Pembrolizumab and chemotherapy in high-risk, early-stage, ER/HER2 breast cancer: a randomized phase 3 trial.

Addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with high-risk, early-stage, triple-negative breast cancer. However, whether the addition of neoadjuvant pembrolizumab to chemotherapy would improve outcomes in high-risk, early-stage, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER/HER2) breast cancer remains unclear. We conducted a double-blind, placebo-controlled phase 3 study (KEYNOTE-756) in which patients with previously untreated ER/HER2 grade 3 high-risk invasive breast cancer (T1c-2 (≥2 cm), cN1-2 or T3-4, cN0-2) were randomly assigned (1:1) to neoadjuvant pembrolizumab 200 mg or placebo Q3W given with paclitaxel QW for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide Q2W or Q3W. After surgery (with/without adjuvant radiation therapy), patients received adjuvant pembrolizumab or placebo for nine cycles plus adjuvant endocrine therapy. Dual primary endpoints were pathological complete response and event-free survival in the intention-to-treat population. In total, 635 patients were assigned to the pembrolizumab-chemotherapy arm and 643 to the placebo-chemotherapy arm. At the study's prespecified first interim analysis, the pathological complete response rate was 24.3% (95% confidence interval (CI), 21.0-27.8%) in the pembrolizumab-chemotherapy arm and 15.6% (95% CI, 12.8-18.6%) in the placebo-chemotherapy arm (estimated treatment difference, 8.5 percentage points; 95% CI, 4.2-12.8; P = 0.00005). Event-free survival was not mature in this analysis. During the neoadjuvant phase, treatment-related adverse events of grade ≥3 were reported in 52.5% and 46.4% of patients in the pembrolizumab-chemotherapy and placebo-chemotherapy arms, respectively. In summary, the addition of pembrolizumab to neoadjuvant chemotherapy significantly improved the pathological complete response rate in patients with high-risk, early-stage ER/HER2 breast cancer. Safety was consistent with the known profiles of each study treatment. Follow-up continues for event-free survival. ClinicalTrials.gov identifier: NCT03725059 .