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HR+ Breast Cancer: Factors in Selecting a CDK4/6 Inhibitor

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: Wednesday, Aug 29, 2018



Transcript:

Joyce A. O’Shaughnessy, MD: Regarding the choice of CDK4/6 inhibitors in the metastatic setting, right now the answer of utilizing all 3 in the first-line setting with an aromatase inhibitor would be very reasonable. At this ASCO meeting, we’ve heard data from MONALEESA-3 combining ribociclib with fulvestrant and including in the first-line setting. The NCCN [National Comprehensive Cancer Network] guidelines do allow a CDK4/6 inhibitor plus fulvestrant as first-line therapy. We have several choices, and they’re all really well shored up with phase III clinical trial data.

There are data. Richard Finn has shown data looking at luminal A versus luminal B biology with palbociclib in PALOMA-2. The ER-driven luminal A biology had just a tremendous benefit from palbociclib. The luminal B patients benefited, as well, but there was even greater differential benefit in the more indolent biology.

The thing about palbociclib and ribociclib is that they have fewer adverse effects than abemaciclib. They cause neutropenia, and you have to have a week off, but very few patients develop febrile neutropenia, diminutively low. Patients don’t have very much at all in the way of GI [gastrointestinal] toxicity. There certainly is some fatigue. But abemaciclib is associated with diarrhea—and most of it is low grade, but it’s still diarrhea—sometimes anorexia and sometimes some nausea. It abates over time, patients’ tachyphylaxis, and it improves and is very manageable with loperamide. It’s all very manageable. But again, it has more toxicity.

Aim that where the patients are going to get the most benefit, potentially where they have full-throttle cancer, highly proliferative disease, and it’s potentially better to keep target inhibition going, or in cancers that recur very, very rapidly, suggesting potentially multiple mechanisms of resistance to endocrine therapy requiring a broader-spectrum agent. Truthfully, these hypotheses need to be put into randomized trials to really know for sure, but that’s the idea. Patients are likely to respond very well to CDK4/6 inhibitors and endocrine therapy. Choose the one that has the least toxicity, but for the patients who have the worst clinical features, their toxicity can potentially be a secondary consideration. You’ve got to have efficacy, basically. The most potent of the CDK4/6 inhibitors might be a better choice.

Matthew P. Goetz, MD: When we see a woman who presents with metastatic ER-positive breast cancer, and that woman has a relatively low-level volume disease—perhaps nonvisceral disease or bone-only disease—I’m quite comfortable using an endocrine agent such as letrozole or an aromatase inhibitor [AI] in combination with palbociclib or ribociclib. We know as we look very carefully at the subgroup analysis that there does not appear to be one group that necessarily benefits more or less in those trials, the PALOMA trials and the MONALEESA trials.

As we think about some of these higher-risk patients with features such as liver metastases, it’s pretty clear that the response rate that was seen, both in MONARCH 2 and MONARCH 3, was substantial. In fact, it approached a 50% mark in those clinical trials. I think because of that, clinicians can feel quite comfortable. Whereas they might have used chemotherapy in the past for these patients, abemaciclib along with hormonal therapy, either an AI or fulvestrant, could be used with great confidence in that scenario.

Transcript Edited for Clarity 
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Transcript:

Joyce A. O’Shaughnessy, MD: Regarding the choice of CDK4/6 inhibitors in the metastatic setting, right now the answer of utilizing all 3 in the first-line setting with an aromatase inhibitor would be very reasonable. At this ASCO meeting, we’ve heard data from MONALEESA-3 combining ribociclib with fulvestrant and including in the first-line setting. The NCCN [National Comprehensive Cancer Network] guidelines do allow a CDK4/6 inhibitor plus fulvestrant as first-line therapy. We have several choices, and they’re all really well shored up with phase III clinical trial data.

There are data. Richard Finn has shown data looking at luminal A versus luminal B biology with palbociclib in PALOMA-2. The ER-driven luminal A biology had just a tremendous benefit from palbociclib. The luminal B patients benefited, as well, but there was even greater differential benefit in the more indolent biology.

The thing about palbociclib and ribociclib is that they have fewer adverse effects than abemaciclib. They cause neutropenia, and you have to have a week off, but very few patients develop febrile neutropenia, diminutively low. Patients don’t have very much at all in the way of GI [gastrointestinal] toxicity. There certainly is some fatigue. But abemaciclib is associated with diarrhea—and most of it is low grade, but it’s still diarrhea—sometimes anorexia and sometimes some nausea. It abates over time, patients’ tachyphylaxis, and it improves and is very manageable with loperamide. It’s all very manageable. But again, it has more toxicity.

Aim that where the patients are going to get the most benefit, potentially where they have full-throttle cancer, highly proliferative disease, and it’s potentially better to keep target inhibition going, or in cancers that recur very, very rapidly, suggesting potentially multiple mechanisms of resistance to endocrine therapy requiring a broader-spectrum agent. Truthfully, these hypotheses need to be put into randomized trials to really know for sure, but that’s the idea. Patients are likely to respond very well to CDK4/6 inhibitors and endocrine therapy. Choose the one that has the least toxicity, but for the patients who have the worst clinical features, their toxicity can potentially be a secondary consideration. You’ve got to have efficacy, basically. The most potent of the CDK4/6 inhibitors might be a better choice.

Matthew P. Goetz, MD: When we see a woman who presents with metastatic ER-positive breast cancer, and that woman has a relatively low-level volume disease—perhaps nonvisceral disease or bone-only disease—I’m quite comfortable using an endocrine agent such as letrozole or an aromatase inhibitor [AI] in combination with palbociclib or ribociclib. We know as we look very carefully at the subgroup analysis that there does not appear to be one group that necessarily benefits more or less in those trials, the PALOMA trials and the MONALEESA trials.

As we think about some of these higher-risk patients with features such as liver metastases, it’s pretty clear that the response rate that was seen, both in MONARCH 2 and MONARCH 3, was substantial. In fact, it approached a 50% mark in those clinical trials. I think because of that, clinicians can feel quite comfortable. Whereas they might have used chemotherapy in the past for these patients, abemaciclib along with hormonal therapy, either an AI or fulvestrant, could be used with great confidence in that scenario.

Transcript Edited for Clarity 
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Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
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