CDK4/6 Inhibitors in Breast Cancer: Ongoing Research

Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center


Adam M. Brufsky, MD, PhD: Clearly, CDK4/6 inhibitors have changed the standard of care in this disease. I think that 1 thing a lot of us are interested in is seeing real-world data. We now have the ability with these giant databases to see how women who are treated with CDK4/6 inhibitors live. And I think it’s going to be really important. It’s probably going to be more important than the clinical trials’ data, which are a little bit more controlled. It’s a little bit harder to really tease out what the effect of abemaciclib, or palbociclib, or ribociclib, is.

I think that is number 1. So, we’ll have to see some of these big data sets and see what happens. Number 2, the big open question for a lot of us is, when someone progresses on an endocrine therapy and CDK4/6 inhibitor, is it because they are resistant to the CDK4/6 inhibitor? Or is it because they’re resistant to the underlying endocrine therapy? So, there are a number of clinical trials addressing that, at least 2, and we’re actually doing 1 here in Pittsburgh, too. It’s a 150-patient randomized phase II trial, where what we’re doing is actually treating people who have progressed on, say, letrozole and a CDK4/6 inhibitor, and randomizing them to, say, fulvestrant with or without a CDK4/6 inhibitor.

The idea is that if they become resistant, a third of women who are on long-term aromatase inhibitors develop an ESR1 mutation, an estrogen receptor mutation. And so, maybe that’s why they progress, not because of the underlying CDK4/6 inhibitor. I think I fall into that camp that believes it’s going to be very similar to the trastuzumab story, where progression is likely going to be due to the underlying hormonal therapy and not necessarily the CDK4/6 inhibitor. It’s been very difficult to find biomarkers for response to CDK4/6 inhibitors, and as a result, it’s been very difficult to find biomarkers for progression. Until we find those biomarkers for progression, how do we really know that it’s due to the CDK4/6 inhibitor resistance? We don’t. I think that’s why these trials are extremely important.

There is another set of trials that I think is really interesting. When you go back and look at the early preclinical data with palbociclib and some of the other drugs, there seems to be activity in HER2-positive disease. There are a number of trials now—some of which have started to report, some of which I think are going to report in the next year or so—where what people are doing is giving CDK4/6 inhibitors for HER2-positive metastatic breast cancer. A lot of that’s triple-positive—it’s ER/PR/HER2–positive—but some of it is ER-negative/HER2-positive disease.

It’s going to be really interesting to see the activity of these drugs, and abemaciclib is 1 of them. The palbociclib trials, ribociclib trials—there are all those trials out there, and those results are going to be really, really cool to see. But I think that’s where the field is going right now, at least the things that are really making me most excited in the next couple of months to years. I think it’s really cool. It’s a really neat therapy that I think has definitely changed the standard of care.

Just to summarize this whole field, I think that we now have 3 CDK4/6 inhibitors, all with a slightly different toxicity profile and treatment profile. I think that in the metastatic setting, they all have activity of a slightly different kind. One of the things I didn’t touch on is who shouldn’t get them. I think, interestingly enough from the MONARCH-3 trial data that was just presented at ESMO, that if women have a disease-free survival in the adjuvant setting longer than 3 years, there’s not as much benefit from the CDK4/6 inhibitors. So, maybe there’s a subset of patients who don’t need it upfront, who could get the single-agent endocrinotherapy and then go to a CDK4/6 inhibitor plus something else when they progress.

The other thing is, do these drugs work in the adjuvant setting? There are a bunch of adjuvant trials now—PALLAS, PALLET, PENELOPE, all of these trials—where people are using CDK4/6 inhibitors in the neoadjuvant setting, a post-neoadjuvant setting if you have residual disease, or in the adjuvant setting if you have recurrence. And I think those will be very interesting. So, the field is really exciting, and we’re going to try to bring this into early-stage breast cancer.

Transcript Edited for Clarity 
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