subtle differences, in particular with abemaciclib because you can give it in later lines of therapy. But really, I think at least to a first approximation, except for toxicity, they’re all pretty much the same.

Second-line trials are shown here. I think that we get about a doubling of progression-free survival. There are survival benefits with ribociclib and abemaciclib that look to be statistically significant and are substantial. I think the big difference with the palbociclib trial is the patient population. It’s really important to note that a lot of people had chemotherapy on PALOMA-3—about 45%, 50% of the patients. I think people who’ve been pretreated with chemotherapy might not necessarily have a potential survival benefit with CDK4, but I think it’s pretty close. These trials really weren’t designed for those endpoints anyway.

This just looks at the survival benefit of abemaciclib and fulvestrant, showing what we said before. This is second-line therapy. There is a 9.4-month overall survival benefit, which is really substantial. I think the big thing you can tell women is, “Look, you’re almost at 4 years of overall survival now from a disease that you read on the internet would be a lot less.” I think this is a really good thing in advancing the field in this way. This is actually second-line therapy. This isn’t even first-line therapy.

This is 48 months after progression, probably after a year of initial endocrine therapy. You’re really talking 5 years, not necessarily 4.

MONALEESA-3 shows the same thing. Relative risk of death was reduced by about 28%. Again, the median survival has not been reached in this trial, which is really gratifying to see. You’re out almost 4 years, and more than 50% of the patients are still alive.

Again, the big difference among all these agents is really how they are given. And, the toxicities. Abemaciclib and palbociclib come in dosage forms, so if you want to dose reduce somebody, you have to potentially get another prescription. Ribociclib is a 200-milligram tablet, and you can just alternate the tablet strength. The major toxicities are neutropenia; thrombocytopenia, to a lesser extent; and fatigue, really just with abemaciclib. You also have to watch for diarrhea with abemaciclib.

You have to watch for increased QTc interval with ribociclib. I think in this day and age, QTc has become very important with some of the drugs that are circulating. But nonetheless, it’s something that needs watched. And again, with palbociclib, it is the same thing. There is rare diarrhea, anorexia, and fatigue.

Transcript edited for clarity.