CDK4/6 Inhibitors in the Metastatic Breast Cancer Setting

Transcript:

Komal Jhaveri, MD, FACP: At this point we can switch gears and move on to hormone receptor [HR]-positive metastatic setting. Is there a CDK4/6 inhibitor that we should use? There are 3 approved. Is there 1 popular with you, and why? Maybe you can walk us through.

VK Gadi, MD, PhD: I’ll start with the tough one.The earliest drug out there was palbociclib. Very exciting phase 2 data. Then we got the PALOMA-2 [NCT01740427] and PALOMA-3 [NCT01942135] data, with the backbone of an AI [aromatase inhibitor] and the second line with a backbone of fulvestrant, both [being] positive. I was so happy when the PALOMA-3 [trial] data came out. I was in the audience, called my nurse, and said that we can get this for my young patients, because we had young patients on that trial with ovarian suppression.

What’s emerged, though, is that these CDK4/6 inhibitors are probably not replaceable over each other. They might be different chemical entities with different efficacies based on what they’re going to engage in the cell-cycle machinery. So what we’ve learned now in the long-term follow-up looking at overall survival is the palbociclib molecule doesn’t seem to be able to achieve that, at least based on the studies we’ve seen. That’s an issue because [with] overall survival, when you can get it, as Aditya mentioned, [that is] the most important thing that should be driving our decision-making. I’ll let the others speak to the other molecules, but we’re in a little bit of a flux moment with the role of palbociclib at this time in the metastatic setting.

Komal Jhaveri, MD, FACP: So for your new start now, you’re not necessarily thinking about palbociclib, you’re shying away from that?

VK Gadi, MD, PhD: I’m probably shying away from it, and leaning toward the others.

Komal Jhaveri, MD, FACP: What about you, Greg? Is there a popular one in your practice?

Gregory Vidal, MD, PhD: I’ll take the bait, and for different reasons. Prior to this, palbociclib was my No. 1 prescribed medication in the CDK4/6 space. I’m a little, for many reasons, on the abemaciclib utilization. Although I probably do 50-50 abemaciclib and ribociclib for different reasons. One of them is just trying to get the EKGs into the system with the way my clinic is set up. So that’s been a little bit difficult. But I have to say, you can’t ignore the amount of data that’s available for ribociclib. Every single one of its trials, even if the PFS [progression-free survival] looked the same across the different drugs, there’s one drug showing overall survival throughout. Abemaciclib has won overall survival. I suspect it will get from MONARCH 3 also in that early space. So, then those drugs are somewhat competing with each other, but it’s about patient tolerability. Ribociclib is a better patient experience than abemaciclib, mainly because of the diarrhea. So you pick one, you choose one. I use abemaciclib a lot in the adjuvant setting. I just continue that use in the metastatic setting.

Komal Jhaveri, MD, FACP: I know we spoke about QTc prolongation. Have you utilized EKGs in your clinic, or do you use the home monitoring that Novartis also offers for the patients to make it easier? Have you used the KardiaMobile?

Gregory Vidal, MD, PhD: I have used the KardiaMobile, and have used it pretty successfully. The issue, though with that is, again, the way my clinic is set up, that oftentimes I have nurse practitioners sometimes covering my clinic for me in case, if my clinic is overbooked, for example, and they’re not necessarily all breast-learned nurse practitioners, and on 1 or 2 occasions that EKG was missed. To me, that’s a little bit concerning in my system. So there’s a lot of education that has to happen for me to feel fully comfortable. I suspect the more comfortable you get with it in the system and using it, then all of that will come. So there’s an education component to it.

Komal Jhaveri, MD, FACP: Aditya, have you switched over your patients from palbociclib? Do you use palbociclib for new starts? How are you processing all of this data that we have?

Aditya Bardia, MD, MPH: It’s similar to what was said before. If there’s a new patient, [I] start the movement more toward ribociclib, given the consistent improvement in overall survival. If I already have a patient on palbociclib doing well for 2 or 3 years, I would just continue that. We don’t have any data that switching would necessarily improve their overall survival. So I just continue.

Komal Jhaveri, MD, FACP: What about toxicity? If you have patients who develop, say, you have ribociclib and say, this patient is the one who had this grade 3 elevation in LFT [liver function test] or grade 3 QTc. It’s rare, thankfully, but if it happens, then how do you think about using and switching? Are there any data that were presented at the meeting that maybe you could speak to as well in that respect?

Aditya Bardia, MD, MPH: Absolutely. This is something we’ve done in clinical practice. I recently had a patient who had LFT increase because of ribociclib and switched to palbociclib, and so far [they are] doing well. So I think that is a strategy one could consider if a patient has difficulty tolerating CDK4/6 inhibitors. [As with] AI, you can switch them.

There’s a different question if a patient has disease progression on first-line AI plus palbociclib, should you continue the CDK4/6 inhibitor in the second-line setting? We’ve seen consistent data from [the PACE clinical trial; NCT03147287] and at ASCO [American Society of Clinical Oncology annual meeting] 2023 from the PALMIRA trial [NCT03809988] that there was no benefit in continuing palbociclib in the second-line setting. This is a bit contradicted to the MAINTAIN trial [NCT02632045] where there was benefit, but the difference with MAINTAIN was there was a switch from palbociclib to ribociclib. So maybe if you switch that [you] could still have some value. I think we’ll get definite evidence from the postMONARCH trial [NCT05169567], which is a phase 3 trial designed to answer this question. Patients who have disease progression on first-line CDK4/6 randomization to fulvestrant vs fulvestrant plus abemaciclib. If that trial is positive, I think that would be practice changing.

Komal Jhaveri, MD, FACP: I think that would be very helpful. You had a comment?

Timothy Pluard, MD: I was going to say [that] I think the landscape is changing so rapidly that now we’ll have surges to try with continuation strategies. To your question earlier about the LFTs, the grade 3 LFTs, there was some data here. It was a series of, I think, 36 or 38 patients who had grade 3 LFT abnormalities on ribociclib. Once they recovered, which actually took months for those LFTs to come down, they were switched to either palbociclib or abemaciclib. They did not have recurrence of their LFT abnormalities. So, there is an option, and I think that there’s been some concern about cross-toxicity once you’ve had the hepatotoxicity from ribociclib, but it doesn’t appear to be the case.

Komal Jhaveri, MD, FACP: I think that is comforting to know because that’s what we’ll end up doing in our practices. Right? So it’s good to see data that there is something happening. This is real-world data.

Transcript edited for clarity.

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