Adding Pembrolizumab to Chemotherapy Increased Pathological Complete Response, Improved Residual Cancer Burden in Early-Stage, High-Risk ER+/HER2- Breast Cancer

New data from the KEYNOTE-756 trial (NCT03725059) of pembrolizumab (Keytruda; Merck) found that adding the immune checkpoint inhibitor to chemotherapy significantly increased the pathological complete response (pCR) rate and shifted residual cancer burden (RCB) to lower categories in patients with early-stage, high-risk endocrine receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The data were presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) in Texas.

“Although patients with early-stage ER-positive, HER2-negative breast cancer generally have a better prognosis than those with other breast cancer subtypes, there is a high-risk subpopulation for whom neoadjuvant chemotherapy is indicated,” said presenter Joyce O’Shaughnessy, MD, a medical oncologist at Baylor University Medical Center. “Pembrolizumab combined with neoadjuvant chemotherapy improves pCR rates and event-free survival in patients with early-stage breast cancer.”

Findings from the phase 3 KEYNOTE-756 study demonstrated that among patients with high-risk, high-grade, early-stage ER-positive, HER2-negative breast cancer, the addition of pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pCR in the intent-to-treat (ITT) population, regardless of tumor programmed death-ligand 1 (PD-L1) status.

In the trial, eligible patients were randomly assigned 1:1 to receive neoadjuvant pembrolizumab 200 mg once every 3 weeks or placebo, both given with paclitaxel once every week for 12 weeks, followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After definitive surgery with or without radiation therapy, patients received pembrolizumab or placebo for 9 cycles in addition to standard endocrine therapy.

After definitive surgery with or without radiation therapy, patients received pembrolizumab or placebo for 9 cycles in addition to standard endocrine therapy. Image Credit: © annamaria - stock.adobe.com

Patients were stratified based on region (Eastern Europe, China, or other), tumor PD-L1 status, nodal involvement, ER positivity, and anthracycline schedule. Dual primary endpoints are pCR and event-free survival (EFS). Secondary endpoints include overall survival (OS), safety, and pCR defined as the absence of invasive tumor cells in the breast and axillary lymph nodes (ypT0 ypN0 and ypT0/Tis). RCB was an exploratory endpoint.

During the presentation at SABCS, O’Shaughnessy explained that 1278 patients were randomized in the study. Approximately 2% of patients in both arms discontinued neoadjuvant therapy due to disease progression, 75% started adjuvant pembrolizumab, and 81% started adjuvant placebo. The study arms were generally well balanced regarding key characteristics such as age, PD-L1 activity, and geographic location. Additionally, 37% had stage 3 disease, 90% were clinically node-positive, and 94% of the cancers had an ER of 10% or higher.

At the final pCR analysis, median follow-up was 33.2 months. In the ITT population, pembrolizumab plus chemotherapy showed a statistically significant improvement in pCR vs placebo plus chemotherapy, at 24.3% and 15.6%, respectively. The results were consistent for the secondary pCR definitions ypT0 ypN0 (21.3% vs 12.8%, respectively) and ypT0/Tis (29.4% vs 18.2%, respectively).

Additionally, there were more patients with RCB-0 in the pembrolizumab arm compared to the placebo arm (24.7% and 15.6%, respectively), and with RCB-1 (10.2%. vs 8.1%, respectively). There were fewer patients in the RCB-2 (40.8% vs 45.3%, respectively) and RCB-3 (20.5% vs 28.9%, respectively) categories in the pembrolizumab group vs the placebo group.

Finally, in the neoadjuvant phase, grade 3 or higher treatment-related adverse event rates were 52.5% with pembrolizumab plus chemotherapy vs 46.4% with placebo and chemotherapy. There was 1 death in the pembrolizumab arm due to acute myocardial infarction which was unrelated to pembrolizumab.

O’Shaughnessy emphasized that increasing expression of PD-L1 was prognostic of higher pCR rates in both the placebo and pembrolizumab arms. Additionally, the majority in each treatment arm (>85%) received full chemotherapy exposure, but those who received less than the planned chemotherapy doses had worse pCR rates. pCR rates were improved with the addition of pembrolizumab regardless of whether patients received the full chemotherapy doses.

Reference

O’Shaughnessy J. Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for late-stage high-risk ER+/HER2- breast cancer: KEYNOTE-756. Presented at: San Antonio Breast Cancer Symposium. December 5-9, 2023.