CDK4/6 Inhibitors & Endocrine Therapy: Selecting a Regimen

Sara M. Tolaney, MD, MPH:There are 3 FDA-approved CDK4/6 inhibitors for metastatic breast cancer. Those include palbociclib, ribociclib, and abemaciclib. All 3 of these agents have had very consistent improvements in progression-free survival in both the first- and second-line settings. So I think all 3 of these agents are actually very reasonable choices.

Sometimes there are some differences in toxicity profiles that may influence you to choose 1 agent over another. For example, both palbociclib and ribociclib are associated with pretty significant rates of neutropenia. About two-thirds of patients that will experience grade 3 or 4 neutropenia, and almost half those patients will require some type of dose hold or dose reduction due to neutropenia. For example, if you have a patient who has borderline white counts and mildly low neutrophil counts, you’re not really going to want to choose palbociclib or ribociclib in that patient; you’ll probably sway toward using abemaciclib. Abemaciclib is a little different in that it has lower rates of neutropenia—about a 20% rate of grade 3 or 4 neutropenia. But it is associated with more GI [gastrointestinal] toxicity, so we do see about a 10% rate of grade 3 or 4 diarrhea in patients receiving abemaciclib.

So if you have a patient who has underlying issues with irritable bowel syndrome or underlying issues with colitis and frequent diarrhea, you [are] probably not going to choose abemaciclib and, instead, would choose either palbociclib or ribociclib. Again, I think there are just small nuances in terms of toxicities that may help you differentiate which agent to choose. At this time, there’s no randomized data comparing the 3 CDK4/6 inhibitors to one another. So we don’t have any data directly comparing them to know if there’s a difference in efficacy.

There’s been much interest in trying to see if we can select which patients are going to benefit the most from CDK4/6 inhibitors and whether or not there may be some patients who may not benefit from CKD4/6 inhibitors. One very interesting analysis that was done was a combined analysis of about 1000 patients from MONARCH 2 and MONARCH 3, which looked to see if there were clinical factors that could help us better understand which patients are deriving benefit from CDK4/6 inhibition.

What they found, very consistently, was that those patients who had liver metastases, who had low PR [progesterone receptor] expression and high-grade tumors, were patients who tended to have worse outcomes in terms of their underlying prognosis. But those were also the very patients who derived the biggest benefit from the addition of abemaciclib. The hazard ratio for those patients with those 3 risk factors was more in the area of 0.4 compared with the 0.5 range, and their objective responses were more in the range of about 30%. So we did see that these patients did derive more benefit than we thought in the overall populations from these trials.

Another analysis that was also done was trying to see whether there were patients who may not derive any benefit from CDK4/6 inhibition. When they did look at, for example, patients who had bone metastases, they still found that these patients do derive benefit from the addition of abemaciclib, but the hazard ratio in the bone metastases patients is a little higher, for example, than in those patients with visceral involvement.

So again, there really is no subgroup that’s not deriving benefit from the addition of CDK4/6 inhibition, but it is those patients who have the visceral disease, high-grade tumors, and low PR status that are the patients who tend to derive even greater benefit.

They also did a very interesting analysis looking at those patients who had a short treatment-free interval and have also found that those patients also tend to derive greater benefit from the addition of abemaciclib than the average population—again, pointing to the fact that high-risk tumors tend to have even greater benefit from CDK4/6 inhibition.

In trying to decide which endocrine therapy to use with the CDK4/6 inhibitor, we’re really trying to look at what their prior exposure was to endocrine treatment to better understand which agent may work best. For example, in this case, this is a patient who recurred about 13 months after discontinuation of an aromatase inhibitor making 1 wonder how sensitive she may be to re-exposure to aromatase inhibition. Usually I feel pretty comfortable re-exposing someone to an AI [aromatase inhibitor] if it’s been significantly longer than a year since prior aromatase inhibition. In this case, she’s right of the edge of that time frame, so that’s why I would choose to use fulvestrant for this particular patient. However, if this patient had been 3 years out from their adjuvant AI, I may have chosen to use an aromatase inhibitor for that particular patient.

In terms of better understanding if there is going to be more benefit from the addition of the CDK4/6 inhibitor to an aromatase inhibitor or fulvestrant, there are certainly no data to suggest that an AI and a CDK4/6 inhibitor may be better than fulvestrant and a CDK4/6 inhibitor. We do have trials that have compared the aromatase inhibitor alone with fulvestrant alone in the first-line setting. The FALCON study did look at this and found that for those patients who had bone-only metastases with de novo metastatic disease, fulvestrant was superior to an aromatase inhibitor. But otherwise, in the overall population, they were about the same. And so, you know, it’s hard to say you should be using 1 over the other, and we don’t have data, again, in combination with the CDK4/6 inhibitor to know whether 1 would outperform the other.

Transcript edited for clarity.

Case: A 58-Year-Old Woman With Metastatic ER+ Ductal Carcinoma

• 58-year-old woman with estrogen-receptor-positive (ER+), progesterone-receptor-negative (PR-), HER2-negative (HER2-) invasive ductal carcinoma (IDC) of L breast; she completed adjuvant anastrozole for 5 years
• Now, 13 months later, she presents with 4 small (<1.0 cm) asymptomatic lesions in the left lung and mediastinal and hilar lymphadenopathy.
• Mediastinoscopy was performed and confirmed ER+ PR- Her2- carcinoma
• ECOG PS: 0
• The patient was started on abemaciclib + fulvestrant