Dr McArthur on Neoadjuvant Pembrolizumab Plus Chemotherapy in ER+/HER2– Breast Cancer

Heather Lynn McArthur, MD, MPH, associate professor, the Department of Internal Medicine, member, Hematology and Oncology Division, UT Southwestern Medical Center, clinical director, the Breast Cancer Program, Simmons Cancer Center, and Komen Distinguished Chair in Clinical Breast Cancer Research, discusses the primary results from the phase 3 KEYNOTE-756 study (NCT03725059) of neoadjuvant pembrolizumab (Keytruda) plus chemotherapy in early-stage, high-risk, estrogen receptor (ER)–positive, HER2-negative breast cancer.

In the KEYNOTE-756 study, patients with stage II/III disease and specific high-risk breast cancer characteristics were randomly assigned to receive either neoadjuvant pembrolizumab or placebo plus paclitaxel, followed by pembrolizumab or placebo in combination with additional chemotherapy. After completion of definitive surgery, patients continued treatment with either adjuvant pembrolizumab or placebo plus endocrine therapy. The trial stratified patients according to tumor PD-L1 status, nodal involvement, ER positivity, and anthracycline schedule.

Results from the interim analysis revealed that pembrolizumab plus chemotherapy significantly improved pathologic complete response (pCR) rates compared with placebo plus chemotherapy. Moreover, consistent benefits were generally seen with the pembrolizumab regimen across all patient subsets regardless of ER expression levels or PD-L1 status.

During the neoadjuvant phase, pembrolizumab plus chemotherapy demonstrated a manageable safety profile that was consistent with that of its individual components. Notably, overall survival results were immature at the time of analysis, and further assessment of event-free survival (EFS) is ongoing.

Similar to the review process seen with the phase 3 KEYNOTE-522 study (NCT03036488) in triple-negative breast cancer, the FDA may await more mature EFS data to confirm that the improvement in pCR translates to survival benefit, and ultimately improves cure rates. Investigators expect that the subsequent presentation of EFS data could lead to FDA approval and approvals from other health authorities, potentially changing clinical practice.

This development adds to the expanding list of promising therapeutic strategies in breast cancer, including CDK4/6 inhibitors for high-risk, hormone receptor–positive disease, and PARP inhibitors for high-risk, BRCA-mutated breast cancer. The challenge will be to integrate these new approaches into clinical practice effectively, McArthur concludes.