Future Directions: CDK4/6 Inhibitors in Breast Cancer
Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Sara Hurvitz, MD: All of the CDK4/6 inhibitors are now being evaluated in the curative setting. There are several studies that have been reported, or are ongoing, looking at the use of a CDK4/6 inhibitor in the neoadjuvant setting for patients with hormone receptor-positive breast cancer. And those studies have consistently shown that the addition of a CDK4/6 inhibitor does drop the Ki-67 from day 0 to day 14, which we think is a good surrogate marker for long-term outcome. That said, we don’t have event-free survival, overall survival, or long-term data from these relatively small studies at this time. So, the use of these inhibitors in the neoadjuvant setting is not standard of care at this time outside of a clinical trial.
In addition, there are several large ongoing or planned adjuvant clinical trials that will be enrolling thousands of patients looking at the use of either palbociclib, ribociclib, and soon abemaciclib in the adjuvant setting. And these studies are going to pave the way for the future for our patients who have ER-positive early-stage breast cancer. The question comes up how long should we be giving these agents in the adjuvant setting. Is it a year? Is it 2 years? So, studies like these are going to be important for us to define how long patients should be on a therapy like this and which patients should be receiving this therapy. Certainly, not all patients with hormone receptor-positive stage I/stage II breast cancer need additional therapy. So, these studies are going to be important in helping us define the risk groups that should receive these therapies.
Hope S. Rugo, MD: Right now, we are seeing the opening of multiple adjuvant trials, as you just heard about, and we’ll hear data in the near future from the neoadjuvant setting, or we’ve already seen some data in the neoadjuvant setting, using all of these drugs: CDK4/6 inhibitors and the mTOR inhibitor everolimus. And we’re going to see alpha-specific PI3-kinase inhibitors with neoadjuvant data this year in 2017, so lots and lots of data about neoadjuvant use. And lots and lots of patients will be randomized in the adjuvant setting. I was trying to count up how many patients, and I think it’s over 15,000 worldwide with the 3 different agents and the multiple trials.
The interesting post-neoadjuvant therapy, as we heard about, is also quite intriguing to understand whether we could select a group of patients who were of sufficiently high risk where we’re going to want to give a CDK4/6 inhibitor by that risk differential. How did you respond to neoadjuvant chemotherapy, rather than just did you have positive nodes or not? And that will be very interesting, I think, to see. So, there isn’t, right now, any role for these drugs. We have randomized trials going on also with, of course, everolimus; slow to accrue, but we’ll see data in that setting. We’re going to have to balance the quality of life aspects of the drugs and the cost versus the benefit that we see over the next many years when we start seeing these data coming in from early-stage trials.
But what about if you have a patient who’s in your clinic who either isn’t eligible for one of those trials or is not really willing to be randomized, which is a different issue? So, if you take a patient who’s not really eligible, still has positive margins, has involvement of skin or muscle, and really has extremely high-risk disease—36 positive nodes—in those patients, I’ve actually tried to use drug off-label and again, very much off-label, have no idea how long to treat the patients. But where the risk of recurrence is so incredibly high and these are young patients where they’re motivated, I’m motivated to try and look at the best tolerated agent with the best data in the first-line metastatic setting.
There’s also another situation where I’ve actually been using CDK4/6 inhibitors where patients have had multiple local recurrences where you know that their risk of developing metastatic disease is close to 100%. So, by the time they’ve had their second resectable local recurrence post-mastectomy, these patients are going to get metastatic breast cancer. They’ve progressed through several hormone agents, and I’ve tried to use CDK4/6 inhibitors in that setting as well, if anything, to prolong the time until a patient develops metastatic disease, but of course with our current hope that someday we’ll be able to prevent metastatic disease in these patients with the highest risk hormone receptor-positive breast cancer.