Matthew P. Goetz, MD: The paradigm for treating patients with ER [estrogen receptor]—positive breast cancer has been to use a drug that targets the estrogen receptor. This, of course, has been an exciting paradigm—using a targeted agent against the estrogen receptor—for many years. What has changed, however, with the advent of CDK4/6 inhibitors is the fact that we are now able to target another critical pathway, the cyclin D–CDK4/6 axis, which we know is associated with resistance to endocrine therapy. By targeting this, we can actually effectively prolong the time until patients progress, and we can do it with excellent quality of life.
I think there have been a lot of attempts to, if you will, introduce new agents into this setting. But obviously, we have to be cognizant of quality of life. The CDK4/6 inhibitors have indeed changed the paradigm because A) they’re effective, B) the effect is substantial with improvements in median progression-free survival of over a year, C) improvements are not just in low-risk but also in high-risk groups, and 4) we do this all with excellent quality of life. Truly, the paradigm has changed, and this is good for patients.
Joyce A. O’Shaughnessy, MD: There’s a very strong rationale for targeting CDK4/6 in ER-positive metastatic breast cancer. The estrogen receptor leads to the transcription of cyclin D1 and all the cyclin D’s, which then form complexes with CDK4/6 to drive the cell cycle. That’s the major way that the estrogen receptor drives proliferation through CDK4/6. In addition, there are all the other pathways that impinge on nuclear estrogen receptor and phosphorylation and drive proliferation to pathways such as HER2, PI3-kinase, and Wnt/beta-Catenin. These are all the pathways that we know can eventually cause resistance to endocrine therapy; they, too, all impinge on the estrogen receptor, which leads to the transcription of cyclin D and CDK4/6. All the pathways come down and basically lead to overexpression of cyclin D1, driving the cancer cells to the CDK4/6 pathway. Basically, the cyclin D1—CDK4/6 complex is the lynchpin of proliferation for ER-positive breast cancer.
Stephen Johnston, MA, PhD, FRCP: We currently have 3 CDK4/6 inhibitors that are approved based on the trials that have been done in advanced breast cancer. The first drug available was called palbociclib, and that is approved both as first-line and second-line treatment in combination with an aromatase inhibitor [AI], which was the first treatment option; or for patients who progress on a single-agent aromatase inhibitor, it was approved in combination with fulvestrant. This was based on the PALOMA-2 and the PALOMA-3 trials, respectively.
Another CDK4/6 inhibitor, ribociclib, has also been approved in the first-line setting based on the MONALEESA-2 trial, where it showed significant prolongation of disease-free survival and progression-free survival in combination with an AI compared with an AI alone.
The third drug, which is slightly different in terms of its toxicity profile and scheduling, is called abemaciclib, and this was approved based on the MONARCH trials. MONARCH 3 was the trial for the first-line indication in combination with an AI. The MONARCH 2 trial led to the approval of abemaciclib with fulvestrant in the second line for patients progressing on an AI. There’s also an approval for this drug in a single-agent setting based on MONARCH 1, where patients had had 1 or 2 lines of previous therapy, including chemotherapy, and the drug showed activity as a single agent.
There is a spectrum of different settings for these 3 drugs. Palbociclib and ribociclib are very similar. They’re given on schedules of 3 weeks on, 1 week off, with hematological toxicity being the rate-limiting factor. Whereas abemaciclib lends itself to more continuous dosing, 150 mg twice a day, with a different toxicity profile: much less in the way of hematological toxicity but some early onset diarrhea that can be managed with appropriate premedication, prophylaxis, and dose reductions in some cases. We’re seeing very interesting drugs with high levels of activity but subtle differences between abemaciclib and the other two, which are very similar, palbociclib and ribociclib.
I think what patients and clinicians need to understand is the management of the reversible toxicities that these CDK4/6 inhibitors have. They key issue is that they do have some level of hematological toxicity, which clinicians are well used to dealing with in chemotherapy. But the key thing is that the neutropenia we see here is very different from chemotherapy-induced neutropenia.
Firstly, it is quickly reversible. With palbociclib and ribociclib, we treat for 3 weeks, and then we give a week break. The neutrophil counts will come back up for the vast majority of patients within 7 days. Some patients may need a longer time for recovery and a subsequent dose reduction. The incidence of complications due to neutropenia, namely febrile sepsis, is very low, and that’s where it’s very different from chemotherapy. This is primarily because chemotherapy can damage the gut and infection can get into the system, whereas these drugs have a very low level of impact on other organs, just reversible neutropenia.
In terms of the GI [gastrointestinal] toxicity that we see with abemaciclib, it is a short-lived diarrhea that occurs within the first 1 to 2 weeks in some patients. It’s often very mild and low grade, but if it is grade 2 or grade 3, appropriate dose reduction and prophylaxis with loperamide can actually manage the symptoms very well.
Transcript Edited for Clarity