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CDK4/6 Inhibitors Revolutionize Hormone-Positive Breast Cancer Care

Chelsea LoCascio
Published: Friday, Oct 27, 2017

Denise Yardley, MD
Denise Yardley, MD
CDK4/6 inhibitors have recently taken the forefront of the landscape when it comes to hormone-positive breast cancer, experts say.

“The CDK4/6 inhibitors have been exciting for the last 3 years, and 2015 welcomed the PALOMA-1 data that really took the clinical science of the CDK4/6 dysregulation in cancers and [worked to inhibit] that with the CDK4/6 inhibitor,” said Denise A. Yardley, MD.

In an interview during the 2017 OncLive® State of the Science SummitTM on Advanced Breast Cancer, Yardley, a senior investigator of breast cancer research at Sarah Cannon Research Institute, discussed the promise of CDK4/6 inhibitors in estrogen receptor (ER)–positive breast cancer, as well as the potential with immunotherapy agents.

OncLive: Your presentation is on ER-positive breast cancer. Can you give an overview of what you talked about?

Yardley: My presentation looked at some of the changes in the management of hormone receptor (HR)–positive, HER2-negative breast cancer. I really embraced all phases of treatment, such as going to early adjuvant breast cancer treatment recommendations, and some of the recommendations with regard to extended adjuvant therapy.

Then, I evolved into the changing standard now for the first-line HR-positive, HER2-negative patients with metastatic breast cancer. That really focused on the changing algorithm to incorporate CDK4/6 inhibitors in the first-line setting, and then we looked at some data of later-line therapy with some of the recent [FDA] approvals of palbociclib (Ibrance) and abemaciclib (Verzenio) in combination with fulvestrant (Faslodex). Then, from that, the next topic that was natural was looking at hormone resistance, so we really covered and focused a little bit more on different spectrums of hormone resistance.

What are the current recommendations for adjuvant endocrine therapy?

The current recommendations for adjuvant endocrine therapy are still evolving. It takes a look at the premenopausal patients and the utilization of tamoxifen in that setting. If we look at the trials that are out there with axillary dissection with access minimized (ADAM) and adjuvant tamoxifen longer against shorter (ATLAS), and then looking at extending the therapy from tamoxifen from 5 to 10 years, the data are quite consistent. We have had the data there resonate very well throughout many of the trials. The problem is, is it a one-size-fits-all approach?

What we are learning is we’re still tailoring it to the patient and their risks, so we are trying to look at modifiers or even incorporate some of the genomic assays that help distinguish that. When we look at the aromatase inhibitors (AI), the story is a little more muddy than challenging. We have some trials that are positive, like the MA17R study, that looked at 10 years of letrozole after a 5-year backbone of tamoxifen. This showed that there was a disease-free survival (DFS) advantage, but, again, it encompassed that patients did well in both groups of that trial, with outcomes of 90% disease-free overall survival.

Now, the NSABP B-42 trial did not echo the same results of the MA17R, but the design and the statistics were a little different; however, even though DFS was not overall statistically significant, [it showed that] breast cancer-free interval distance recurrence was a significant finding.

In some of the other trials looking at the DATA trial and the IDEAL trial, in the subsets of the patients who had tumors that were ER-positive, those subsets who had prior chemotherapy for adjuvant therapy or had high-risk disease were groups who do seem to benefit when we look at subgroup analysis. For the AI, the challenge is to discuss that higher [-risk] patient tolerance. What is their risk of disease recurrence to tailor that and pair that with the recommendation of extended adjuvant AI therapy?

What else are we seeing with CDK4/6 inhibitors?

The initial [approval] was palbociclib; you could affect outcomes and show the doubling of the disease control rate or DFS. In February 2015, that opened the door for accelerated approval of palbociclib in that setting.

The confirmatory trial, PALOMA-2, resonated that the signal was real and reproducible; that went on to lead to an approval this year in March 2017. PALOMA-3 took on a different look—still wanting to test the role of CDK4/6 inhibitors in the patients HR-positive metastatic breast cancer but looked at patients who have been on prior endocrine therapy, failed that, and then went on to receive fulvestrant with the CDK4/6 inhibitor. It showed that, while advantage wasn’t as statistically significant as what we saw in the first-line setting, the signal was clearly there and was statistically significant at 5 months. The margin of benefit was a little bit smaller, but there was a later-line therapy group of patients.




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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Medical Crossfire®: Translating Lessons Learned with PARP Inhibition to the Treatment of Breast Cancer—Expert Exchanges on Novel Strategies to Personalize CareAug 29, 20181.5
Community Practice Connections™: 1st Annual International Congress of Oncology Pathology™: Towards Harmonization of Pathology and Oncology StandardsAug 30, 20182.0
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