Efficacy of CDK4/6 Inhibitors in HR+ mBC



Michael Untch, MD: I would like to ask a question to my United States colleagues on this topic. At the moment, in all the clinical practice, what we are doing is trying to get a biopsy from the metastases we can reach. Let’s say a lymph node or a liver or whatever. What are we doing at the moment from this biopsy? ER, PR, Ki-67, and HER2, period.

Now, tests are coming. I have been approached by Foundation Medicine, and I already did some of these tests to look for actual targetable mutations from the metastatic side. Since these tests are coming—as usual almost always from the United States and swept over the ocean—are you using these tests? Because, Hope and Joyce, it’s nice to have ER, PR, Ki-67 and HER2, but we know that the world is much more complicated in the year 2017.

Joyce A. O’Shaughnessy, MD: Yes, I am using both the biopsies. If we’re going to go to the trouble of getting a biopsy, I will usually send it off for next-generation sequencing. But I think the most exciting thing in my practice is the serial determination of CT DNA in the blood work, being able to get the Guardant360 or FoundationACT right now, too. Because, they ask, “Why are you doing that? Is that a waste of resources?” And I think the main thing for me is HER2 mutations, they’re probably the actionable…

Adam M. Brufsky, MD, PhD: Which we’ll get to the HER2 mutations a little later.

Joyce A. O’Shaughnessy, MD: Yes. But also, I’ll tell you, I’m getting it quite frequently when patients are progressing on CDK4/6 inhibitors, because I do really want to know what resistance mechanisms. And I’m actually working with Aditya Bardia. We’ve noticed some RB1 mutations coming out again. These are just small anecdotal reports at this time. They’re hypothesis generating. But, anyway, it is a good way for us to start to query, what are some of the resistance mechanisms coming up?

Adam M. Brufsky, MD, PhD: But in the United States, it’s not standard of care. It’s still somewhat difficult to get it paid for by our payers.

Hope S. Rugo, MD: But I have to say, not being standard of care, I’m hard pressed to find a patient who hasn’t had it sent.

Adam M. Brufsky, MD, PhD: Right, absolutely.

Hope S. Rugo, MD: People have it sent on multiple tumors, and I would say that the number of patients for whom their actionable mutation is vanishingly small. We all remember is the 1 or 2 patients where we found something and it’s really exciting, but they’re small.

Adam M. Brufsky, MD, PhD: But I would say again, we’ll come back to this when we talk about HER2. At least in my experience when I’m starting to think about this, I think ER, ERS1, will be actionable at some point. Do we change the fulvestrant, which we’ll also talk about in a minute, or do we continue an AI? That’s number 1. Number 2, I think HER2 tyrosine kinase mutations are probably a little more frequent than we believe. Would we switch the patient potentially to a HER2 tyrosine kinase inhibitor? And last but not least, something we don’t talk about is ER amplification. And I think it turns out that people who are ER-amplified may actually respond to high-dose estrogen.

So, there’s a lot of things in there that are potentially theoretically possible, but we’ll talk about that a little bit later when we talk more about HER2 and triple negative and bring this back. But we’ve talked a little bit about resistance and I think we want to bring this back to some practical things that have happened. So, the first thing is to talk a little bit about PALOMA-2. Was anybody surprised that PALOMA-2 pretty much replicated PALOMA-1?

Michael Gnant, MD: I was not surprised.

Adam M. Brufsky, MD, PhD: No, I think none of us were surprised by that.

Hope S. Rugo, MD: Also, if you do the trials, you have people who are on who progressed on tamoxifen to develop metastatic disease and are still on 4 years later, longer than they were on their adjuvant tamoxifen.

Adam M. Brufsky, MD, PhD: Correct, something is going on that’s good. And the next question really talking about resistance in various mechanisms is ribociclib. At last year’s ESMO, we saw the first data from MONALEESA-2. Does someone want to comment on that? Michael, do you know about the design of MONALEESA-2?

Michael Untch, MD: Well, I think sitting at this table are people who were on the trial. They might be the specialist to comment.

Adam M. Brufsky, MD, PhD: There we go.

Michael Gnant, MD: Well, I was not contributing to the trial, but I think I know the design. It was pretty similar to PALOMA-2, and it is single-agent letrozole versus the combination of ribociclib and letrozole. The results, I think, were absolutely confirmatory, very reassuring. Again, they showed that incredible 10 to 12 months achieved of PFS, which we have actually never seen. Because when you look at tamoxifen or AI, we were happy about 4 and a half months in all of this. So, jump starting luminal breast cancer into the ballpark of what we have seen with HER2 and others. I think for me, as a clinician, this was extremely reassuring.

Transcript Edited for Clarity

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