CDK4/6 Inhibition Refined in HR+ Breast Cancer, as Novel Combos Emerge

Sara A. Hurvitz, MD

The trifecta of CDK4/6 inhibitors in the hormone receptor (HR)-positive breast cancer paradigm has had a significant impact on patient outcomes. The next major advances in the field will likely include combinations with PI3K inhibitors and potentially checkpoint blockade, says, Sara A. Hurvitz, MD.

While similar in efficacy, the 3 anti-CDK4/6 agents—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—do differ in associated toxicities. Moreover, abemaciclib is the sole CDK4/6 inhibitor approved for use as a single agent, and has been shown to induce intratumor T-cell inflammatory signature and have synergy with checkpoint inhibitors.

Novel approaches are currently being explored in clinical trials. For example, the ongoing phase Ib JPCE trial is evaluating the combination of abemaciclib with the PD-1 inhibitor pembrolizumab (Keytruda; NCT02779751).

PI3K inhibitors are also being looked at in combination with CDK4/6 inhibitors. An ongoing phase I trial is exploring the combination of ribociclib, the PI3K-alpha inhibitor BYL719, and letrozole in patients with advanced estrogen receptor—positive breast cancer (NCT01872260).

OncLive: Please discuss your presentation on CDK4/6 inhibitors.

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Hurvitz, director of the Breast Oncology Program, medical director of the Clinical Research Unit, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, shared insight on the 3 CDK4/6 inhibitors approved in HR-positive breast cancer, and looked toward the future of these agents, which will likely include combination strategies.Hurvitz: Dr Slamon and I discussed the CDK4/6 inhibitors story. I spoke about endocrine therapy. Endocrine therapy for breast cancer was actually the first form of targeted therapies; it is targeting the hormone pathway. However, the hormone pathway is implicated by driving breast cancer in two-thirds to three-quarters of breast cancers—so we have a variety of agents that are able to treat this form of breast cancer. However, the problem is that, in the metastatic setting, the vast majority will have progression of their disease or treatment resistance will develop.

In looking at those agents, are there data that support one CDK4/6 inhibitor over another?

Dr Slamon went into the CDK4/6 inhibitor story and how his laboratory showed that HR-positive breast cancer is actually quite sensitive to inhibition of the cell cycle pathway, [leading to] the development of palbociclib, ribociclib, and abemaciclib. All 3 agents—palbociclib, ribociclib, and abemaciclib—have been evaluated in large phase III clinical trials but have never been compared with one another in a large phase III clinical trial. That said, in doing cross-trial comparisons—which we are not supposed to do, but we all do it—the efficacy data appear to be quite similar when comparing the 3 drugs. The improvement in median progression-free survival, when you add one of these drugs to endocrine therapy, is very similar on the order of 10 to 12 months in the first-line setting. The hazard ratios are virtually overlapping between the 3 drugs, so with the data that we have today we can’t say one is more effective than the other.

What does differ among the agents is the toxicity profile. Abemaciclib tends to have less neutropenia; only 20% to 25% of patients will have grade 3/4 neutropenia and, for this reason, patients can be dosed continuously. They don’t need 1 week off to recover their counts, and the dosing is twice a day. On the other hand, it’s associated with gastrointestinal toxicity, with grade 3/4 diarrhea that can occur. Patients need to be educated about this and have Imodium or another antidiarrheal medication on hand.

What are your thoughts on combining CDK4/6 inhibitors with immunotherapy?

What are some ongoing, potentially practice-changing studies in the HR-positive subset?

Ribociclib and palbociclib have similar rates of grade 3/4 neutropenia—on the order of two-thirds of patients have it. Therefore, they’re both dosed [in a] 3-weeks-on/1-week-off schedule. Ribociclib has a requirement that an electrocardiogram should be done in the first 2 cycles to look at the QTc interval. There were a handful of patients in the phase III clinical trial of ribociclib who had QTc prolongation. For this reason, in a patient who is going to be on a medication that can prolong the QTc interval, or in one who has a prolonged QTc interval at baseline, I would likely select palbociclib over ribociclib. All that being weighed and considered, [the agents] appear to have very similar efficacy. The combination of CDK4/6 inhibition with immunotherapy makes sense because there is evidence, at least with abemaciclib, that the immune system may infiltrate the tumor bed after treatment. This is based on tissue acquisition data from the neoMONARCH study that we presented. There are other preclinical data from clinicians looking at the way CDK4/6 inhibitors work and their impact on the immune system. There are going to be studies looking at combination strategies, and that makes a lot of sense. Other areas that are interesting where clinical trials are going to be very helpful for us is combination strategies. [We are] looking at PI3K pathway inhibitors in combination with CDK4/6 inhibitors, because tumors that develop resistance to CDK4/6 inhibition tend to have upregulation or activation of the PI3K pathway.

What else do we know about acquired resistance to therapies in breast cancer?

Also, it’s going to be very important for us to have clinical trial data to guide what the best treatment is for a patient whose disease has progressed on a CDK4/6 inhibitor. Right now, the best treatment is unknown. There are no data to support continuing a CDK4/6 inhibitor in somebody whose disease has progressed on it. A lot of clinicians are doing that without data, and we need studies to show whether or not that kind of strategy is beneficial, since these drugs do have toxicity and cost associated with them. There is a theory that tumor clones can grow up during the development of resistance that are treated by an alternative pathway inhibitor, and allowing another clone to grow up that is sensitive to the drug that was used previously. This has been shown not only with CDK4/6 inhibitors preclinically, but also PARP inhibition. Therefore, a switching strategy is a very rationale type of strategy to interrogate in a clinical trial.

Schaer DA, Beckmann RP, Dempsey JA, et al. The CDK4/6 inhibitor abemaciclib induces a t cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 2018;22(11):2978-2994. doi: 10.1016/j.celrep.2018.02.053