Joyce O’Shaughnessy, MD: Abemaciclib is the most potent of the 3 CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors. It’s about 14-fold more potent against CDK4, which is the major proliferative cyclin-dependent kinase in ER [estrogen receptor]-positive breast cancer. It is also given continuously. It’s not given with the 7-day break to allow for recovery of neutrophils. That’s probably most important in more highly proliferative disease. If breast cancer is slower growing, that 7-day break required once a month probably doesn’t make any difference.

But with the more aggressive breast cancers, taking that 7 days off may be more problematic because we know that once the drug is out of the body—and the half-life is about a day, day-and-a-half for these agents—you will see a rebound in cell growth. These are cytostatic agents. You will see a rebound in growth. That’s probably an important consideration, the fact that you don’t need to take the 7 days off and it’s very, very potent, so that you can get very good clamp down on CDK4. That’s important in these aggressive breast cancers. You’ve got a very strong proliferative signal coming in from FGFR [fibroblast growth factor receptor], for example. That’s a very, very adverse amplification to have in these breast cancers.

The other issue that I think about is that abemaciclib, of course, is mainly a CDK4/6 inhibitor, but it does hit a broader profile of proliferative proteins such as cyclin D2, to some extent. Cyclin D2 is another very important cyclin-dependent kinase. It complexes with cyclin E, where CDK4/6 complexes with cyclin D1. Now, in an interesting presentation here at AACR [American Association for Cancer Research], we saw updated results from Dr Nick Turner regarding the PALOMA-3 trial, which was fulvestrant plus or minus palbociclib looking at about 300 patients who had archival tissue available.

They did gene expression profiling and looked at cyclin E. Cyclin E is a bit of a concern because it could be a resistance mechanism to the CDK4/6 inhibitors that complex with cyclin D, which are really inhibiting well. But if you’ve got a lot of cyclin E around, patients may not benefit from palbociclib, and basically that is what was found. Looking above the median and below the median, patients with a lower cyclin E expression really benefitted greatly from the palbociclib, and those with cyclin E above the median benefitted from palbociclib, but much less. That was really quite interesting, and it really suggests that cyclin E CDK2 could be a very important mechanism of resistance to palbociclib. We know that abemaciclib can inhibit CDK2. So, in patients with the more aggressive and concerning cancers, all the cyclins are probably on. All systems are on in proliferation, and that’s how I think of it. Abemaciclib’s mechanism of action may just be broader.

Another interesting point from Nick Turner’s update of the PALOMA-3 trial is that they did look at the luminal A versus the luminal B breast cancers, and about 20% of patients were considered to be HER2 [human epidermal growth factor receptor 2] enriched by gene expression profiling. All 3 subsets benefitted including, interestingly, the HER2 enriched patients, and of course these are ER [estrogen receptor]-positive, HER2-negative patients from the PALOMA-3 trial. But interestingly, the differential benefit from palbociclib came in the luminal A breast cancers: the more endocrine therapy-sensitive, less highly proliferative disease. There was benefit in luminal B, but it just wasn’t as great, suggesting that there are other mechanisms of proliferation stimulus in those luminal B patients who are more genomically unstable and have more alterations and more ways for those cancer cells to grow.

Palbociclib was certainly beneficial, just not as differentially so. And so, we haven’t seen a breakdown yet from abemaciclib for the luminal A versus luminal B groups. But we have seen, in the data I presented here at AACR, an analysis of the higher grade versus lower grade groups, and abemaciclib is interestingly more effective, differentially so, in higher-grade disease. PR [progesterone receptor] negativity goes along with luminal B disease as well, with greater benefit in that more concerning population.

Transcript Edited for Clarity