Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Hope S. Rugo, MD: I’m very interested in novel combination therapies that could help to improve response even further or prevent the development of resistance in the most resistant hormone receptor-positive cancers. Preclinical data suggest that if you combine PI3-kinase inhibition with inhibition of CDK4/6, you actually can overcome resistance. In the preclinical setting, it looks like you need to start that combination up front rather than adding in the PI3-kinase inhibitor after development of resistance. But in the clinic, that may or may not be the case.
So, to me, the most interesting combinations that are farthest along in study, although still early, are looking at the combination of CDK4/6 inhibitors and PI3-kinase or mTOR inhibition. And there are actually some plans for randomized trials to be opening in the very near future, looking at, for example, everolimus/ribociclib and a hormone agent. There is a combined CDK. There’s a combined mTOR PI3-kinase inhibitor, gedatolisib, that’s being studied in combination with CDK4/6 inhibition and hormone therapy, quite interesting and highly effective. The biggest issue for us in these combinations is learning how to overcome toxicity and learning what the right drug dosages are, so that you don’t enhance toxicity while you’re improving efficacy because then you have a double-edged sword.
There’s also great interest from a neoadjuvant trial, and some preclinical data as well looking at abemaciclib, called neoMONARCH where patients who received abemaciclib either with an aromatase inhibitor or not in the neoadjuvant setting had a very nice, rapid suppression of proliferation. But in addition to that, they also saw this infiltration of T cells and if you looked at the subset of T cells, they were CD8-positive, which is what we’ve defined as TILs, or tumor infiltrating lymphocytes. And it turns out in early-stage breast cancer that having more TILs has correlated with response to the checkpoint inhibitors or immune-modifying drugs.
So, there’s a lot of interest in combining CDK4/6 inhibitors with these checkpoint inhibitors or other immune-modifying agents. That’s actually being studied and we’ll have some very early data, maybe in the next year or so, looking at those combinations and see where they go moving forward because one of the frustrations of treating hormone receptor-positive disease with immune checkpoint inhibitors is they’re not very immune active, so they don’t care. If you could generate a little bit of immune activity using a CDK4/6 inhibitor, that might make a treatment combination like that much more effective. So, that’s kind of an exciting area of study as well.
Sara Hurvitz, MD: While the data for the use of CDK4/6 inhibitors in metastatic breast cancer are very promising, patients do progress for the most part and so thus, disease resistance does occur.
Data from our laboratory, as well as other laboratories, have indicated that combined use of the PI3-kinase pathway inhibitor with a CDK4/6 inhibitor and hormonal blockade may actually circumvent a pathway of resistance and be synergistic in its activity. And so, studies are ongoing now to look at the triplet combination of a PI3-kinase inhibitor with a CDK4/6 inhibitor and hormonal blockade. Additionally, there are good data to suggest that CDK4/6 inhibition should work.
Additionally, there are good data that CDK4/6 inhibition should also work in HER2-positive breast cancer. And so, clinical trials evaluating combination strategies with HER2 blockade and a CDK4/6 inhibitor are underway.
In the past several years, we’ve seen the results from multiple clinical trials now that underscore the significant impact CDK4/6 inhibitors are having for patients living with metastatic breast cancer. I think the hope for the future is getting to patients earlier and hopefully curing the disease more commonly with the use of these agents, and hopefully curing more patients with this disease by using these agents in the curative setting.
The continued search for biomarkers to identify. The continued search through clinical trials, including neoadjuvant tissue acquisition studies for biomarkers that will indicate resistance or response to therapy, is going to be critical in paving the way of the future in how we use these agents, who receives, and what combination strategies are going to give us the best outcomes for patients.