Abemaciclib With Endocrine as Frontline Therapy

Joyce O’Shaughnessy, MD:With regard to which of the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors I would consider for this particular patient with the de novo metastatic disease with the multiple liver metastasis and mildly elevated liver function tests but pretty asymptomatic, I would utilize abemaciclib because of the tempo of her disease. She has grade 3 disease with a rapidly growing mass in the breast and now multiple liver metastasis. And the reason I would utilize the abemaciclib is mainly because of subset analyses that have looked at liver metastasis, grade 3 disease, progesterone receptor-negative disease, several of the characteristics that define this woman’s cancer have been looked at with abemaciclib. And in the first-line setting, there can be a difference of improvement at 30% response rates looking at letrozole with or without the abemaciclib, even in these concerning clinical characteristics, the more aggressive virulent type disease.

The first-line data for all of the CDK4/6 inhibitors show excellent improvement in progression-free survival with palbociclib, ribociclib, abemaciclib, really identical in terms of the overall populations. So any of them would be reasonable options truthfully. The issue is what about this particular virulent subset. Most patients with first-line metastatic breast cancer do not have this aggressive biology. So the totality of the data are going to be more reflective of patients with more indolent or moderate disease. The biology and the natural history of those with aggressive disease will not be necessarily manifest in the overall data.

You have to look at some of the subsets to really understand. The thing about abemaciclib is it’s every day. There is no break with abemaciclib to allow for narrow recovery. And so with more virulent disease, there may be some benefit. We don’t know because there are no head-to-head comparisons, but there may be some benefit from a continuous inhibition of CDK4/6 as opposed to the 3 weeks on, 1 week off schedule that’s required for the palbociclib and ribociclib. So that’s the theoretical reason, potentially a little bit broader spectrum of activity, but again, these are not based on head-to-head comparisons but more subset analysis.

But in the MONARCH 2 and MONARCH 3 clinical trials, both first-line with letrozole and then second-line with fulvestrant, when abemaciclib was added to these endocrine therapies and looking at some of the key clinical characteristics; liver metastasis, short treatment-free interval, progesterone receptor-negative, grade 3 disease, there were very large improvements in both response rates and progression-free survival with the abemaciclib. And a bit more so even than patients with more indolent features such as bone-only disease, progesterone receptor-positive, longer treatment-free interval. They too benefitted from abemaciclib, but interestingly not to the same extent that the more virulent cancer did.

Now, the other agents as well also have activity in liver metastasis and grade 3 disease, progesterone receptor-negative. But the in-depth analysis has been done most with abemaciclib in these patients with the more concerning clinical characteristics. And the fact that you don’t have to take the week off is appealing to me. So no head-to-head comparisons, but that’s the reason that I generally, if I’m going to forego chemotherapy, when I’m on that borderline does this patient need chemotherapy or could I utilize a CDK4/6 inhibitor, that’s where I will choose abemaciclib for that particular patient. For the more indolent patients, I don’t choose abemaciclib. I utilize palbociclib or ribociclib for the patients with bone-only disease or more ER [estrogen receptor]-driven disease because there’s less GI [gastrointestinal] toxicity. The abemaciclib I find patients do fine with it, but I want continuous inhibition of CDK4/6 for patients with more virulent disease.

I’ve had a chance to have a fair amount of experience with all of the CDK4/6 inhibitors. And because abemaciclib is also approved later-line for patients and has been studied later-line, I’ve had the opportunity to see some very robust responses, including in patients with diffuse liver metastasis, even in heavily pretreated patients. That truthfully was what made me interested in abemaciclib, was seeing these patients very late-line and seeing the non-cross resistance, the real robust activity.

One patient in particular was a veterinarian, African American veterinarian. She was very heavily pretreated by the time the CDK4/6 inhibitors became available, and she had not been exposed to one. And she had basically had all of our available endocrine therapies and chemotherapies at that time. She had diffuse liver metastasis, even some hyperammonemia. She was having some liver failure. She had just finished radiation therapy for brain metastasis. Her performance status was not good, and I treated her with fulvestrant and abemaciclib, and she had a major response that lasted for about a year with an excellent quality of life. So that kind of put me back on my heels a little bit, I will say, and that’s been of great interest to me. I have several other patients who were in that category. So, when I saw the subset analysis of those patients with the liver metastasis, the more virulent disease, shorter treatment-free intervals, etcetera, it made sense to me based on my clinical experience.

Transcript edited for clarity.

Case: A 62-Year-Old Woman WithDe NovoInvasive Ductal Carcinoma

• A 62-year-old woman presented to her gynecologist with a large mass in her right breast
• Breast MRI confirmed the presence of a 6-cm mass and axillary adenopathy
• Labs: ALT 95, AST 70 (elevated)
• Core needle biopsy confirmed ER+ PR (-) HER2(-) carcinoma, grade 3
• CT chest, abdomen, and pelvis showed widely scattered liver metastases