Role of CDK4/6 Inhibitors as First-Line Therapy for Metastatic HR+ Breast Cancer
Comprehensive insight to the selection of CDK4/6 inhibitors as first-line therapy for patients with metastatic HR+ breast cancer, followed by a brief review of available endocrine partners.
Transcript:
Jules Cohen, MD: Dr Iyengar, this patient has completed their treatment and is on the maintenance aromatase inhibitor [AI]. How would you monitor the patient going forward?
Neil M. Iyengar, MD: In the adjuvant setting on an AI, clinical monitoring is probably our best tool in terms of recurrence monitoring. Having the patient in the clinic for regular breast exams and an annual mammography is the predominant way that I monitor these patients. Patients on adjuvant hormone therapy, especially if they’ve received chemotherapy, are at risk for other long-term comorbidities in the survivorship setting, particularly cardiometabolic comorbidities. Making sure that this patient is following up with her primary care physician and checking off the boxes in terms of routine health screening and screening for other cancers is an important part of cancer survivorship.
Jules Cohen, MD: To go further into the case, 2½ years into her treatment with anastrozole, the patient presented after developing new symptoms—fatigue and right upper quadrant abdominal pain—that negatively affect her quality of life. Her ECOG performance status is 1, and an imaging work-up showed 5 new subcentimeter liver metastases, which was confirmed by biopsy. The tumor still is estrogen receptor [ER] positive, progesterone receptor [PR] negative, and HER2 [human epidermal growth factor receptor 2] negative. Dr Slamon, would you like to discuss first-line therapy for metastatic ER+ disease?
Dennis J. Slamon, MD, PhD: At this point, there are sufficient data that these patients benefit in a substantive way with a combined hormonal therapy and CDK4/6 blockade. There are 3 approved CDK4/6 drugs that have very similar hazard ratios and show a good progression-free survival. Two of those 3 have reported overall survival data that are very positive and among the largest survivals we’ve seen in this subtype of breast cancer. That’s the right treatment at this point for this patient.
Jules Cohen, MD: Dr Mortimer, do you prefer a specific CDK4/6 inhibitor?
Joanne Mortimer, MD, FACP, FASCO: My preference for an CDK4/6 inhibitor is ribociclib [Kisqali] because it seems to have the best survival data. There are issues with administration of ribociclib with checking cardiac function, but given an improvement in overall survival, it’s worthwhile to get the ECGs [electrocardiograms] and look at the QTc interval every 2 weeks for the first 6 weeks of treatment. We should also check their labs because survival is the most important end point for these women.
Jules Cohen, MD: Dr Iyengar, are you a convert to ribociclib, or are you still a palbociclib [Ibrance] or abemaciclib [Kisqali] guy?
Neil M. Iyengar, MD: I agree with Dr Mortimer. Ribociclib is my default choice in the metastatic setting. That’s essentially because of the overall survival data. When thinking about ribociclib or abemaciclib from a toxicity standpoint, patients have to deal with diarrhea on abemaciclib, whereas neutropenia isn’t necessarily a day-to-day toxicity that patients experience or that impacts patient experience. It can be but isn’t typically. I prefer ribociclib from a toxicity standpoint as well. There are certain scenarios in which I might consider abemaciclib up front over ribociclib, particularly if CNS [central nervous system] protection might be important for that patient. In general, ribociclib is my agent of choice in the first-line setting.
Jules Cohen, MD: Dr Slamon, do you have an opinion or an explanation for why palbociclib, to my knowledge, still has the lion’s share of the market vs the other 2 drugs?
Dennis J. Slamon, MD, PhD: The first drug out of the gate makes a big difference. They had at least a 1- to 1½-year head start on the observation that this class of drugs, led first by palbociclib, makes an impact on progression-free survival. I agree that our default drug of choice, if the patient doesn’t have any cardiac problems, is ribociclib. The data are compelling. There’s some controversy that’s being discussed at the San Antonio Breast Cancer Symposium, about whether these drugs are all the same or different. They’re clearly different. They all have the same target, so there’s that question. They clearly inhibit CDK4/6 a bit differently in terms of 4 being preferential over 6. Abemaciclib is a much broader inhibitor in the sense that it’s a dirty kinase, not set in a pejorative way, but it hits many other things besides CDK4/6, which may benefit or become a liability long term. Time will tell.Dr Iyengar has already mentioned the GI [gastrointestinal] toxicity, which is a real consideration. A schoolteacher having grade 2 diarrhea is a life-altering adverse effect.
Jules Cohen, MD: My wife is a schoolteacher.
Dennis J. Slamon, MD, PhD: It’s something that you don’t see with ribociclib or palbociclib, but because the survival data are so impressive and consistent in ribociclib, that’s our default.
Jules Cohen, MD: Dr Mortimer, can you speak to the other indications for abemaciclib? Does it have a few extra indications that the other 2 drugs haven’t achieved?
Joanne Mortimer, MD, FACP, FASCO: Neil mentioned the potential for CNS penetration. I don’t know who I’d think is at risk, but patients who’ve had brain metastases certainly are. Abemaciclib is probably the preferable CDK4/6 inhibitor over the other 2 because there are data that CNS penetration is an adverse effect and even evidence of efficacy in that population.
Jules Cohen, MD: What about in the adjuvant setting?
Joanne Mortimer, MD, FACP, FASCO: The adjuvant setting is very important. Abemaciclib and the monarchE study demonstrated progression-free survival. It will be 2028 before overall survival is assessable. The addition of abemaciclib for 2 years improved progression-free survival in a population of patients who had 1 to 3 positive nodes at presentation. Ki-67 was a component of eligibility being greater than 20. There’s a lovely editorial by Mitch Dowsett in the JCO [Journal of Clinical Oncology] that looks at how reproducible or irreproducible Ki-67 is. Using Ki-67 hasn’t been incorporated in the NCCN [National Comprehensive Cancer Network] or ASCO [American Society of Clinical Oncology] guidelines. There are 1 to 3 positive nodes in a large tumor, and 4 or more node-positive is a reason to give abemaciclib for 2 years. The end point is progression-free survival. Hopefully, we’ll see the overall survival advantage by 2028. This is a population that has a favorable outcome. It’s going to take a long time to see the overall survival advantage.
Jules Cohen, MD: Dr Iyengar, do you prefer fulvestrant [Faslodex] or an aromatase inhibitor in the first line?
Neil M. Iyengar, MD: This is a very patient-specific decision. Typically, my default is an aromatase inhibitor, and that’s thinking about subsequent lines of therapy and what my endocrine therapy partner may be. That being said, for an individual who relapsed on adjuvant aromatase inhibition, who has a natural history that may be consistent within ESR1 mutation, or if we identify that on next-generation sequencing in the first-line setting, then that might sway me toward using fulvestrant instead of an aromatase inhibitor. But an AI is still my default in the first-line setting.
Transcript edited for clarity.
