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 (NCT03725059).

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

With results like this, immunotherapy could become another standard of care in this setting. This presents a unique clinical dilemma: the co-administration 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 demonstrates the 8.5% improvement in neoadjuvant therapy with the addition of pembrolizumab, if that translates into an event-free survival[EFS] benefit, and becomes another standard of care. The reason why that is complicated is that we cannot co-administer 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