Case 2: CDK4/6 Inhibitor Recommendations in ER+ Breast Cancer

Hope Rugo, MD, FASCO: Adam, is there any patient for whom you don’t to use a CDK4/6 inhibitor first?

Adam Brufsky, MD, PhD: Yes, if the patient is in a resource-constrained area of the world where these drugs are not available or they’re very expensive. For example, in the Philippines, where I was about a year ago, they tend to use CDK4/6 inhibitors for about 4 months, on average. The reason it’s 4 months is because it’s not paid by insurance. The family gets together, and they have enough money for about 4 months of therapy. You have to really consider that on a more global scale, but in the United States, there are very few people I would probably not give it to.

I think maybe somebody with a predicted overall survival in their lives, a competing cause of death that maybe is less than the benefit they would get from it; someone who has trouble taking pills; an older woman who has a lot of issues or is otherwise frail and on a lot of medicines and confused about what she’s taking. But that’s very uncommon. I think one of the issues that really occurs here is the woman who is at 36 months or more after a completion of adjunct therapy. What do you do for her?

It’s really more than 36 months. It’s like 8 years out. And the limited data are a bit conflicting—showing that with some of the CDK4/6 inhibitors, there is no benefit, but with others there is. I think that I’d make a nuanced decision on that. I have done both. I have put those women who’ve relapsed after 8 to 10 years on hormone alone and others on hormone and a CDK4/6 inhibitor. I think that decision is based on the volume of the disease, the patient’s tolerance, etc. But those are the only people I wouldn’t give it to.

Hope Rugo, MD, FASCO: With that situation, it’s really interesting. The patients I’ve been seeing more recently who are 10 to 12 years out had received 10 years of endocrine therapy. Those are people I’d definitely give CDK4/6 inhibitors to.

Adam Brufsky, MD, PhD: Correct. I agree.

Hope Rugo, MD, FASCO: They tend to have small amounts of visceral disease. I think just because we’re treating them more aggressively. All our patients, except for maybe a few, will eventually progress on CDK4/6 inhibitors and hormone therapy. Do you usually rebiopsy? Do you order blood testing? Do you go back to the archival setting? Are you looking for mutations like PIK3CA, Ian?

Ian Krop, MD, PhD: Obviously, we want to biopsy to prove they have metastatic disease, so we perform an initial biopsy in the metastatic setting. But after progression on a CDK4/6 inhibitor, we haven’t been doing biopsies on a regular clinical basis. Certainly, there’s a lot of interest from a research standpoint, and we’ve been trying to get both blood biopsies and tissue biopsies to try to understand mechanisms of CDK4/6 resistance.

I haven’t necessarily been doing it purely for clinical purposes. Obviously, we want to know whether they have a PIK3CA mutation, but we typically will get that on their diagnostic metastatic biopsy. It’s not likely to change. The other things weren’t really going to affect your management very much, so I haven’t been doing it.

Hope Rugo, MD, FASCO: Adam, what kinds of therapeutic options do you present to your patients after they’ve progressed on a CDK4/6 inhibitor?

Adam Brufsky, MD, PhD: There are a lot. First, we obviously do some sort of blood-based DNA sequencing on these patients at that time. It’s the test du jour, whichever one you like, in looking for the PI3-kinase mutation. If they have one, then they should definitely get fulvestrant and alpelisib. That, as you know, covers about 40% of people. So what do we do for the other 60%? I tend to think about fulvestrant and everolimus as one of my go-to agents.

Those are probably the big ones that I would do—my 2 major choices. There is a bit of data that has come out—again, this is not standard of care or FDA approved at this point. There was a group at Harvard that put together an experience of patients who actually had progressed on palbociclib and then were given abemaciclib, half of them were given it almost immediately after. And actually, it was a PFS [progession-free survival] benefit of about 8 months in the people who got it right after.

It’s not even a trial. It’s an experience with maybe 80 or 100 patients. But, again, there may be something to that. There have been a number of randomized trials exploring that very question. One is actually people who progressed on an AI [aromatase inhibitor] plus a CDK4/6 and are randomized to fulvestrant or fulvestrant and a CDK.

Switching the endocrine partner is an interesting thought. Those are the sort of things that I’ve discussed with people. Unless they have a truly, really rapidly progressive disease, then I would think of chemotherapy. But short of that, I wouldn’t really try a hormonal agent again.

Hope Rugo, MD, FASCO: There are also some trials examining whether immunotherapy helps in specific settings, as well as in combination. There are some very interesting data within an AKT inhibitor, capivasertib, and there are also some data that will come up with ipatasertib and that may or may not require a PIK3CA mutation in the tumor itself. Then, there’s a lot of work going on in managing the toxicity of PI3-kinase inhibitor toxicity, including hyperglycemia and rash.

I think we’re going to see a lot of additional data in the second- and greater-line settings in people who recur. And, of course, a number of studies are underway and enrolling more than 15,000 women and testing CDK4/6 inhibitors in the early-stage setting. We hope to see data in the next year, which hopefully won’t be delayed by this current pandemic. I think that may also change what our options and discussions are in the metastatic setting.

This has been a really interesting conversation. I appreciate everybody’s contributions to this really important area—management of patients with hormone receptor–positive metastatic disease. Now we’ll go on to our next case.

Transcript edited for clarity.