Objective. To evaluate the efficacy and safety of pembrolizumab in combination with neoadjuvant chemotherapy followed by adjuvant pembrolizumab in early-stage triple-negative breast cancer.
Design. International, multicenter, randomized, double-blind, phase 3 trial.
Intervention. Patients were randomly assigned in a 2:1 fashion to receive either pembrolizumab or placebo. Patients received 4 cycles of neoadjuvant pembrolizumab or placebo once every 3 weeks, in addition to weekly paclitaxel 80 mg/m2 plus carboplatin AUC5 once every 3 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 once every 3 weeks. Patients then underwent definitive surgery 3 to 6 weeks after completion of neoadjuvant therapy. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Adjuvant capecitabine was not allowed.
Setting and participants. A total of 1174 patients underwent randomization: 784 patients in the pembrolizumab/chemotherapy group and 390 patients in the placebo/chemotherapy group. Eligible patients had newly diagnosed, centrally confirmed triple-negative breast cancer (nonmetastatic: T1c, N1-2 or T2-4, N0-2). Patients were eligible regardless of PD-L1 status, and those with inflammatory breast cancer and multifocal primaries were eligible.
Main outcome measures. The primary endpoints of this study were pathologic complete response (pCR) rate (defined as ypT0/ypTis, ypN0) at the time of surgery and event-free survival (EFS) in the intention-to-treat population. Secondary endpoints included pCR in all patients, pCR among patients with PD-L1–positive tumors, EFS among patients with PD-L1–positive tumors, and overall survival among all patients and those with PD-L1–positive tumors. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent, Santa Clara, CA). Expression was characterized according to the combined positive score, with a score of 1% or greater being considered positive.
Results. The baseline characteristics were well balanced between the treatment arms. At the time of the second interim analysis, the median duration of follow-up was 15.5 months. The pCR rate among the first 602 patients who were randomized was 64.8% in the pembrolizumab/chemotherapy group and 51.2% in the placebo group (P < 0.001; 95% confidence interval, 5.4-21.8). The pCR rate in the PD-L1–positive population was 68.9% in the pembrolizumab/chemotherapy group, as compared to 54.9% in the placebo group. In the PD-L1–negative population, the pCR rate was 45.3% in the pembrolizumab/chemotherapy group, as compared to 30.3% in the placebo group. At the time of analysis, 104 events had occurred, and the estimated percentage of patients at 18 months who were alive without disease progression was 91% in the pembrolizumab group and 85% in the placebo group. The median was not reached in either group.
Grade 3 or higher adverse events in the neoadjuvant phase were seen in 76.8% and 72.2% of patients in the pembrolizumab and placebo arms, respectively. Serious treatment-related adverse events occurred in 32% of patients in the pembrolizumab group compared to 19% in the placebo group. Febrile neutropenia and anemia were the most common. Discontinuation of the trial drug due to adverse events occurred in 23% of patients in the pembrolizumab arm and in 12% in the placebo arm. The majority of treatment-related adverse events occurred in the neoadjuvant phase. In the adjuvant phase, treatment-related adverse events occurred in 48% and 43% of patients in the pembrolizumab and placebo groups, respectively.