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

Gina Columbus
Published: Tuesday, May 01, 2018

Sara A. Hurvitz, MD
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).

In an interview during the 2018 OncLive® State of the Science SummitTM 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.

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

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. 

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. 

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

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. 

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