HR+ Metastatic Breast Cancer: Continuing CDK4/6 Inhibition Beyond Progression

Expert panelists consider when it is appropriate to continue the use of CDK4/6 inhibitors beyond progression in HR+ metastatic breast cancer.


Sara M. Tolaney, MD, MPH: Now that we have these agents to use in the first-line setting, what do you think about continuing CDK4/6 inhibition beyond progressive disease? Do you do it? What did you think of the MAINTAIN data?

Eva M. Ciruelos Gil, MD, PhD: Yes, the PADA and MAINTAIN trials are small, but really intelligent trials. This is emergent. I think this is similar to the ADAPT trial in terms of when somebody has an important question, you don’t need a big phase 3 trial for this question to be discussed at least, or to be followed. MAINTAIN is a trial that was presented earlier this year, and we know that maintaining ribociclib after progression on palbociclib, or even ribociclib, is good and is better than discontinuing CDK inhibition. So, this could be a new standard. I wouldn’t recommend this practice because we need phase 3 data on that. There’s an abemaciclib trial in which patients who have been pretreated with palbociclib or ribociclib, when they progress, they are randomly assigned to stay on abemaciclib versus hormonal treatment. This trial may have the final answer to that question. But I think maintaining the inhibition of CDK; I don’t know if different CDKs, such as 4/6 or many others that play an important role in the acquired resistances, will be relevant, but they are in urgent clinical need by these second-line patients because of the post-CDK scenarios.

Let’s also put an eye on biology. PATA has tested ESR1 mutations. HARMONIA is testing the only direct comparison between palbociclib and ribociclib in a specific subset of patients. Selected by intrinsic subtype, there are around 20% of patients who are HER2 enriched, or even more if you test the metastatic samples, metastatic disease. Maybe these patients need a more potent CDK inhibitor. Maybe palbociclib is not enough in that case; maybe this is the best niche for ribociclib. We don’t know. We are doing this direct comparison in the HARMONIA trial. There are many remaining questions.

Sara M. Tolaney, MD, MPH: It’s amazing how much data continue to come out about these.

Eva M. Ciruelos Gil, MD, PhD: Sure.

Sara M. Tolaney, MD, MPH: I think your point about MAINTAIN is excellent. I honestly thoughtit was very impressive data for a randomized phase 2 investigator-initiated trial. I will say, occasionally I use CDK4/6 inhibition beyond progression in a very select patient population, where I think maybe continuation would be of benefit. But I think the question will be, as you pointed out, does it matter which agent you use? Do you need to switch the CDK4/6 inhibitor?

Eva M. Ciruelos Gil, MD, PhD: Yes. A small proportion of patients in MAINTAIN started with and maintained ribociclib and benefited in the same way as patients who were pretreated with palbociclib, so we never know. It opens the possibility of retreating with a CDK inhibitor when patients relapse after having adjuvant abemaciclib because more patients are receiving this drug in the earlier scenario as well.

Sara M. Tolaney, MD, MPH: That’s an excellent point. We don’t have any data about how to appropriately treat someone who relapses after having abemaciclib.

Eva M. Ciruelos Gil, MD, PhD: Sure.

Sara M. Tolaney, MD, MPH: We’ll see more data come out. As you point out, the PACE study may get presented at San Antonio Breast Cancer Symposium 2022, which is predominantly looking at post-palbociclib. Those data will be interesting to see if it matters.

Transcript edited for clarity.

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