Pembrolizumab Combined with Chemotherapy in High-Risk, Early-Stage ER+/HER2− Breast Cancer: A Randomized Phase 3 Trial

Academic Background

Breast cancer is one of the most common cancers among women worldwide, with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) breast cancer accounting for a significant proportion. Although existing adjuvant chemotherapy and endocrine therapy have improved patient outcomes to some extent, the long-term survival rates of patients with high-risk, early-stage ER+/HER2− breast cancer remain unsatisfactory. In recent years, immune checkpoint inhibitors (such as Pembrolizumab) have demonstrated significant efficacy in various cancer types, especially in triple-negative breast cancer (TNBC). However, the efficacy of Pembrolizumab in ER+/HER2− breast cancer remains unclear. Therefore, this study aimed to explore the efficacy and safety of Pembrolizumab combined with neoadjuvant chemotherapy in patients with high-risk, early-stage ER+/HER2− breast cancer.

Source of the Paper

This paper was authored by Fatima Cardoso et al., with contributors from multiple internationally renowned institutions, including the Champalimaud Clinical Center, Baylor University Medical Center, and the Affiliated Cancer Hospital of Zhengzhou University. The paper was published in the February 2025 issue of Nature Medicine, with the DOI: 10.1038/s41591-024-03415-7.

Research Process

1. Study Design

This study was a randomized, double-blind, placebo-controlled phase 3 clinical trial (KEYNOTE-756), enrolling a total of 1,278 patients with high-risk, early-stage ER+/HER2− breast cancer. Patients were randomly assigned in a 1:1 ratio to the Pembrolizumab–chemotherapy arm (635 patients) or the placebo–chemotherapy arm (643 patients).

2. Treatment Process

• Neoadjuvant Phase: Patients received Pembrolizumab (200 mg every 3 weeks) or placebo combined with paclitaxel (weekly) for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide (every 2 weeks or every 3 weeks).
• Surgery: After neoadjuvant treatment, patients underwent surgery (with or without adjuvant radiation therapy).
• Adjuvant Phase: Post-surgery, patients received nine cycles of Pembrolizumab or placebo combined with endocrine therapy.

3. Primary Endpoints

The primary endpoints of the study were pathological complete response rate (pCR) and event-free survival (EFS). pCR was defined as the absence of residual invasive cancer in the breast and lymph nodes at the time of surgery.

Main Results

1. Pathological Complete Response Rate

At the prespecified first interim analysis, the pCR rate in the Pembrolizumab–chemotherapy arm was 24.3% (95% CI, 21.0–27.8%), significantly higher than the 15.6% (95% CI, 12.8–18.6%) in the placebo–chemotherapy arm (estimated treatment difference, 8.5 percentage points; p=0.00005).

2. Subgroup Analysis

A higher pCR rate with Pembrolizumab–chemotherapy was observed in patients with higher PD-L1 expression. Additionally, in patients with estrogen receptor positivity <10%, the pCR rate was also significantly improved with Pembrolizumab–chemotherapy.

3. Safety

During the neoadjuvant phase, treatment-related adverse events (AEs) of grade ≥3 were reported in 52.5% and 46.4% of patients in the Pembrolizumab–chemotherapy and placebo–chemotherapy arms, respectively. The most frequently occurring treatment-related AEs included alopecia, nausea, fatigue, and anemia.

Conclusion

Pembrolizumab combined with neoadjuvant chemotherapy significantly improved the pathological complete response rate in patients with high-risk, early-stage ER+/HER2− breast cancer, with manageable safety. These results provide strong evidence for the use of Pembrolizumab in this patient population and lay the foundation for future clinical practice and further research.

Key Highlights of the Study

1. Key Findings: Pembrolizumab combined with chemotherapy significantly improved the pCR rate in patients with high-risk, early-stage ER+/HER2− breast cancer.
2. Innovation: This is the first large-scale phase 3 clinical trial to evaluate the efficacy of Pembrolizumab in ER+/HER2− breast cancer.
3. Clinical Significance: The findings offer a new treatment option for patients with high-risk, early-stage ER+/HER2− breast cancer, potentially improving their long-term outcomes.

Other Valuable Information

The study also found that Pembrolizumab combined with chemotherapy was more effective in patients with higher PD-L1 expression and estrogen receptor positivity <10%. This suggests that personalized treatment strategies based on patients’ biological characteristics may be necessary in the future.

This study provides new perspectives and strategies for the treatment of high-risk, early-stage ER+/HER2− breast cancer, with significant scientific and clinical application value.