The Evolving Landscape of CDK4/6 Inhibitors in Adjuvant HR+/HER2– Breast Cancer

The landscape for hormone receptor–positive, HER2-negative breast cancer has been profoundly reshaped by the integration of CDK4/6 inhibitors. These agents have rapidly become a cornerstone of treatment in the adjuvant setting, particularly for patients with high-risk disease, including those who have received prior chemotherapy.

Looking to the future in the therapeutic landscape, it will continue to evolve at a rapid pace. A significant potential challenge lies ahead with the anticipated results from trials like the phase 3 KEYNOTE-756 trial (NCT03725059).

CancerNetwork® spoke with Heather McArthur, MD, Komen Distinguished Chair in Clinical Breast Cancer Research at the University of Texas Southwestern Medical Center, at the International Congress on the Future of Breast Cancer® East, hosted by Physicians' Education Resource®, spoke about how findings from this study demonstrated an 8.5% improvement with the addition of pembrolizumab (Keytruda) in neoadjuvant therapy, which translates into a meaningful event-free survival benefit.

With results like this, immunotherapy could become another standard of care in this setting. This presents a unique clinical dilemma: the coadministration of CDK4/6 inhibitors with immune therapy is currently not feasible due to the heightened risk of significant lung and liver toxicity. This potential sequencing challenge represents a critical area that clinicians will need to navigate in the not too distant future.

Transcript:

Adjuvant CDK4/6 inhibitors have become a cornerstone of treatment for high-risk hormone receptor–positive disease, particularly those patients who have received prior chemotherapy. It will be challenging if the ongoing anticipated immunotherapy results from KEYNOTE-756, which demonstrate the 8.5% improvement in neoadjuvant therapy with the addition of pembrolizumab, if those translate into an event-free survival benefit and become another standard of care. The reason why that is complicated is that we cannot coadminister CDK4/6 inhibitors together with immune therapy because of the risk for lung and liver toxicity. That is a potential clinical challenge that we’ll be facing in the not too distant future.

Reference

Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7