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HR+ Breast Cancer: Differences Between CDK4/6 Inhibitors

Insights From: Joyce A. OShaughnessy, MD, Balor University Medical Center; Stephen Johnston, MA, PhD, FRCP, The Royal Marsden Hospital; Matthew P. Goetz, MD, The Mayo Clinic
Published: Tuesday, Aug 14, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: We have 3 FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Palbociclib and ribociclib inhibit both, of course, CDK4 and 6, and they lead with cumulative dosing to neutropenia because they inhibit CDK6, which can cause some marrow suppression and neutropenia. You treat for 21 days, and then you give a week off to allow for recovery of the bone marrow. Abemaciclib is 14 times more potent in inhibiting cyclin D4, CDK4, than it is for CDK6. So it doesn’t have as much neutropenia or as much bone marrow suppression. As a result, you can give it continuously. CDK4 is the more important of the CDKs that complexes with cyclin D1, particularly to drive proliferation.

When you have a very aggressive cancer that’s very highly proliferative, you need very strong target inhibition. You’re not going to give the patient chemotherapy where otherwise you may have done that. It’s reasonable to consider a drug where you don’t have to give the week off. Now truthfully, we do not have a head-to-head comparison. All these agents work in every single clinical subset that we have, from liver metastases to multiple sites of metastases to short disease-free intervals. But what if you ask, Where is the benefit of abemaciclib the best? Where do you see the most differential benefits?

For abemaciclib, it’s that aggressive cancer. It just makes sense that if you can just keep the inhibition of that target going continuously without a break, it might potentially have a slight advantage. It certainly does for abemaciclib. That’s where you see the greatest benefit, in the most highly aggressive breast cancers with short treatment-free intervals, heavy metastases, loss of the progesterone receptor, grade 3, and liver metastasis. These are the most difficult to treat with ER [estrogen receptor]–positive disease.

Matthew P. Goetz, MD: If we look across the CDK4/6 inhibitors, ribociclib and palbociclib are probably the most similar in terms of their efficacy or ability in potency to inhibit CDK4 and CDK6. They’re similar in terms of their toxicity in terms of neutropenia, but we begin to see some differences with ribociclib in that there’s some GI [gastrointestinal] toxicity that’s seen—hepatotoxicity and effects on QT interval—in a small proportion of patients. As we move across to abemaciclib, we really see a different molecule, a greater potency against CDK4 and CDK6. We also see this difference: Whereas ribociclib and palbociclib are dosed on a 3 week on, 1 week off basis, abemaciclib is dosed continuously.

As one looks across the different clinical trials and thinks about efficacy, it appears that there’s broad efficacy and quite similar efficacy across trials. One theoretical advantage about abemaciclib is the fact that it is dosed continuously, and thereby one could reduce the chance of this so-called rebound G1/S activation that could potentially occur during the period of time that the patient is off the drug during that week-off period. This is probably most important for patients who are developing significant adverse effects related to the neutropenia and undergoing prolonged treatment delays. Obviously, another significant difference in terms of the molecules, the toxicity profile, has been mentioned. Whereas neutropenia is the predominant toxicity with ribociclib and palbociclib, neutropenia is less common—in fact, grade 3 or 4 events occur in perhaps only 10% or so of patients—with abemaciclib. But we do see diarrhea with abemaciclib. Rarely, we have seen some hepatic toxicity with abemaciclib as well as rare VTE, or venous thromboembolic, events.

Transcript Edited for Clarity 
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Transcript: 

Joyce A. O’Shaughnessy, MD: We have 3 FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Palbociclib and ribociclib inhibit both, of course, CDK4 and 6, and they lead with cumulative dosing to neutropenia because they inhibit CDK6, which can cause some marrow suppression and neutropenia. You treat for 21 days, and then you give a week off to allow for recovery of the bone marrow. Abemaciclib is 14 times more potent in inhibiting cyclin D4, CDK4, than it is for CDK6. So it doesn’t have as much neutropenia or as much bone marrow suppression. As a result, you can give it continuously. CDK4 is the more important of the CDKs that complexes with cyclin D1, particularly to drive proliferation.

When you have a very aggressive cancer that’s very highly proliferative, you need very strong target inhibition. You’re not going to give the patient chemotherapy where otherwise you may have done that. It’s reasonable to consider a drug where you don’t have to give the week off. Now truthfully, we do not have a head-to-head comparison. All these agents work in every single clinical subset that we have, from liver metastases to multiple sites of metastases to short disease-free intervals. But what if you ask, Where is the benefit of abemaciclib the best? Where do you see the most differential benefits?

For abemaciclib, it’s that aggressive cancer. It just makes sense that if you can just keep the inhibition of that target going continuously without a break, it might potentially have a slight advantage. It certainly does for abemaciclib. That’s where you see the greatest benefit, in the most highly aggressive breast cancers with short treatment-free intervals, heavy metastases, loss of the progesterone receptor, grade 3, and liver metastasis. These are the most difficult to treat with ER [estrogen receptor]–positive disease.

Matthew P. Goetz, MD: If we look across the CDK4/6 inhibitors, ribociclib and palbociclib are probably the most similar in terms of their efficacy or ability in potency to inhibit CDK4 and CDK6. They’re similar in terms of their toxicity in terms of neutropenia, but we begin to see some differences with ribociclib in that there’s some GI [gastrointestinal] toxicity that’s seen—hepatotoxicity and effects on QT interval—in a small proportion of patients. As we move across to abemaciclib, we really see a different molecule, a greater potency against CDK4 and CDK6. We also see this difference: Whereas ribociclib and palbociclib are dosed on a 3 week on, 1 week off basis, abemaciclib is dosed continuously.

As one looks across the different clinical trials and thinks about efficacy, it appears that there’s broad efficacy and quite similar efficacy across trials. One theoretical advantage about abemaciclib is the fact that it is dosed continuously, and thereby one could reduce the chance of this so-called rebound G1/S activation that could potentially occur during the period of time that the patient is off the drug during that week-off period. This is probably most important for patients who are developing significant adverse effects related to the neutropenia and undergoing prolonged treatment delays. Obviously, another significant difference in terms of the molecules, the toxicity profile, has been mentioned. Whereas neutropenia is the predominant toxicity with ribociclib and palbociclib, neutropenia is less common—in fact, grade 3 or 4 events occur in perhaps only 10% or so of patients—with abemaciclib. But we do see diarrhea with abemaciclib. Rarely, we have seen some hepatic toxicity with abemaciclib as well as rare VTE, or venous thromboembolic, events.

Transcript Edited for Clarity 
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